Post on 16-Feb-2019
Lucia Zappi IRCCS Universitagrave San Martino IST
luciazappiistgeit
ldquohelliptutto ersquo una grande fatica Sembra assurdo ma anche solo pettinarmi o vestirmi richiede uno sforzo immane Scendere dal letto o andare al bagno egrave il massimo che possa fare Fare le faccende egrave veramente troppo non sarei neppure capace di sollevare lrsquoaspirapolverehelliprdquo
NCCN Definizione
Cancer related fatigue is a distressing persistent subjective sense of physical emotional andor cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning
La cancer-related fatigue egrave stata riconosciuta come
entitagrave nosologica a seacute stante dalla ICD 10 (X classificazione internazionale delle malattie)
Incidenza
78-96 della popolazione oncologica 50 prima del trattamento Aumenta durante il trattamento e persiste
anche dopo la terapia (17- 30 dei survivors)
Incidenza trattamento correlata
Chemioterapia 60-90 Radioterapia 65-100 Immunoterapia 70-81
Classificazione
GRADO 1 GRADO 2 GRADO 3 GRADO 4
Fatigue ingravescente ma non interferenza con le normali attivitagrave
Moderata incapacitagrave a svolgere alcune attivitagrave
Severa incapacitagrave a svolgere gran parte delle attivitagrave
Allettamento Grave disabilitagrave
NCI CTC 2004
The impact of fatigue results of a survey by the Fatigue Coalition
Physical Impact Financial Impact Social and Emotional Impact
Difficulty in carryng out tasks 56
71 of patients lost one or more days of work
59 reported difficulty in socializing with friends and family
Difficulty in climbing stairs 56
31 lost an entire week of work
37 had difficulty in maintaing relationships
Difficulty in walking long distance 69
28 had to stop work 30 found intercourse with partner difficult
Difficulty in continuing exercise 67
A Iop Ann Oncol 2004
RILEVANZA CLINICA DELLA FATIGUE
Vogelzang NJ et al Semin Hematol 1997 34 (Suppl 2) 4-12
Lrsquoimportanza del trattamento di questo sintomo viene percepita in modo differente dal medico rispetto al paziente
0 20 40 60 80 100
Risposta ()
Oncologi
Pazienti
Fatigue
Dolore
Entrambi allo stesso modo
Although fatigue is usually the most commonly reported adverse symptom during cancer therapy up until recently there was little effort directed at reducing fatigue before during or after cancer therapy
Von Roenn J H amp Paice J A
Control of common non-pain cancer symptoms Seminars in Oncology 32 200ndash210 - 2005
For clinical interventions to be effective patients with fatigue who would benefit from treatment must first be identified Vogelzang et al (1997) interviewed 419 cancer patients 50 did not discuss treatment options for fatigue with their oncologists only 27 reported that their oncologist offered treatment recommendations for their fatigue Curt et al (2000) similarly reported that 40 of patients with fatigue did not receive any treatment recommendations
bull fatigue severity temporal characteristics (eg onset duration) bull exacerbating and alleviating factors bull impact on functioning and quality of life symptom-related distress bull other symptoms pain menopausal symptoms sleep disturbances depression and cognitive dysfunction Since fatigue is a subjective sensation it is important to use validated standardised assessment instruments
Fatigue assessment
CANCER RELATED FATIGUE
Direct effects of cancer and tumour burden
Comorbid medical conditions bull Anemia bull Malnutrition bull Thyroid dysfunction bull Infection
Treatment side effects bull Chemotherapy bull Radiotherapy bull Surgery bull Medication sid effects
Exacerbating comorbid symptoms bull Chronic pain bull Sleep disturbances bull Deconditioning
Psychosocial factors bull Coping with chronic illness bull Anxiety bull Depression
Causes of fatigue (Atkinson et al 2002 Cella et al 1998 Portenoy and Itri 1999)
Meccanismi fisiopatologici
Peripheral fatigue originates in the muscles and related tissues( alterations in
adenosine triphosphate - ATP) Central fatigue develops in the central nervous system
Proposed mechanisms cytokine dysregulation hypothalamic-pituitary-adrenal (HPA) axis dysfunction 5 hydroxy tryptophan (5-HT) neurotransmitter
dysregulation circadian rhythm disruption and vagal afferent activation
Cytokine Dysregulation
Proinflammatory cytokines such as interleukin (IL)-1β IL-6 and tumor necrosis factor (TNF)-α have been evaluated as markers of cancer-related fatigue
Specific cytokines may contribute to fatigue
through more specific pathways IL-1 and IL-6 and TNF-α have been shown to
suppress erythropoiesis TNF has been associated with alterations in
central nervous system neurotransmission interferon-γ can act as chachectins IL-6 have also been associated with depression
Interventions
pharmacological interventions exercise behavioural management use of assistive devices lifestyle management nutritional support complementary or alternative therapy counselling
NCCN Guidelines Activity enhancement
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3 Treatment-Related Fatigue and Exercise in Patients with Cancer A Systematic Review
January 2000 and October 2006 English peer- reviewed nursing and health care journals age 18 or older literature search conducted in October 2006 using the
CINAHLreg Medlinereg Ovidreg and ProQuestreg databases
topics fatigue cancer and exercise Results 10 studies Sample size ranged from 12 to 108 Level of evidence moderate to high
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
focused question ldquoWhat is the relationship
between cancer treatment fatigue and exerciserdquo
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
This systematic review considered the effect of
exercise on fatigue in patients with multiple myeloma breast lung prostate cancers both early and late stages of disease patients receiving chemotherapy or radiation
setting of interventions
home-based exercises (8 ) out-of home exercises (2)
Home-based exercise interventions
walking bicycling or swimming
RESULTS improvement in vigor and reduction in fatigue with a
trend toward improved body esteem Pinto 2005 improved sleep increased lean body weight and less
fatigue with exercise Coleman 2003 progressively increased time in minutes walked per day improved QOL and a significant decrease of fatigue
Courneya 2003 moderated aerobic exercise and resistance training
decreased the overall perception of fatigue Crowley 2003
Out of home exercise interventions Controlled setting with professional instructors with a focus on
muscle strengthening flexibility and endurance Researchers found exercise to be well-tolerated and
feasible in a variety of malignancies No noticeable change in fatigue occurred but reported
bodily pain decreased Losito Murphy amp Thomas 2006 Improved physical and emotional well-being Borst 2005
Participation in a group exercise program was beneficial because patient support increased motivation
Conclusions
Patients with cancer may be challenged to initiate and maintain an exercise program for more than 3 months without unswerving professional support
This support can be made more effective if the
recommended exercise program is regularly adjusted to the patientsrsquo health status and considers shifting hemoglobin levels vital signs respiratory health and subjective feelings that influence the outcomes of exercise
Fatigue and the nutritional approaches
At the organism level cancer-associated fatigue involves the dysregulation of several interrelated physiological
biochemical and psychological systems At the tissue and cellular levels fatigue is
related to reductions in the efficiency of cellular energy systems mainly found in mitochondria
Oxidative stress intracellular excess of reactive oxygen (ROS) and nitrogen (RNS) free radical species over intracellular antioxidants It results in oxidation of cellular structures such as membrane lipids and proteins and
mutation of nuclear DNA Maes M (2009) Inflammatory and oxidative and nitrosative
stress pathways underpinning chronic fatigue somatization and psychosomatic symptoms Current Opinions in Psychiatry 22 75ndash83
ROSRNS damage
Membrane oxidation induces permeability changes in mitochondria and this
loss of electron transport function essential requirement of mitochondrial oxidative phosphorylation (ATP)
I Nutraceutici Acidi grassi polinsaturi essenziali (Omega 3
Omega 6) Acido Antranilico Acido ascorbico (o Vitamina C) Acido Folico (o Folacina o Vitamina M) Acido Lipoico (o Acido Tiottico o Vitamina N) Antocianine (o Antociani) Bioflavonoidi o (Flavonoidi o Vitamina C2) Caffeina L-Carnitina Carotenoidi Coenzima Q-10 (o Ubichinone o Vitamina Q) Colina (o Vitamina J) Creatina D-ribosio Ficocianine Fruttosio Glucosammina Inositolo (o Vitamina B7) Isoflavoni Licopene Lievito di birra Maltodestrine Octacosanolo Picnogenolo Policosanoli Proantocianidine (o PAC) Probiotici Resveratrolo Sali minerali (Calcio Cromo Fluoro Fosforo Iodio Magnesio Potassio Ferro Selenio Sodio Zinco) Steroli vegetali (o Fitosteroli) Taurina Teanina Teina Triptofano Vitamine 5-HTP (5-idrossitriptofano)
Lipid replacement therapy
NTFactorreg a lipid replacement oral
supplement containing phospholipids phosphoglycolipids cardiolipids
and other membrane lipids
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
ldquohelliptutto ersquo una grande fatica Sembra assurdo ma anche solo pettinarmi o vestirmi richiede uno sforzo immane Scendere dal letto o andare al bagno egrave il massimo che possa fare Fare le faccende egrave veramente troppo non sarei neppure capace di sollevare lrsquoaspirapolverehelliprdquo
NCCN Definizione
Cancer related fatigue is a distressing persistent subjective sense of physical emotional andor cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning
La cancer-related fatigue egrave stata riconosciuta come
entitagrave nosologica a seacute stante dalla ICD 10 (X classificazione internazionale delle malattie)
Incidenza
78-96 della popolazione oncologica 50 prima del trattamento Aumenta durante il trattamento e persiste
anche dopo la terapia (17- 30 dei survivors)
Incidenza trattamento correlata
Chemioterapia 60-90 Radioterapia 65-100 Immunoterapia 70-81
Classificazione
GRADO 1 GRADO 2 GRADO 3 GRADO 4
Fatigue ingravescente ma non interferenza con le normali attivitagrave
Moderata incapacitagrave a svolgere alcune attivitagrave
Severa incapacitagrave a svolgere gran parte delle attivitagrave
Allettamento Grave disabilitagrave
NCI CTC 2004
The impact of fatigue results of a survey by the Fatigue Coalition
Physical Impact Financial Impact Social and Emotional Impact
Difficulty in carryng out tasks 56
71 of patients lost one or more days of work
59 reported difficulty in socializing with friends and family
Difficulty in climbing stairs 56
31 lost an entire week of work
37 had difficulty in maintaing relationships
Difficulty in walking long distance 69
28 had to stop work 30 found intercourse with partner difficult
Difficulty in continuing exercise 67
A Iop Ann Oncol 2004
RILEVANZA CLINICA DELLA FATIGUE
Vogelzang NJ et al Semin Hematol 1997 34 (Suppl 2) 4-12
Lrsquoimportanza del trattamento di questo sintomo viene percepita in modo differente dal medico rispetto al paziente
0 20 40 60 80 100
Risposta ()
Oncologi
Pazienti
Fatigue
Dolore
Entrambi allo stesso modo
Although fatigue is usually the most commonly reported adverse symptom during cancer therapy up until recently there was little effort directed at reducing fatigue before during or after cancer therapy
Von Roenn J H amp Paice J A
Control of common non-pain cancer symptoms Seminars in Oncology 32 200ndash210 - 2005
For clinical interventions to be effective patients with fatigue who would benefit from treatment must first be identified Vogelzang et al (1997) interviewed 419 cancer patients 50 did not discuss treatment options for fatigue with their oncologists only 27 reported that their oncologist offered treatment recommendations for their fatigue Curt et al (2000) similarly reported that 40 of patients with fatigue did not receive any treatment recommendations
bull fatigue severity temporal characteristics (eg onset duration) bull exacerbating and alleviating factors bull impact on functioning and quality of life symptom-related distress bull other symptoms pain menopausal symptoms sleep disturbances depression and cognitive dysfunction Since fatigue is a subjective sensation it is important to use validated standardised assessment instruments
Fatigue assessment
CANCER RELATED FATIGUE
Direct effects of cancer and tumour burden
Comorbid medical conditions bull Anemia bull Malnutrition bull Thyroid dysfunction bull Infection
Treatment side effects bull Chemotherapy bull Radiotherapy bull Surgery bull Medication sid effects
Exacerbating comorbid symptoms bull Chronic pain bull Sleep disturbances bull Deconditioning
Psychosocial factors bull Coping with chronic illness bull Anxiety bull Depression
Causes of fatigue (Atkinson et al 2002 Cella et al 1998 Portenoy and Itri 1999)
Meccanismi fisiopatologici
Peripheral fatigue originates in the muscles and related tissues( alterations in
adenosine triphosphate - ATP) Central fatigue develops in the central nervous system
Proposed mechanisms cytokine dysregulation hypothalamic-pituitary-adrenal (HPA) axis dysfunction 5 hydroxy tryptophan (5-HT) neurotransmitter
dysregulation circadian rhythm disruption and vagal afferent activation
Cytokine Dysregulation
Proinflammatory cytokines such as interleukin (IL)-1β IL-6 and tumor necrosis factor (TNF)-α have been evaluated as markers of cancer-related fatigue
Specific cytokines may contribute to fatigue
through more specific pathways IL-1 and IL-6 and TNF-α have been shown to
suppress erythropoiesis TNF has been associated with alterations in
central nervous system neurotransmission interferon-γ can act as chachectins IL-6 have also been associated with depression
Interventions
pharmacological interventions exercise behavioural management use of assistive devices lifestyle management nutritional support complementary or alternative therapy counselling
NCCN Guidelines Activity enhancement
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3 Treatment-Related Fatigue and Exercise in Patients with Cancer A Systematic Review
January 2000 and October 2006 English peer- reviewed nursing and health care journals age 18 or older literature search conducted in October 2006 using the
CINAHLreg Medlinereg Ovidreg and ProQuestreg databases
topics fatigue cancer and exercise Results 10 studies Sample size ranged from 12 to 108 Level of evidence moderate to high
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
focused question ldquoWhat is the relationship
between cancer treatment fatigue and exerciserdquo
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
This systematic review considered the effect of
exercise on fatigue in patients with multiple myeloma breast lung prostate cancers both early and late stages of disease patients receiving chemotherapy or radiation
setting of interventions
home-based exercises (8 ) out-of home exercises (2)
Home-based exercise interventions
walking bicycling or swimming
RESULTS improvement in vigor and reduction in fatigue with a
trend toward improved body esteem Pinto 2005 improved sleep increased lean body weight and less
fatigue with exercise Coleman 2003 progressively increased time in minutes walked per day improved QOL and a significant decrease of fatigue
Courneya 2003 moderated aerobic exercise and resistance training
decreased the overall perception of fatigue Crowley 2003
Out of home exercise interventions Controlled setting with professional instructors with a focus on
muscle strengthening flexibility and endurance Researchers found exercise to be well-tolerated and
feasible in a variety of malignancies No noticeable change in fatigue occurred but reported
bodily pain decreased Losito Murphy amp Thomas 2006 Improved physical and emotional well-being Borst 2005
Participation in a group exercise program was beneficial because patient support increased motivation
Conclusions
Patients with cancer may be challenged to initiate and maintain an exercise program for more than 3 months without unswerving professional support
This support can be made more effective if the
recommended exercise program is regularly adjusted to the patientsrsquo health status and considers shifting hemoglobin levels vital signs respiratory health and subjective feelings that influence the outcomes of exercise
Fatigue and the nutritional approaches
At the organism level cancer-associated fatigue involves the dysregulation of several interrelated physiological
biochemical and psychological systems At the tissue and cellular levels fatigue is
related to reductions in the efficiency of cellular energy systems mainly found in mitochondria
Oxidative stress intracellular excess of reactive oxygen (ROS) and nitrogen (RNS) free radical species over intracellular antioxidants It results in oxidation of cellular structures such as membrane lipids and proteins and
mutation of nuclear DNA Maes M (2009) Inflammatory and oxidative and nitrosative
stress pathways underpinning chronic fatigue somatization and psychosomatic symptoms Current Opinions in Psychiatry 22 75ndash83
ROSRNS damage
Membrane oxidation induces permeability changes in mitochondria and this
loss of electron transport function essential requirement of mitochondrial oxidative phosphorylation (ATP)
I Nutraceutici Acidi grassi polinsaturi essenziali (Omega 3
Omega 6) Acido Antranilico Acido ascorbico (o Vitamina C) Acido Folico (o Folacina o Vitamina M) Acido Lipoico (o Acido Tiottico o Vitamina N) Antocianine (o Antociani) Bioflavonoidi o (Flavonoidi o Vitamina C2) Caffeina L-Carnitina Carotenoidi Coenzima Q-10 (o Ubichinone o Vitamina Q) Colina (o Vitamina J) Creatina D-ribosio Ficocianine Fruttosio Glucosammina Inositolo (o Vitamina B7) Isoflavoni Licopene Lievito di birra Maltodestrine Octacosanolo Picnogenolo Policosanoli Proantocianidine (o PAC) Probiotici Resveratrolo Sali minerali (Calcio Cromo Fluoro Fosforo Iodio Magnesio Potassio Ferro Selenio Sodio Zinco) Steroli vegetali (o Fitosteroli) Taurina Teanina Teina Triptofano Vitamine 5-HTP (5-idrossitriptofano)
Lipid replacement therapy
NTFactorreg a lipid replacement oral
supplement containing phospholipids phosphoglycolipids cardiolipids
and other membrane lipids
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
NCCN Definizione
Cancer related fatigue is a distressing persistent subjective sense of physical emotional andor cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning
La cancer-related fatigue egrave stata riconosciuta come
entitagrave nosologica a seacute stante dalla ICD 10 (X classificazione internazionale delle malattie)
Incidenza
78-96 della popolazione oncologica 50 prima del trattamento Aumenta durante il trattamento e persiste
anche dopo la terapia (17- 30 dei survivors)
Incidenza trattamento correlata
Chemioterapia 60-90 Radioterapia 65-100 Immunoterapia 70-81
Classificazione
GRADO 1 GRADO 2 GRADO 3 GRADO 4
Fatigue ingravescente ma non interferenza con le normali attivitagrave
Moderata incapacitagrave a svolgere alcune attivitagrave
Severa incapacitagrave a svolgere gran parte delle attivitagrave
Allettamento Grave disabilitagrave
NCI CTC 2004
The impact of fatigue results of a survey by the Fatigue Coalition
Physical Impact Financial Impact Social and Emotional Impact
Difficulty in carryng out tasks 56
71 of patients lost one or more days of work
59 reported difficulty in socializing with friends and family
Difficulty in climbing stairs 56
31 lost an entire week of work
37 had difficulty in maintaing relationships
Difficulty in walking long distance 69
28 had to stop work 30 found intercourse with partner difficult
Difficulty in continuing exercise 67
A Iop Ann Oncol 2004
RILEVANZA CLINICA DELLA FATIGUE
Vogelzang NJ et al Semin Hematol 1997 34 (Suppl 2) 4-12
Lrsquoimportanza del trattamento di questo sintomo viene percepita in modo differente dal medico rispetto al paziente
0 20 40 60 80 100
Risposta ()
Oncologi
Pazienti
Fatigue
Dolore
Entrambi allo stesso modo
Although fatigue is usually the most commonly reported adverse symptom during cancer therapy up until recently there was little effort directed at reducing fatigue before during or after cancer therapy
Von Roenn J H amp Paice J A
Control of common non-pain cancer symptoms Seminars in Oncology 32 200ndash210 - 2005
For clinical interventions to be effective patients with fatigue who would benefit from treatment must first be identified Vogelzang et al (1997) interviewed 419 cancer patients 50 did not discuss treatment options for fatigue with their oncologists only 27 reported that their oncologist offered treatment recommendations for their fatigue Curt et al (2000) similarly reported that 40 of patients with fatigue did not receive any treatment recommendations
bull fatigue severity temporal characteristics (eg onset duration) bull exacerbating and alleviating factors bull impact on functioning and quality of life symptom-related distress bull other symptoms pain menopausal symptoms sleep disturbances depression and cognitive dysfunction Since fatigue is a subjective sensation it is important to use validated standardised assessment instruments
Fatigue assessment
CANCER RELATED FATIGUE
Direct effects of cancer and tumour burden
Comorbid medical conditions bull Anemia bull Malnutrition bull Thyroid dysfunction bull Infection
Treatment side effects bull Chemotherapy bull Radiotherapy bull Surgery bull Medication sid effects
Exacerbating comorbid symptoms bull Chronic pain bull Sleep disturbances bull Deconditioning
Psychosocial factors bull Coping with chronic illness bull Anxiety bull Depression
Causes of fatigue (Atkinson et al 2002 Cella et al 1998 Portenoy and Itri 1999)
Meccanismi fisiopatologici
Peripheral fatigue originates in the muscles and related tissues( alterations in
adenosine triphosphate - ATP) Central fatigue develops in the central nervous system
Proposed mechanisms cytokine dysregulation hypothalamic-pituitary-adrenal (HPA) axis dysfunction 5 hydroxy tryptophan (5-HT) neurotransmitter
dysregulation circadian rhythm disruption and vagal afferent activation
Cytokine Dysregulation
Proinflammatory cytokines such as interleukin (IL)-1β IL-6 and tumor necrosis factor (TNF)-α have been evaluated as markers of cancer-related fatigue
Specific cytokines may contribute to fatigue
through more specific pathways IL-1 and IL-6 and TNF-α have been shown to
suppress erythropoiesis TNF has been associated with alterations in
central nervous system neurotransmission interferon-γ can act as chachectins IL-6 have also been associated with depression
Interventions
pharmacological interventions exercise behavioural management use of assistive devices lifestyle management nutritional support complementary or alternative therapy counselling
NCCN Guidelines Activity enhancement
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3 Treatment-Related Fatigue and Exercise in Patients with Cancer A Systematic Review
January 2000 and October 2006 English peer- reviewed nursing and health care journals age 18 or older literature search conducted in October 2006 using the
CINAHLreg Medlinereg Ovidreg and ProQuestreg databases
topics fatigue cancer and exercise Results 10 studies Sample size ranged from 12 to 108 Level of evidence moderate to high
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
focused question ldquoWhat is the relationship
between cancer treatment fatigue and exerciserdquo
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
This systematic review considered the effect of
exercise on fatigue in patients with multiple myeloma breast lung prostate cancers both early and late stages of disease patients receiving chemotherapy or radiation
setting of interventions
home-based exercises (8 ) out-of home exercises (2)
Home-based exercise interventions
walking bicycling or swimming
RESULTS improvement in vigor and reduction in fatigue with a
trend toward improved body esteem Pinto 2005 improved sleep increased lean body weight and less
fatigue with exercise Coleman 2003 progressively increased time in minutes walked per day improved QOL and a significant decrease of fatigue
Courneya 2003 moderated aerobic exercise and resistance training
decreased the overall perception of fatigue Crowley 2003
Out of home exercise interventions Controlled setting with professional instructors with a focus on
muscle strengthening flexibility and endurance Researchers found exercise to be well-tolerated and
feasible in a variety of malignancies No noticeable change in fatigue occurred but reported
bodily pain decreased Losito Murphy amp Thomas 2006 Improved physical and emotional well-being Borst 2005
Participation in a group exercise program was beneficial because patient support increased motivation
Conclusions
Patients with cancer may be challenged to initiate and maintain an exercise program for more than 3 months without unswerving professional support
This support can be made more effective if the
recommended exercise program is regularly adjusted to the patientsrsquo health status and considers shifting hemoglobin levels vital signs respiratory health and subjective feelings that influence the outcomes of exercise
Fatigue and the nutritional approaches
At the organism level cancer-associated fatigue involves the dysregulation of several interrelated physiological
biochemical and psychological systems At the tissue and cellular levels fatigue is
related to reductions in the efficiency of cellular energy systems mainly found in mitochondria
Oxidative stress intracellular excess of reactive oxygen (ROS) and nitrogen (RNS) free radical species over intracellular antioxidants It results in oxidation of cellular structures such as membrane lipids and proteins and
mutation of nuclear DNA Maes M (2009) Inflammatory and oxidative and nitrosative
stress pathways underpinning chronic fatigue somatization and psychosomatic symptoms Current Opinions in Psychiatry 22 75ndash83
ROSRNS damage
Membrane oxidation induces permeability changes in mitochondria and this
loss of electron transport function essential requirement of mitochondrial oxidative phosphorylation (ATP)
I Nutraceutici Acidi grassi polinsaturi essenziali (Omega 3
Omega 6) Acido Antranilico Acido ascorbico (o Vitamina C) Acido Folico (o Folacina o Vitamina M) Acido Lipoico (o Acido Tiottico o Vitamina N) Antocianine (o Antociani) Bioflavonoidi o (Flavonoidi o Vitamina C2) Caffeina L-Carnitina Carotenoidi Coenzima Q-10 (o Ubichinone o Vitamina Q) Colina (o Vitamina J) Creatina D-ribosio Ficocianine Fruttosio Glucosammina Inositolo (o Vitamina B7) Isoflavoni Licopene Lievito di birra Maltodestrine Octacosanolo Picnogenolo Policosanoli Proantocianidine (o PAC) Probiotici Resveratrolo Sali minerali (Calcio Cromo Fluoro Fosforo Iodio Magnesio Potassio Ferro Selenio Sodio Zinco) Steroli vegetali (o Fitosteroli) Taurina Teanina Teina Triptofano Vitamine 5-HTP (5-idrossitriptofano)
Lipid replacement therapy
NTFactorreg a lipid replacement oral
supplement containing phospholipids phosphoglycolipids cardiolipids
and other membrane lipids
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Incidenza
78-96 della popolazione oncologica 50 prima del trattamento Aumenta durante il trattamento e persiste
anche dopo la terapia (17- 30 dei survivors)
Incidenza trattamento correlata
Chemioterapia 60-90 Radioterapia 65-100 Immunoterapia 70-81
Classificazione
GRADO 1 GRADO 2 GRADO 3 GRADO 4
Fatigue ingravescente ma non interferenza con le normali attivitagrave
Moderata incapacitagrave a svolgere alcune attivitagrave
Severa incapacitagrave a svolgere gran parte delle attivitagrave
Allettamento Grave disabilitagrave
NCI CTC 2004
The impact of fatigue results of a survey by the Fatigue Coalition
Physical Impact Financial Impact Social and Emotional Impact
Difficulty in carryng out tasks 56
71 of patients lost one or more days of work
59 reported difficulty in socializing with friends and family
Difficulty in climbing stairs 56
31 lost an entire week of work
37 had difficulty in maintaing relationships
Difficulty in walking long distance 69
28 had to stop work 30 found intercourse with partner difficult
Difficulty in continuing exercise 67
A Iop Ann Oncol 2004
RILEVANZA CLINICA DELLA FATIGUE
Vogelzang NJ et al Semin Hematol 1997 34 (Suppl 2) 4-12
Lrsquoimportanza del trattamento di questo sintomo viene percepita in modo differente dal medico rispetto al paziente
0 20 40 60 80 100
Risposta ()
Oncologi
Pazienti
Fatigue
Dolore
Entrambi allo stesso modo
Although fatigue is usually the most commonly reported adverse symptom during cancer therapy up until recently there was little effort directed at reducing fatigue before during or after cancer therapy
Von Roenn J H amp Paice J A
Control of common non-pain cancer symptoms Seminars in Oncology 32 200ndash210 - 2005
For clinical interventions to be effective patients with fatigue who would benefit from treatment must first be identified Vogelzang et al (1997) interviewed 419 cancer patients 50 did not discuss treatment options for fatigue with their oncologists only 27 reported that their oncologist offered treatment recommendations for their fatigue Curt et al (2000) similarly reported that 40 of patients with fatigue did not receive any treatment recommendations
bull fatigue severity temporal characteristics (eg onset duration) bull exacerbating and alleviating factors bull impact on functioning and quality of life symptom-related distress bull other symptoms pain menopausal symptoms sleep disturbances depression and cognitive dysfunction Since fatigue is a subjective sensation it is important to use validated standardised assessment instruments
Fatigue assessment
CANCER RELATED FATIGUE
Direct effects of cancer and tumour burden
Comorbid medical conditions bull Anemia bull Malnutrition bull Thyroid dysfunction bull Infection
Treatment side effects bull Chemotherapy bull Radiotherapy bull Surgery bull Medication sid effects
Exacerbating comorbid symptoms bull Chronic pain bull Sleep disturbances bull Deconditioning
Psychosocial factors bull Coping with chronic illness bull Anxiety bull Depression
Causes of fatigue (Atkinson et al 2002 Cella et al 1998 Portenoy and Itri 1999)
Meccanismi fisiopatologici
Peripheral fatigue originates in the muscles and related tissues( alterations in
adenosine triphosphate - ATP) Central fatigue develops in the central nervous system
Proposed mechanisms cytokine dysregulation hypothalamic-pituitary-adrenal (HPA) axis dysfunction 5 hydroxy tryptophan (5-HT) neurotransmitter
dysregulation circadian rhythm disruption and vagal afferent activation
Cytokine Dysregulation
Proinflammatory cytokines such as interleukin (IL)-1β IL-6 and tumor necrosis factor (TNF)-α have been evaluated as markers of cancer-related fatigue
Specific cytokines may contribute to fatigue
through more specific pathways IL-1 and IL-6 and TNF-α have been shown to
suppress erythropoiesis TNF has been associated with alterations in
central nervous system neurotransmission interferon-γ can act as chachectins IL-6 have also been associated with depression
Interventions
pharmacological interventions exercise behavioural management use of assistive devices lifestyle management nutritional support complementary or alternative therapy counselling
NCCN Guidelines Activity enhancement
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3 Treatment-Related Fatigue and Exercise in Patients with Cancer A Systematic Review
January 2000 and October 2006 English peer- reviewed nursing and health care journals age 18 or older literature search conducted in October 2006 using the
CINAHLreg Medlinereg Ovidreg and ProQuestreg databases
topics fatigue cancer and exercise Results 10 studies Sample size ranged from 12 to 108 Level of evidence moderate to high
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
focused question ldquoWhat is the relationship
between cancer treatment fatigue and exerciserdquo
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
This systematic review considered the effect of
exercise on fatigue in patients with multiple myeloma breast lung prostate cancers both early and late stages of disease patients receiving chemotherapy or radiation
setting of interventions
home-based exercises (8 ) out-of home exercises (2)
Home-based exercise interventions
walking bicycling or swimming
RESULTS improvement in vigor and reduction in fatigue with a
trend toward improved body esteem Pinto 2005 improved sleep increased lean body weight and less
fatigue with exercise Coleman 2003 progressively increased time in minutes walked per day improved QOL and a significant decrease of fatigue
Courneya 2003 moderated aerobic exercise and resistance training
decreased the overall perception of fatigue Crowley 2003
Out of home exercise interventions Controlled setting with professional instructors with a focus on
muscle strengthening flexibility and endurance Researchers found exercise to be well-tolerated and
feasible in a variety of malignancies No noticeable change in fatigue occurred but reported
bodily pain decreased Losito Murphy amp Thomas 2006 Improved physical and emotional well-being Borst 2005
Participation in a group exercise program was beneficial because patient support increased motivation
Conclusions
Patients with cancer may be challenged to initiate and maintain an exercise program for more than 3 months without unswerving professional support
This support can be made more effective if the
recommended exercise program is regularly adjusted to the patientsrsquo health status and considers shifting hemoglobin levels vital signs respiratory health and subjective feelings that influence the outcomes of exercise
Fatigue and the nutritional approaches
At the organism level cancer-associated fatigue involves the dysregulation of several interrelated physiological
biochemical and psychological systems At the tissue and cellular levels fatigue is
related to reductions in the efficiency of cellular energy systems mainly found in mitochondria
Oxidative stress intracellular excess of reactive oxygen (ROS) and nitrogen (RNS) free radical species over intracellular antioxidants It results in oxidation of cellular structures such as membrane lipids and proteins and
mutation of nuclear DNA Maes M (2009) Inflammatory and oxidative and nitrosative
stress pathways underpinning chronic fatigue somatization and psychosomatic symptoms Current Opinions in Psychiatry 22 75ndash83
ROSRNS damage
Membrane oxidation induces permeability changes in mitochondria and this
loss of electron transport function essential requirement of mitochondrial oxidative phosphorylation (ATP)
I Nutraceutici Acidi grassi polinsaturi essenziali (Omega 3
Omega 6) Acido Antranilico Acido ascorbico (o Vitamina C) Acido Folico (o Folacina o Vitamina M) Acido Lipoico (o Acido Tiottico o Vitamina N) Antocianine (o Antociani) Bioflavonoidi o (Flavonoidi o Vitamina C2) Caffeina L-Carnitina Carotenoidi Coenzima Q-10 (o Ubichinone o Vitamina Q) Colina (o Vitamina J) Creatina D-ribosio Ficocianine Fruttosio Glucosammina Inositolo (o Vitamina B7) Isoflavoni Licopene Lievito di birra Maltodestrine Octacosanolo Picnogenolo Policosanoli Proantocianidine (o PAC) Probiotici Resveratrolo Sali minerali (Calcio Cromo Fluoro Fosforo Iodio Magnesio Potassio Ferro Selenio Sodio Zinco) Steroli vegetali (o Fitosteroli) Taurina Teanina Teina Triptofano Vitamine 5-HTP (5-idrossitriptofano)
Lipid replacement therapy
NTFactorreg a lipid replacement oral
supplement containing phospholipids phosphoglycolipids cardiolipids
and other membrane lipids
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Incidenza trattamento correlata
Chemioterapia 60-90 Radioterapia 65-100 Immunoterapia 70-81
Classificazione
GRADO 1 GRADO 2 GRADO 3 GRADO 4
Fatigue ingravescente ma non interferenza con le normali attivitagrave
Moderata incapacitagrave a svolgere alcune attivitagrave
Severa incapacitagrave a svolgere gran parte delle attivitagrave
Allettamento Grave disabilitagrave
NCI CTC 2004
The impact of fatigue results of a survey by the Fatigue Coalition
Physical Impact Financial Impact Social and Emotional Impact
Difficulty in carryng out tasks 56
71 of patients lost one or more days of work
59 reported difficulty in socializing with friends and family
Difficulty in climbing stairs 56
31 lost an entire week of work
37 had difficulty in maintaing relationships
Difficulty in walking long distance 69
28 had to stop work 30 found intercourse with partner difficult
Difficulty in continuing exercise 67
A Iop Ann Oncol 2004
RILEVANZA CLINICA DELLA FATIGUE
Vogelzang NJ et al Semin Hematol 1997 34 (Suppl 2) 4-12
Lrsquoimportanza del trattamento di questo sintomo viene percepita in modo differente dal medico rispetto al paziente
0 20 40 60 80 100
Risposta ()
Oncologi
Pazienti
Fatigue
Dolore
Entrambi allo stesso modo
Although fatigue is usually the most commonly reported adverse symptom during cancer therapy up until recently there was little effort directed at reducing fatigue before during or after cancer therapy
Von Roenn J H amp Paice J A
Control of common non-pain cancer symptoms Seminars in Oncology 32 200ndash210 - 2005
For clinical interventions to be effective patients with fatigue who would benefit from treatment must first be identified Vogelzang et al (1997) interviewed 419 cancer patients 50 did not discuss treatment options for fatigue with their oncologists only 27 reported that their oncologist offered treatment recommendations for their fatigue Curt et al (2000) similarly reported that 40 of patients with fatigue did not receive any treatment recommendations
bull fatigue severity temporal characteristics (eg onset duration) bull exacerbating and alleviating factors bull impact on functioning and quality of life symptom-related distress bull other symptoms pain menopausal symptoms sleep disturbances depression and cognitive dysfunction Since fatigue is a subjective sensation it is important to use validated standardised assessment instruments
Fatigue assessment
CANCER RELATED FATIGUE
Direct effects of cancer and tumour burden
Comorbid medical conditions bull Anemia bull Malnutrition bull Thyroid dysfunction bull Infection
Treatment side effects bull Chemotherapy bull Radiotherapy bull Surgery bull Medication sid effects
Exacerbating comorbid symptoms bull Chronic pain bull Sleep disturbances bull Deconditioning
Psychosocial factors bull Coping with chronic illness bull Anxiety bull Depression
Causes of fatigue (Atkinson et al 2002 Cella et al 1998 Portenoy and Itri 1999)
Meccanismi fisiopatologici
Peripheral fatigue originates in the muscles and related tissues( alterations in
adenosine triphosphate - ATP) Central fatigue develops in the central nervous system
Proposed mechanisms cytokine dysregulation hypothalamic-pituitary-adrenal (HPA) axis dysfunction 5 hydroxy tryptophan (5-HT) neurotransmitter
dysregulation circadian rhythm disruption and vagal afferent activation
Cytokine Dysregulation
Proinflammatory cytokines such as interleukin (IL)-1β IL-6 and tumor necrosis factor (TNF)-α have been evaluated as markers of cancer-related fatigue
Specific cytokines may contribute to fatigue
through more specific pathways IL-1 and IL-6 and TNF-α have been shown to
suppress erythropoiesis TNF has been associated with alterations in
central nervous system neurotransmission interferon-γ can act as chachectins IL-6 have also been associated with depression
Interventions
pharmacological interventions exercise behavioural management use of assistive devices lifestyle management nutritional support complementary or alternative therapy counselling
NCCN Guidelines Activity enhancement
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3 Treatment-Related Fatigue and Exercise in Patients with Cancer A Systematic Review
January 2000 and October 2006 English peer- reviewed nursing and health care journals age 18 or older literature search conducted in October 2006 using the
CINAHLreg Medlinereg Ovidreg and ProQuestreg databases
topics fatigue cancer and exercise Results 10 studies Sample size ranged from 12 to 108 Level of evidence moderate to high
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
focused question ldquoWhat is the relationship
between cancer treatment fatigue and exerciserdquo
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
This systematic review considered the effect of
exercise on fatigue in patients with multiple myeloma breast lung prostate cancers both early and late stages of disease patients receiving chemotherapy or radiation
setting of interventions
home-based exercises (8 ) out-of home exercises (2)
Home-based exercise interventions
walking bicycling or swimming
RESULTS improvement in vigor and reduction in fatigue with a
trend toward improved body esteem Pinto 2005 improved sleep increased lean body weight and less
fatigue with exercise Coleman 2003 progressively increased time in minutes walked per day improved QOL and a significant decrease of fatigue
Courneya 2003 moderated aerobic exercise and resistance training
decreased the overall perception of fatigue Crowley 2003
Out of home exercise interventions Controlled setting with professional instructors with a focus on
muscle strengthening flexibility and endurance Researchers found exercise to be well-tolerated and
feasible in a variety of malignancies No noticeable change in fatigue occurred but reported
bodily pain decreased Losito Murphy amp Thomas 2006 Improved physical and emotional well-being Borst 2005
Participation in a group exercise program was beneficial because patient support increased motivation
Conclusions
Patients with cancer may be challenged to initiate and maintain an exercise program for more than 3 months without unswerving professional support
This support can be made more effective if the
recommended exercise program is regularly adjusted to the patientsrsquo health status and considers shifting hemoglobin levels vital signs respiratory health and subjective feelings that influence the outcomes of exercise
Fatigue and the nutritional approaches
At the organism level cancer-associated fatigue involves the dysregulation of several interrelated physiological
biochemical and psychological systems At the tissue and cellular levels fatigue is
related to reductions in the efficiency of cellular energy systems mainly found in mitochondria
Oxidative stress intracellular excess of reactive oxygen (ROS) and nitrogen (RNS) free radical species over intracellular antioxidants It results in oxidation of cellular structures such as membrane lipids and proteins and
mutation of nuclear DNA Maes M (2009) Inflammatory and oxidative and nitrosative
stress pathways underpinning chronic fatigue somatization and psychosomatic symptoms Current Opinions in Psychiatry 22 75ndash83
ROSRNS damage
Membrane oxidation induces permeability changes in mitochondria and this
loss of electron transport function essential requirement of mitochondrial oxidative phosphorylation (ATP)
I Nutraceutici Acidi grassi polinsaturi essenziali (Omega 3
Omega 6) Acido Antranilico Acido ascorbico (o Vitamina C) Acido Folico (o Folacina o Vitamina M) Acido Lipoico (o Acido Tiottico o Vitamina N) Antocianine (o Antociani) Bioflavonoidi o (Flavonoidi o Vitamina C2) Caffeina L-Carnitina Carotenoidi Coenzima Q-10 (o Ubichinone o Vitamina Q) Colina (o Vitamina J) Creatina D-ribosio Ficocianine Fruttosio Glucosammina Inositolo (o Vitamina B7) Isoflavoni Licopene Lievito di birra Maltodestrine Octacosanolo Picnogenolo Policosanoli Proantocianidine (o PAC) Probiotici Resveratrolo Sali minerali (Calcio Cromo Fluoro Fosforo Iodio Magnesio Potassio Ferro Selenio Sodio Zinco) Steroli vegetali (o Fitosteroli) Taurina Teanina Teina Triptofano Vitamine 5-HTP (5-idrossitriptofano)
Lipid replacement therapy
NTFactorreg a lipid replacement oral
supplement containing phospholipids phosphoglycolipids cardiolipids
and other membrane lipids
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Classificazione
GRADO 1 GRADO 2 GRADO 3 GRADO 4
Fatigue ingravescente ma non interferenza con le normali attivitagrave
Moderata incapacitagrave a svolgere alcune attivitagrave
Severa incapacitagrave a svolgere gran parte delle attivitagrave
Allettamento Grave disabilitagrave
NCI CTC 2004
The impact of fatigue results of a survey by the Fatigue Coalition
Physical Impact Financial Impact Social and Emotional Impact
Difficulty in carryng out tasks 56
71 of patients lost one or more days of work
59 reported difficulty in socializing with friends and family
Difficulty in climbing stairs 56
31 lost an entire week of work
37 had difficulty in maintaing relationships
Difficulty in walking long distance 69
28 had to stop work 30 found intercourse with partner difficult
Difficulty in continuing exercise 67
A Iop Ann Oncol 2004
RILEVANZA CLINICA DELLA FATIGUE
Vogelzang NJ et al Semin Hematol 1997 34 (Suppl 2) 4-12
Lrsquoimportanza del trattamento di questo sintomo viene percepita in modo differente dal medico rispetto al paziente
0 20 40 60 80 100
Risposta ()
Oncologi
Pazienti
Fatigue
Dolore
Entrambi allo stesso modo
Although fatigue is usually the most commonly reported adverse symptom during cancer therapy up until recently there was little effort directed at reducing fatigue before during or after cancer therapy
Von Roenn J H amp Paice J A
Control of common non-pain cancer symptoms Seminars in Oncology 32 200ndash210 - 2005
For clinical interventions to be effective patients with fatigue who would benefit from treatment must first be identified Vogelzang et al (1997) interviewed 419 cancer patients 50 did not discuss treatment options for fatigue with their oncologists only 27 reported that their oncologist offered treatment recommendations for their fatigue Curt et al (2000) similarly reported that 40 of patients with fatigue did not receive any treatment recommendations
bull fatigue severity temporal characteristics (eg onset duration) bull exacerbating and alleviating factors bull impact on functioning and quality of life symptom-related distress bull other symptoms pain menopausal symptoms sleep disturbances depression and cognitive dysfunction Since fatigue is a subjective sensation it is important to use validated standardised assessment instruments
Fatigue assessment
CANCER RELATED FATIGUE
Direct effects of cancer and tumour burden
Comorbid medical conditions bull Anemia bull Malnutrition bull Thyroid dysfunction bull Infection
Treatment side effects bull Chemotherapy bull Radiotherapy bull Surgery bull Medication sid effects
Exacerbating comorbid symptoms bull Chronic pain bull Sleep disturbances bull Deconditioning
Psychosocial factors bull Coping with chronic illness bull Anxiety bull Depression
Causes of fatigue (Atkinson et al 2002 Cella et al 1998 Portenoy and Itri 1999)
Meccanismi fisiopatologici
Peripheral fatigue originates in the muscles and related tissues( alterations in
adenosine triphosphate - ATP) Central fatigue develops in the central nervous system
Proposed mechanisms cytokine dysregulation hypothalamic-pituitary-adrenal (HPA) axis dysfunction 5 hydroxy tryptophan (5-HT) neurotransmitter
dysregulation circadian rhythm disruption and vagal afferent activation
Cytokine Dysregulation
Proinflammatory cytokines such as interleukin (IL)-1β IL-6 and tumor necrosis factor (TNF)-α have been evaluated as markers of cancer-related fatigue
Specific cytokines may contribute to fatigue
through more specific pathways IL-1 and IL-6 and TNF-α have been shown to
suppress erythropoiesis TNF has been associated with alterations in
central nervous system neurotransmission interferon-γ can act as chachectins IL-6 have also been associated with depression
Interventions
pharmacological interventions exercise behavioural management use of assistive devices lifestyle management nutritional support complementary or alternative therapy counselling
NCCN Guidelines Activity enhancement
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3 Treatment-Related Fatigue and Exercise in Patients with Cancer A Systematic Review
January 2000 and October 2006 English peer- reviewed nursing and health care journals age 18 or older literature search conducted in October 2006 using the
CINAHLreg Medlinereg Ovidreg and ProQuestreg databases
topics fatigue cancer and exercise Results 10 studies Sample size ranged from 12 to 108 Level of evidence moderate to high
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
focused question ldquoWhat is the relationship
between cancer treatment fatigue and exerciserdquo
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
This systematic review considered the effect of
exercise on fatigue in patients with multiple myeloma breast lung prostate cancers both early and late stages of disease patients receiving chemotherapy or radiation
setting of interventions
home-based exercises (8 ) out-of home exercises (2)
Home-based exercise interventions
walking bicycling or swimming
RESULTS improvement in vigor and reduction in fatigue with a
trend toward improved body esteem Pinto 2005 improved sleep increased lean body weight and less
fatigue with exercise Coleman 2003 progressively increased time in minutes walked per day improved QOL and a significant decrease of fatigue
Courneya 2003 moderated aerobic exercise and resistance training
decreased the overall perception of fatigue Crowley 2003
Out of home exercise interventions Controlled setting with professional instructors with a focus on
muscle strengthening flexibility and endurance Researchers found exercise to be well-tolerated and
feasible in a variety of malignancies No noticeable change in fatigue occurred but reported
bodily pain decreased Losito Murphy amp Thomas 2006 Improved physical and emotional well-being Borst 2005
Participation in a group exercise program was beneficial because patient support increased motivation
Conclusions
Patients with cancer may be challenged to initiate and maintain an exercise program for more than 3 months without unswerving professional support
This support can be made more effective if the
recommended exercise program is regularly adjusted to the patientsrsquo health status and considers shifting hemoglobin levels vital signs respiratory health and subjective feelings that influence the outcomes of exercise
Fatigue and the nutritional approaches
At the organism level cancer-associated fatigue involves the dysregulation of several interrelated physiological
biochemical and psychological systems At the tissue and cellular levels fatigue is
related to reductions in the efficiency of cellular energy systems mainly found in mitochondria
Oxidative stress intracellular excess of reactive oxygen (ROS) and nitrogen (RNS) free radical species over intracellular antioxidants It results in oxidation of cellular structures such as membrane lipids and proteins and
mutation of nuclear DNA Maes M (2009) Inflammatory and oxidative and nitrosative
stress pathways underpinning chronic fatigue somatization and psychosomatic symptoms Current Opinions in Psychiatry 22 75ndash83
ROSRNS damage
Membrane oxidation induces permeability changes in mitochondria and this
loss of electron transport function essential requirement of mitochondrial oxidative phosphorylation (ATP)
I Nutraceutici Acidi grassi polinsaturi essenziali (Omega 3
Omega 6) Acido Antranilico Acido ascorbico (o Vitamina C) Acido Folico (o Folacina o Vitamina M) Acido Lipoico (o Acido Tiottico o Vitamina N) Antocianine (o Antociani) Bioflavonoidi o (Flavonoidi o Vitamina C2) Caffeina L-Carnitina Carotenoidi Coenzima Q-10 (o Ubichinone o Vitamina Q) Colina (o Vitamina J) Creatina D-ribosio Ficocianine Fruttosio Glucosammina Inositolo (o Vitamina B7) Isoflavoni Licopene Lievito di birra Maltodestrine Octacosanolo Picnogenolo Policosanoli Proantocianidine (o PAC) Probiotici Resveratrolo Sali minerali (Calcio Cromo Fluoro Fosforo Iodio Magnesio Potassio Ferro Selenio Sodio Zinco) Steroli vegetali (o Fitosteroli) Taurina Teanina Teina Triptofano Vitamine 5-HTP (5-idrossitriptofano)
Lipid replacement therapy
NTFactorreg a lipid replacement oral
supplement containing phospholipids phosphoglycolipids cardiolipids
and other membrane lipids
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
The impact of fatigue results of a survey by the Fatigue Coalition
Physical Impact Financial Impact Social and Emotional Impact
Difficulty in carryng out tasks 56
71 of patients lost one or more days of work
59 reported difficulty in socializing with friends and family
Difficulty in climbing stairs 56
31 lost an entire week of work
37 had difficulty in maintaing relationships
Difficulty in walking long distance 69
28 had to stop work 30 found intercourse with partner difficult
Difficulty in continuing exercise 67
A Iop Ann Oncol 2004
RILEVANZA CLINICA DELLA FATIGUE
Vogelzang NJ et al Semin Hematol 1997 34 (Suppl 2) 4-12
Lrsquoimportanza del trattamento di questo sintomo viene percepita in modo differente dal medico rispetto al paziente
0 20 40 60 80 100
Risposta ()
Oncologi
Pazienti
Fatigue
Dolore
Entrambi allo stesso modo
Although fatigue is usually the most commonly reported adverse symptom during cancer therapy up until recently there was little effort directed at reducing fatigue before during or after cancer therapy
Von Roenn J H amp Paice J A
Control of common non-pain cancer symptoms Seminars in Oncology 32 200ndash210 - 2005
For clinical interventions to be effective patients with fatigue who would benefit from treatment must first be identified Vogelzang et al (1997) interviewed 419 cancer patients 50 did not discuss treatment options for fatigue with their oncologists only 27 reported that their oncologist offered treatment recommendations for their fatigue Curt et al (2000) similarly reported that 40 of patients with fatigue did not receive any treatment recommendations
bull fatigue severity temporal characteristics (eg onset duration) bull exacerbating and alleviating factors bull impact on functioning and quality of life symptom-related distress bull other symptoms pain menopausal symptoms sleep disturbances depression and cognitive dysfunction Since fatigue is a subjective sensation it is important to use validated standardised assessment instruments
Fatigue assessment
CANCER RELATED FATIGUE
Direct effects of cancer and tumour burden
Comorbid medical conditions bull Anemia bull Malnutrition bull Thyroid dysfunction bull Infection
Treatment side effects bull Chemotherapy bull Radiotherapy bull Surgery bull Medication sid effects
Exacerbating comorbid symptoms bull Chronic pain bull Sleep disturbances bull Deconditioning
Psychosocial factors bull Coping with chronic illness bull Anxiety bull Depression
Causes of fatigue (Atkinson et al 2002 Cella et al 1998 Portenoy and Itri 1999)
Meccanismi fisiopatologici
Peripheral fatigue originates in the muscles and related tissues( alterations in
adenosine triphosphate - ATP) Central fatigue develops in the central nervous system
Proposed mechanisms cytokine dysregulation hypothalamic-pituitary-adrenal (HPA) axis dysfunction 5 hydroxy tryptophan (5-HT) neurotransmitter
dysregulation circadian rhythm disruption and vagal afferent activation
Cytokine Dysregulation
Proinflammatory cytokines such as interleukin (IL)-1β IL-6 and tumor necrosis factor (TNF)-α have been evaluated as markers of cancer-related fatigue
Specific cytokines may contribute to fatigue
through more specific pathways IL-1 and IL-6 and TNF-α have been shown to
suppress erythropoiesis TNF has been associated with alterations in
central nervous system neurotransmission interferon-γ can act as chachectins IL-6 have also been associated with depression
Interventions
pharmacological interventions exercise behavioural management use of assistive devices lifestyle management nutritional support complementary or alternative therapy counselling
NCCN Guidelines Activity enhancement
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3 Treatment-Related Fatigue and Exercise in Patients with Cancer A Systematic Review
January 2000 and October 2006 English peer- reviewed nursing and health care journals age 18 or older literature search conducted in October 2006 using the
CINAHLreg Medlinereg Ovidreg and ProQuestreg databases
topics fatigue cancer and exercise Results 10 studies Sample size ranged from 12 to 108 Level of evidence moderate to high
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
focused question ldquoWhat is the relationship
between cancer treatment fatigue and exerciserdquo
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
This systematic review considered the effect of
exercise on fatigue in patients with multiple myeloma breast lung prostate cancers both early and late stages of disease patients receiving chemotherapy or radiation
setting of interventions
home-based exercises (8 ) out-of home exercises (2)
Home-based exercise interventions
walking bicycling or swimming
RESULTS improvement in vigor and reduction in fatigue with a
trend toward improved body esteem Pinto 2005 improved sleep increased lean body weight and less
fatigue with exercise Coleman 2003 progressively increased time in minutes walked per day improved QOL and a significant decrease of fatigue
Courneya 2003 moderated aerobic exercise and resistance training
decreased the overall perception of fatigue Crowley 2003
Out of home exercise interventions Controlled setting with professional instructors with a focus on
muscle strengthening flexibility and endurance Researchers found exercise to be well-tolerated and
feasible in a variety of malignancies No noticeable change in fatigue occurred but reported
bodily pain decreased Losito Murphy amp Thomas 2006 Improved physical and emotional well-being Borst 2005
Participation in a group exercise program was beneficial because patient support increased motivation
Conclusions
Patients with cancer may be challenged to initiate and maintain an exercise program for more than 3 months without unswerving professional support
This support can be made more effective if the
recommended exercise program is regularly adjusted to the patientsrsquo health status and considers shifting hemoglobin levels vital signs respiratory health and subjective feelings that influence the outcomes of exercise
Fatigue and the nutritional approaches
At the organism level cancer-associated fatigue involves the dysregulation of several interrelated physiological
biochemical and psychological systems At the tissue and cellular levels fatigue is
related to reductions in the efficiency of cellular energy systems mainly found in mitochondria
Oxidative stress intracellular excess of reactive oxygen (ROS) and nitrogen (RNS) free radical species over intracellular antioxidants It results in oxidation of cellular structures such as membrane lipids and proteins and
mutation of nuclear DNA Maes M (2009) Inflammatory and oxidative and nitrosative
stress pathways underpinning chronic fatigue somatization and psychosomatic symptoms Current Opinions in Psychiatry 22 75ndash83
ROSRNS damage
Membrane oxidation induces permeability changes in mitochondria and this
loss of electron transport function essential requirement of mitochondrial oxidative phosphorylation (ATP)
I Nutraceutici Acidi grassi polinsaturi essenziali (Omega 3
Omega 6) Acido Antranilico Acido ascorbico (o Vitamina C) Acido Folico (o Folacina o Vitamina M) Acido Lipoico (o Acido Tiottico o Vitamina N) Antocianine (o Antociani) Bioflavonoidi o (Flavonoidi o Vitamina C2) Caffeina L-Carnitina Carotenoidi Coenzima Q-10 (o Ubichinone o Vitamina Q) Colina (o Vitamina J) Creatina D-ribosio Ficocianine Fruttosio Glucosammina Inositolo (o Vitamina B7) Isoflavoni Licopene Lievito di birra Maltodestrine Octacosanolo Picnogenolo Policosanoli Proantocianidine (o PAC) Probiotici Resveratrolo Sali minerali (Calcio Cromo Fluoro Fosforo Iodio Magnesio Potassio Ferro Selenio Sodio Zinco) Steroli vegetali (o Fitosteroli) Taurina Teanina Teina Triptofano Vitamine 5-HTP (5-idrossitriptofano)
Lipid replacement therapy
NTFactorreg a lipid replacement oral
supplement containing phospholipids phosphoglycolipids cardiolipids
and other membrane lipids
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
RILEVANZA CLINICA DELLA FATIGUE
Vogelzang NJ et al Semin Hematol 1997 34 (Suppl 2) 4-12
Lrsquoimportanza del trattamento di questo sintomo viene percepita in modo differente dal medico rispetto al paziente
0 20 40 60 80 100
Risposta ()
Oncologi
Pazienti
Fatigue
Dolore
Entrambi allo stesso modo
Although fatigue is usually the most commonly reported adverse symptom during cancer therapy up until recently there was little effort directed at reducing fatigue before during or after cancer therapy
Von Roenn J H amp Paice J A
Control of common non-pain cancer symptoms Seminars in Oncology 32 200ndash210 - 2005
For clinical interventions to be effective patients with fatigue who would benefit from treatment must first be identified Vogelzang et al (1997) interviewed 419 cancer patients 50 did not discuss treatment options for fatigue with their oncologists only 27 reported that their oncologist offered treatment recommendations for their fatigue Curt et al (2000) similarly reported that 40 of patients with fatigue did not receive any treatment recommendations
bull fatigue severity temporal characteristics (eg onset duration) bull exacerbating and alleviating factors bull impact on functioning and quality of life symptom-related distress bull other symptoms pain menopausal symptoms sleep disturbances depression and cognitive dysfunction Since fatigue is a subjective sensation it is important to use validated standardised assessment instruments
Fatigue assessment
CANCER RELATED FATIGUE
Direct effects of cancer and tumour burden
Comorbid medical conditions bull Anemia bull Malnutrition bull Thyroid dysfunction bull Infection
Treatment side effects bull Chemotherapy bull Radiotherapy bull Surgery bull Medication sid effects
Exacerbating comorbid symptoms bull Chronic pain bull Sleep disturbances bull Deconditioning
Psychosocial factors bull Coping with chronic illness bull Anxiety bull Depression
Causes of fatigue (Atkinson et al 2002 Cella et al 1998 Portenoy and Itri 1999)
Meccanismi fisiopatologici
Peripheral fatigue originates in the muscles and related tissues( alterations in
adenosine triphosphate - ATP) Central fatigue develops in the central nervous system
Proposed mechanisms cytokine dysregulation hypothalamic-pituitary-adrenal (HPA) axis dysfunction 5 hydroxy tryptophan (5-HT) neurotransmitter
dysregulation circadian rhythm disruption and vagal afferent activation
Cytokine Dysregulation
Proinflammatory cytokines such as interleukin (IL)-1β IL-6 and tumor necrosis factor (TNF)-α have been evaluated as markers of cancer-related fatigue
Specific cytokines may contribute to fatigue
through more specific pathways IL-1 and IL-6 and TNF-α have been shown to
suppress erythropoiesis TNF has been associated with alterations in
central nervous system neurotransmission interferon-γ can act as chachectins IL-6 have also been associated with depression
Interventions
pharmacological interventions exercise behavioural management use of assistive devices lifestyle management nutritional support complementary or alternative therapy counselling
NCCN Guidelines Activity enhancement
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3 Treatment-Related Fatigue and Exercise in Patients with Cancer A Systematic Review
January 2000 and October 2006 English peer- reviewed nursing and health care journals age 18 or older literature search conducted in October 2006 using the
CINAHLreg Medlinereg Ovidreg and ProQuestreg databases
topics fatigue cancer and exercise Results 10 studies Sample size ranged from 12 to 108 Level of evidence moderate to high
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
focused question ldquoWhat is the relationship
between cancer treatment fatigue and exerciserdquo
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
This systematic review considered the effect of
exercise on fatigue in patients with multiple myeloma breast lung prostate cancers both early and late stages of disease patients receiving chemotherapy or radiation
setting of interventions
home-based exercises (8 ) out-of home exercises (2)
Home-based exercise interventions
walking bicycling or swimming
RESULTS improvement in vigor and reduction in fatigue with a
trend toward improved body esteem Pinto 2005 improved sleep increased lean body weight and less
fatigue with exercise Coleman 2003 progressively increased time in minutes walked per day improved QOL and a significant decrease of fatigue
Courneya 2003 moderated aerobic exercise and resistance training
decreased the overall perception of fatigue Crowley 2003
Out of home exercise interventions Controlled setting with professional instructors with a focus on
muscle strengthening flexibility and endurance Researchers found exercise to be well-tolerated and
feasible in a variety of malignancies No noticeable change in fatigue occurred but reported
bodily pain decreased Losito Murphy amp Thomas 2006 Improved physical and emotional well-being Borst 2005
Participation in a group exercise program was beneficial because patient support increased motivation
Conclusions
Patients with cancer may be challenged to initiate and maintain an exercise program for more than 3 months without unswerving professional support
This support can be made more effective if the
recommended exercise program is regularly adjusted to the patientsrsquo health status and considers shifting hemoglobin levels vital signs respiratory health and subjective feelings that influence the outcomes of exercise
Fatigue and the nutritional approaches
At the organism level cancer-associated fatigue involves the dysregulation of several interrelated physiological
biochemical and psychological systems At the tissue and cellular levels fatigue is
related to reductions in the efficiency of cellular energy systems mainly found in mitochondria
Oxidative stress intracellular excess of reactive oxygen (ROS) and nitrogen (RNS) free radical species over intracellular antioxidants It results in oxidation of cellular structures such as membrane lipids and proteins and
mutation of nuclear DNA Maes M (2009) Inflammatory and oxidative and nitrosative
stress pathways underpinning chronic fatigue somatization and psychosomatic symptoms Current Opinions in Psychiatry 22 75ndash83
ROSRNS damage
Membrane oxidation induces permeability changes in mitochondria and this
loss of electron transport function essential requirement of mitochondrial oxidative phosphorylation (ATP)
I Nutraceutici Acidi grassi polinsaturi essenziali (Omega 3
Omega 6) Acido Antranilico Acido ascorbico (o Vitamina C) Acido Folico (o Folacina o Vitamina M) Acido Lipoico (o Acido Tiottico o Vitamina N) Antocianine (o Antociani) Bioflavonoidi o (Flavonoidi o Vitamina C2) Caffeina L-Carnitina Carotenoidi Coenzima Q-10 (o Ubichinone o Vitamina Q) Colina (o Vitamina J) Creatina D-ribosio Ficocianine Fruttosio Glucosammina Inositolo (o Vitamina B7) Isoflavoni Licopene Lievito di birra Maltodestrine Octacosanolo Picnogenolo Policosanoli Proantocianidine (o PAC) Probiotici Resveratrolo Sali minerali (Calcio Cromo Fluoro Fosforo Iodio Magnesio Potassio Ferro Selenio Sodio Zinco) Steroli vegetali (o Fitosteroli) Taurina Teanina Teina Triptofano Vitamine 5-HTP (5-idrossitriptofano)
Lipid replacement therapy
NTFactorreg a lipid replacement oral
supplement containing phospholipids phosphoglycolipids cardiolipids
and other membrane lipids
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Although fatigue is usually the most commonly reported adverse symptom during cancer therapy up until recently there was little effort directed at reducing fatigue before during or after cancer therapy
Von Roenn J H amp Paice J A
Control of common non-pain cancer symptoms Seminars in Oncology 32 200ndash210 - 2005
For clinical interventions to be effective patients with fatigue who would benefit from treatment must first be identified Vogelzang et al (1997) interviewed 419 cancer patients 50 did not discuss treatment options for fatigue with their oncologists only 27 reported that their oncologist offered treatment recommendations for their fatigue Curt et al (2000) similarly reported that 40 of patients with fatigue did not receive any treatment recommendations
bull fatigue severity temporal characteristics (eg onset duration) bull exacerbating and alleviating factors bull impact on functioning and quality of life symptom-related distress bull other symptoms pain menopausal symptoms sleep disturbances depression and cognitive dysfunction Since fatigue is a subjective sensation it is important to use validated standardised assessment instruments
Fatigue assessment
CANCER RELATED FATIGUE
Direct effects of cancer and tumour burden
Comorbid medical conditions bull Anemia bull Malnutrition bull Thyroid dysfunction bull Infection
Treatment side effects bull Chemotherapy bull Radiotherapy bull Surgery bull Medication sid effects
Exacerbating comorbid symptoms bull Chronic pain bull Sleep disturbances bull Deconditioning
Psychosocial factors bull Coping with chronic illness bull Anxiety bull Depression
Causes of fatigue (Atkinson et al 2002 Cella et al 1998 Portenoy and Itri 1999)
Meccanismi fisiopatologici
Peripheral fatigue originates in the muscles and related tissues( alterations in
adenosine triphosphate - ATP) Central fatigue develops in the central nervous system
Proposed mechanisms cytokine dysregulation hypothalamic-pituitary-adrenal (HPA) axis dysfunction 5 hydroxy tryptophan (5-HT) neurotransmitter
dysregulation circadian rhythm disruption and vagal afferent activation
Cytokine Dysregulation
Proinflammatory cytokines such as interleukin (IL)-1β IL-6 and tumor necrosis factor (TNF)-α have been evaluated as markers of cancer-related fatigue
Specific cytokines may contribute to fatigue
through more specific pathways IL-1 and IL-6 and TNF-α have been shown to
suppress erythropoiesis TNF has been associated with alterations in
central nervous system neurotransmission interferon-γ can act as chachectins IL-6 have also been associated with depression
Interventions
pharmacological interventions exercise behavioural management use of assistive devices lifestyle management nutritional support complementary or alternative therapy counselling
NCCN Guidelines Activity enhancement
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3 Treatment-Related Fatigue and Exercise in Patients with Cancer A Systematic Review
January 2000 and October 2006 English peer- reviewed nursing and health care journals age 18 or older literature search conducted in October 2006 using the
CINAHLreg Medlinereg Ovidreg and ProQuestreg databases
topics fatigue cancer and exercise Results 10 studies Sample size ranged from 12 to 108 Level of evidence moderate to high
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
focused question ldquoWhat is the relationship
between cancer treatment fatigue and exerciserdquo
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
This systematic review considered the effect of
exercise on fatigue in patients with multiple myeloma breast lung prostate cancers both early and late stages of disease patients receiving chemotherapy or radiation
setting of interventions
home-based exercises (8 ) out-of home exercises (2)
Home-based exercise interventions
walking bicycling or swimming
RESULTS improvement in vigor and reduction in fatigue with a
trend toward improved body esteem Pinto 2005 improved sleep increased lean body weight and less
fatigue with exercise Coleman 2003 progressively increased time in minutes walked per day improved QOL and a significant decrease of fatigue
Courneya 2003 moderated aerobic exercise and resistance training
decreased the overall perception of fatigue Crowley 2003
Out of home exercise interventions Controlled setting with professional instructors with a focus on
muscle strengthening flexibility and endurance Researchers found exercise to be well-tolerated and
feasible in a variety of malignancies No noticeable change in fatigue occurred but reported
bodily pain decreased Losito Murphy amp Thomas 2006 Improved physical and emotional well-being Borst 2005
Participation in a group exercise program was beneficial because patient support increased motivation
Conclusions
Patients with cancer may be challenged to initiate and maintain an exercise program for more than 3 months without unswerving professional support
This support can be made more effective if the
recommended exercise program is regularly adjusted to the patientsrsquo health status and considers shifting hemoglobin levels vital signs respiratory health and subjective feelings that influence the outcomes of exercise
Fatigue and the nutritional approaches
At the organism level cancer-associated fatigue involves the dysregulation of several interrelated physiological
biochemical and psychological systems At the tissue and cellular levels fatigue is
related to reductions in the efficiency of cellular energy systems mainly found in mitochondria
Oxidative stress intracellular excess of reactive oxygen (ROS) and nitrogen (RNS) free radical species over intracellular antioxidants It results in oxidation of cellular structures such as membrane lipids and proteins and
mutation of nuclear DNA Maes M (2009) Inflammatory and oxidative and nitrosative
stress pathways underpinning chronic fatigue somatization and psychosomatic symptoms Current Opinions in Psychiatry 22 75ndash83
ROSRNS damage
Membrane oxidation induces permeability changes in mitochondria and this
loss of electron transport function essential requirement of mitochondrial oxidative phosphorylation (ATP)
I Nutraceutici Acidi grassi polinsaturi essenziali (Omega 3
Omega 6) Acido Antranilico Acido ascorbico (o Vitamina C) Acido Folico (o Folacina o Vitamina M) Acido Lipoico (o Acido Tiottico o Vitamina N) Antocianine (o Antociani) Bioflavonoidi o (Flavonoidi o Vitamina C2) Caffeina L-Carnitina Carotenoidi Coenzima Q-10 (o Ubichinone o Vitamina Q) Colina (o Vitamina J) Creatina D-ribosio Ficocianine Fruttosio Glucosammina Inositolo (o Vitamina B7) Isoflavoni Licopene Lievito di birra Maltodestrine Octacosanolo Picnogenolo Policosanoli Proantocianidine (o PAC) Probiotici Resveratrolo Sali minerali (Calcio Cromo Fluoro Fosforo Iodio Magnesio Potassio Ferro Selenio Sodio Zinco) Steroli vegetali (o Fitosteroli) Taurina Teanina Teina Triptofano Vitamine 5-HTP (5-idrossitriptofano)
Lipid replacement therapy
NTFactorreg a lipid replacement oral
supplement containing phospholipids phosphoglycolipids cardiolipids
and other membrane lipids
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
For clinical interventions to be effective patients with fatigue who would benefit from treatment must first be identified Vogelzang et al (1997) interviewed 419 cancer patients 50 did not discuss treatment options for fatigue with their oncologists only 27 reported that their oncologist offered treatment recommendations for their fatigue Curt et al (2000) similarly reported that 40 of patients with fatigue did not receive any treatment recommendations
bull fatigue severity temporal characteristics (eg onset duration) bull exacerbating and alleviating factors bull impact on functioning and quality of life symptom-related distress bull other symptoms pain menopausal symptoms sleep disturbances depression and cognitive dysfunction Since fatigue is a subjective sensation it is important to use validated standardised assessment instruments
Fatigue assessment
CANCER RELATED FATIGUE
Direct effects of cancer and tumour burden
Comorbid medical conditions bull Anemia bull Malnutrition bull Thyroid dysfunction bull Infection
Treatment side effects bull Chemotherapy bull Radiotherapy bull Surgery bull Medication sid effects
Exacerbating comorbid symptoms bull Chronic pain bull Sleep disturbances bull Deconditioning
Psychosocial factors bull Coping with chronic illness bull Anxiety bull Depression
Causes of fatigue (Atkinson et al 2002 Cella et al 1998 Portenoy and Itri 1999)
Meccanismi fisiopatologici
Peripheral fatigue originates in the muscles and related tissues( alterations in
adenosine triphosphate - ATP) Central fatigue develops in the central nervous system
Proposed mechanisms cytokine dysregulation hypothalamic-pituitary-adrenal (HPA) axis dysfunction 5 hydroxy tryptophan (5-HT) neurotransmitter
dysregulation circadian rhythm disruption and vagal afferent activation
Cytokine Dysregulation
Proinflammatory cytokines such as interleukin (IL)-1β IL-6 and tumor necrosis factor (TNF)-α have been evaluated as markers of cancer-related fatigue
Specific cytokines may contribute to fatigue
through more specific pathways IL-1 and IL-6 and TNF-α have been shown to
suppress erythropoiesis TNF has been associated with alterations in
central nervous system neurotransmission interferon-γ can act as chachectins IL-6 have also been associated with depression
Interventions
pharmacological interventions exercise behavioural management use of assistive devices lifestyle management nutritional support complementary or alternative therapy counselling
NCCN Guidelines Activity enhancement
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3 Treatment-Related Fatigue and Exercise in Patients with Cancer A Systematic Review
January 2000 and October 2006 English peer- reviewed nursing and health care journals age 18 or older literature search conducted in October 2006 using the
CINAHLreg Medlinereg Ovidreg and ProQuestreg databases
topics fatigue cancer and exercise Results 10 studies Sample size ranged from 12 to 108 Level of evidence moderate to high
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
focused question ldquoWhat is the relationship
between cancer treatment fatigue and exerciserdquo
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
This systematic review considered the effect of
exercise on fatigue in patients with multiple myeloma breast lung prostate cancers both early and late stages of disease patients receiving chemotherapy or radiation
setting of interventions
home-based exercises (8 ) out-of home exercises (2)
Home-based exercise interventions
walking bicycling or swimming
RESULTS improvement in vigor and reduction in fatigue with a
trend toward improved body esteem Pinto 2005 improved sleep increased lean body weight and less
fatigue with exercise Coleman 2003 progressively increased time in minutes walked per day improved QOL and a significant decrease of fatigue
Courneya 2003 moderated aerobic exercise and resistance training
decreased the overall perception of fatigue Crowley 2003
Out of home exercise interventions Controlled setting with professional instructors with a focus on
muscle strengthening flexibility and endurance Researchers found exercise to be well-tolerated and
feasible in a variety of malignancies No noticeable change in fatigue occurred but reported
bodily pain decreased Losito Murphy amp Thomas 2006 Improved physical and emotional well-being Borst 2005
Participation in a group exercise program was beneficial because patient support increased motivation
Conclusions
Patients with cancer may be challenged to initiate and maintain an exercise program for more than 3 months without unswerving professional support
This support can be made more effective if the
recommended exercise program is regularly adjusted to the patientsrsquo health status and considers shifting hemoglobin levels vital signs respiratory health and subjective feelings that influence the outcomes of exercise
Fatigue and the nutritional approaches
At the organism level cancer-associated fatigue involves the dysregulation of several interrelated physiological
biochemical and psychological systems At the tissue and cellular levels fatigue is
related to reductions in the efficiency of cellular energy systems mainly found in mitochondria
Oxidative stress intracellular excess of reactive oxygen (ROS) and nitrogen (RNS) free radical species over intracellular antioxidants It results in oxidation of cellular structures such as membrane lipids and proteins and
mutation of nuclear DNA Maes M (2009) Inflammatory and oxidative and nitrosative
stress pathways underpinning chronic fatigue somatization and psychosomatic symptoms Current Opinions in Psychiatry 22 75ndash83
ROSRNS damage
Membrane oxidation induces permeability changes in mitochondria and this
loss of electron transport function essential requirement of mitochondrial oxidative phosphorylation (ATP)
I Nutraceutici Acidi grassi polinsaturi essenziali (Omega 3
Omega 6) Acido Antranilico Acido ascorbico (o Vitamina C) Acido Folico (o Folacina o Vitamina M) Acido Lipoico (o Acido Tiottico o Vitamina N) Antocianine (o Antociani) Bioflavonoidi o (Flavonoidi o Vitamina C2) Caffeina L-Carnitina Carotenoidi Coenzima Q-10 (o Ubichinone o Vitamina Q) Colina (o Vitamina J) Creatina D-ribosio Ficocianine Fruttosio Glucosammina Inositolo (o Vitamina B7) Isoflavoni Licopene Lievito di birra Maltodestrine Octacosanolo Picnogenolo Policosanoli Proantocianidine (o PAC) Probiotici Resveratrolo Sali minerali (Calcio Cromo Fluoro Fosforo Iodio Magnesio Potassio Ferro Selenio Sodio Zinco) Steroli vegetali (o Fitosteroli) Taurina Teanina Teina Triptofano Vitamine 5-HTP (5-idrossitriptofano)
Lipid replacement therapy
NTFactorreg a lipid replacement oral
supplement containing phospholipids phosphoglycolipids cardiolipids
and other membrane lipids
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
bull fatigue severity temporal characteristics (eg onset duration) bull exacerbating and alleviating factors bull impact on functioning and quality of life symptom-related distress bull other symptoms pain menopausal symptoms sleep disturbances depression and cognitive dysfunction Since fatigue is a subjective sensation it is important to use validated standardised assessment instruments
Fatigue assessment
CANCER RELATED FATIGUE
Direct effects of cancer and tumour burden
Comorbid medical conditions bull Anemia bull Malnutrition bull Thyroid dysfunction bull Infection
Treatment side effects bull Chemotherapy bull Radiotherapy bull Surgery bull Medication sid effects
Exacerbating comorbid symptoms bull Chronic pain bull Sleep disturbances bull Deconditioning
Psychosocial factors bull Coping with chronic illness bull Anxiety bull Depression
Causes of fatigue (Atkinson et al 2002 Cella et al 1998 Portenoy and Itri 1999)
Meccanismi fisiopatologici
Peripheral fatigue originates in the muscles and related tissues( alterations in
adenosine triphosphate - ATP) Central fatigue develops in the central nervous system
Proposed mechanisms cytokine dysregulation hypothalamic-pituitary-adrenal (HPA) axis dysfunction 5 hydroxy tryptophan (5-HT) neurotransmitter
dysregulation circadian rhythm disruption and vagal afferent activation
Cytokine Dysregulation
Proinflammatory cytokines such as interleukin (IL)-1β IL-6 and tumor necrosis factor (TNF)-α have been evaluated as markers of cancer-related fatigue
Specific cytokines may contribute to fatigue
through more specific pathways IL-1 and IL-6 and TNF-α have been shown to
suppress erythropoiesis TNF has been associated with alterations in
central nervous system neurotransmission interferon-γ can act as chachectins IL-6 have also been associated with depression
Interventions
pharmacological interventions exercise behavioural management use of assistive devices lifestyle management nutritional support complementary or alternative therapy counselling
NCCN Guidelines Activity enhancement
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3 Treatment-Related Fatigue and Exercise in Patients with Cancer A Systematic Review
January 2000 and October 2006 English peer- reviewed nursing and health care journals age 18 or older literature search conducted in October 2006 using the
CINAHLreg Medlinereg Ovidreg and ProQuestreg databases
topics fatigue cancer and exercise Results 10 studies Sample size ranged from 12 to 108 Level of evidence moderate to high
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
focused question ldquoWhat is the relationship
between cancer treatment fatigue and exerciserdquo
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
This systematic review considered the effect of
exercise on fatigue in patients with multiple myeloma breast lung prostate cancers both early and late stages of disease patients receiving chemotherapy or radiation
setting of interventions
home-based exercises (8 ) out-of home exercises (2)
Home-based exercise interventions
walking bicycling or swimming
RESULTS improvement in vigor and reduction in fatigue with a
trend toward improved body esteem Pinto 2005 improved sleep increased lean body weight and less
fatigue with exercise Coleman 2003 progressively increased time in minutes walked per day improved QOL and a significant decrease of fatigue
Courneya 2003 moderated aerobic exercise and resistance training
decreased the overall perception of fatigue Crowley 2003
Out of home exercise interventions Controlled setting with professional instructors with a focus on
muscle strengthening flexibility and endurance Researchers found exercise to be well-tolerated and
feasible in a variety of malignancies No noticeable change in fatigue occurred but reported
bodily pain decreased Losito Murphy amp Thomas 2006 Improved physical and emotional well-being Borst 2005
Participation in a group exercise program was beneficial because patient support increased motivation
Conclusions
Patients with cancer may be challenged to initiate and maintain an exercise program for more than 3 months without unswerving professional support
This support can be made more effective if the
recommended exercise program is regularly adjusted to the patientsrsquo health status and considers shifting hemoglobin levels vital signs respiratory health and subjective feelings that influence the outcomes of exercise
Fatigue and the nutritional approaches
At the organism level cancer-associated fatigue involves the dysregulation of several interrelated physiological
biochemical and psychological systems At the tissue and cellular levels fatigue is
related to reductions in the efficiency of cellular energy systems mainly found in mitochondria
Oxidative stress intracellular excess of reactive oxygen (ROS) and nitrogen (RNS) free radical species over intracellular antioxidants It results in oxidation of cellular structures such as membrane lipids and proteins and
mutation of nuclear DNA Maes M (2009) Inflammatory and oxidative and nitrosative
stress pathways underpinning chronic fatigue somatization and psychosomatic symptoms Current Opinions in Psychiatry 22 75ndash83
ROSRNS damage
Membrane oxidation induces permeability changes in mitochondria and this
loss of electron transport function essential requirement of mitochondrial oxidative phosphorylation (ATP)
I Nutraceutici Acidi grassi polinsaturi essenziali (Omega 3
Omega 6) Acido Antranilico Acido ascorbico (o Vitamina C) Acido Folico (o Folacina o Vitamina M) Acido Lipoico (o Acido Tiottico o Vitamina N) Antocianine (o Antociani) Bioflavonoidi o (Flavonoidi o Vitamina C2) Caffeina L-Carnitina Carotenoidi Coenzima Q-10 (o Ubichinone o Vitamina Q) Colina (o Vitamina J) Creatina D-ribosio Ficocianine Fruttosio Glucosammina Inositolo (o Vitamina B7) Isoflavoni Licopene Lievito di birra Maltodestrine Octacosanolo Picnogenolo Policosanoli Proantocianidine (o PAC) Probiotici Resveratrolo Sali minerali (Calcio Cromo Fluoro Fosforo Iodio Magnesio Potassio Ferro Selenio Sodio Zinco) Steroli vegetali (o Fitosteroli) Taurina Teanina Teina Triptofano Vitamine 5-HTP (5-idrossitriptofano)
Lipid replacement therapy
NTFactorreg a lipid replacement oral
supplement containing phospholipids phosphoglycolipids cardiolipids
and other membrane lipids
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
CANCER RELATED FATIGUE
Direct effects of cancer and tumour burden
Comorbid medical conditions bull Anemia bull Malnutrition bull Thyroid dysfunction bull Infection
Treatment side effects bull Chemotherapy bull Radiotherapy bull Surgery bull Medication sid effects
Exacerbating comorbid symptoms bull Chronic pain bull Sleep disturbances bull Deconditioning
Psychosocial factors bull Coping with chronic illness bull Anxiety bull Depression
Causes of fatigue (Atkinson et al 2002 Cella et al 1998 Portenoy and Itri 1999)
Meccanismi fisiopatologici
Peripheral fatigue originates in the muscles and related tissues( alterations in
adenosine triphosphate - ATP) Central fatigue develops in the central nervous system
Proposed mechanisms cytokine dysregulation hypothalamic-pituitary-adrenal (HPA) axis dysfunction 5 hydroxy tryptophan (5-HT) neurotransmitter
dysregulation circadian rhythm disruption and vagal afferent activation
Cytokine Dysregulation
Proinflammatory cytokines such as interleukin (IL)-1β IL-6 and tumor necrosis factor (TNF)-α have been evaluated as markers of cancer-related fatigue
Specific cytokines may contribute to fatigue
through more specific pathways IL-1 and IL-6 and TNF-α have been shown to
suppress erythropoiesis TNF has been associated with alterations in
central nervous system neurotransmission interferon-γ can act as chachectins IL-6 have also been associated with depression
Interventions
pharmacological interventions exercise behavioural management use of assistive devices lifestyle management nutritional support complementary or alternative therapy counselling
NCCN Guidelines Activity enhancement
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3 Treatment-Related Fatigue and Exercise in Patients with Cancer A Systematic Review
January 2000 and October 2006 English peer- reviewed nursing and health care journals age 18 or older literature search conducted in October 2006 using the
CINAHLreg Medlinereg Ovidreg and ProQuestreg databases
topics fatigue cancer and exercise Results 10 studies Sample size ranged from 12 to 108 Level of evidence moderate to high
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
focused question ldquoWhat is the relationship
between cancer treatment fatigue and exerciserdquo
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
This systematic review considered the effect of
exercise on fatigue in patients with multiple myeloma breast lung prostate cancers both early and late stages of disease patients receiving chemotherapy or radiation
setting of interventions
home-based exercises (8 ) out-of home exercises (2)
Home-based exercise interventions
walking bicycling or swimming
RESULTS improvement in vigor and reduction in fatigue with a
trend toward improved body esteem Pinto 2005 improved sleep increased lean body weight and less
fatigue with exercise Coleman 2003 progressively increased time in minutes walked per day improved QOL and a significant decrease of fatigue
Courneya 2003 moderated aerobic exercise and resistance training
decreased the overall perception of fatigue Crowley 2003
Out of home exercise interventions Controlled setting with professional instructors with a focus on
muscle strengthening flexibility and endurance Researchers found exercise to be well-tolerated and
feasible in a variety of malignancies No noticeable change in fatigue occurred but reported
bodily pain decreased Losito Murphy amp Thomas 2006 Improved physical and emotional well-being Borst 2005
Participation in a group exercise program was beneficial because patient support increased motivation
Conclusions
Patients with cancer may be challenged to initiate and maintain an exercise program for more than 3 months without unswerving professional support
This support can be made more effective if the
recommended exercise program is regularly adjusted to the patientsrsquo health status and considers shifting hemoglobin levels vital signs respiratory health and subjective feelings that influence the outcomes of exercise
Fatigue and the nutritional approaches
At the organism level cancer-associated fatigue involves the dysregulation of several interrelated physiological
biochemical and psychological systems At the tissue and cellular levels fatigue is
related to reductions in the efficiency of cellular energy systems mainly found in mitochondria
Oxidative stress intracellular excess of reactive oxygen (ROS) and nitrogen (RNS) free radical species over intracellular antioxidants It results in oxidation of cellular structures such as membrane lipids and proteins and
mutation of nuclear DNA Maes M (2009) Inflammatory and oxidative and nitrosative
stress pathways underpinning chronic fatigue somatization and psychosomatic symptoms Current Opinions in Psychiatry 22 75ndash83
ROSRNS damage
Membrane oxidation induces permeability changes in mitochondria and this
loss of electron transport function essential requirement of mitochondrial oxidative phosphorylation (ATP)
I Nutraceutici Acidi grassi polinsaturi essenziali (Omega 3
Omega 6) Acido Antranilico Acido ascorbico (o Vitamina C) Acido Folico (o Folacina o Vitamina M) Acido Lipoico (o Acido Tiottico o Vitamina N) Antocianine (o Antociani) Bioflavonoidi o (Flavonoidi o Vitamina C2) Caffeina L-Carnitina Carotenoidi Coenzima Q-10 (o Ubichinone o Vitamina Q) Colina (o Vitamina J) Creatina D-ribosio Ficocianine Fruttosio Glucosammina Inositolo (o Vitamina B7) Isoflavoni Licopene Lievito di birra Maltodestrine Octacosanolo Picnogenolo Policosanoli Proantocianidine (o PAC) Probiotici Resveratrolo Sali minerali (Calcio Cromo Fluoro Fosforo Iodio Magnesio Potassio Ferro Selenio Sodio Zinco) Steroli vegetali (o Fitosteroli) Taurina Teanina Teina Triptofano Vitamine 5-HTP (5-idrossitriptofano)
Lipid replacement therapy
NTFactorreg a lipid replacement oral
supplement containing phospholipids phosphoglycolipids cardiolipids
and other membrane lipids
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Meccanismi fisiopatologici
Peripheral fatigue originates in the muscles and related tissues( alterations in
adenosine triphosphate - ATP) Central fatigue develops in the central nervous system
Proposed mechanisms cytokine dysregulation hypothalamic-pituitary-adrenal (HPA) axis dysfunction 5 hydroxy tryptophan (5-HT) neurotransmitter
dysregulation circadian rhythm disruption and vagal afferent activation
Cytokine Dysregulation
Proinflammatory cytokines such as interleukin (IL)-1β IL-6 and tumor necrosis factor (TNF)-α have been evaluated as markers of cancer-related fatigue
Specific cytokines may contribute to fatigue
through more specific pathways IL-1 and IL-6 and TNF-α have been shown to
suppress erythropoiesis TNF has been associated with alterations in
central nervous system neurotransmission interferon-γ can act as chachectins IL-6 have also been associated with depression
Interventions
pharmacological interventions exercise behavioural management use of assistive devices lifestyle management nutritional support complementary or alternative therapy counselling
NCCN Guidelines Activity enhancement
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3 Treatment-Related Fatigue and Exercise in Patients with Cancer A Systematic Review
January 2000 and October 2006 English peer- reviewed nursing and health care journals age 18 or older literature search conducted in October 2006 using the
CINAHLreg Medlinereg Ovidreg and ProQuestreg databases
topics fatigue cancer and exercise Results 10 studies Sample size ranged from 12 to 108 Level of evidence moderate to high
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
focused question ldquoWhat is the relationship
between cancer treatment fatigue and exerciserdquo
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
This systematic review considered the effect of
exercise on fatigue in patients with multiple myeloma breast lung prostate cancers both early and late stages of disease patients receiving chemotherapy or radiation
setting of interventions
home-based exercises (8 ) out-of home exercises (2)
Home-based exercise interventions
walking bicycling or swimming
RESULTS improvement in vigor and reduction in fatigue with a
trend toward improved body esteem Pinto 2005 improved sleep increased lean body weight and less
fatigue with exercise Coleman 2003 progressively increased time in minutes walked per day improved QOL and a significant decrease of fatigue
Courneya 2003 moderated aerobic exercise and resistance training
decreased the overall perception of fatigue Crowley 2003
Out of home exercise interventions Controlled setting with professional instructors with a focus on
muscle strengthening flexibility and endurance Researchers found exercise to be well-tolerated and
feasible in a variety of malignancies No noticeable change in fatigue occurred but reported
bodily pain decreased Losito Murphy amp Thomas 2006 Improved physical and emotional well-being Borst 2005
Participation in a group exercise program was beneficial because patient support increased motivation
Conclusions
Patients with cancer may be challenged to initiate and maintain an exercise program for more than 3 months without unswerving professional support
This support can be made more effective if the
recommended exercise program is regularly adjusted to the patientsrsquo health status and considers shifting hemoglobin levels vital signs respiratory health and subjective feelings that influence the outcomes of exercise
Fatigue and the nutritional approaches
At the organism level cancer-associated fatigue involves the dysregulation of several interrelated physiological
biochemical and psychological systems At the tissue and cellular levels fatigue is
related to reductions in the efficiency of cellular energy systems mainly found in mitochondria
Oxidative stress intracellular excess of reactive oxygen (ROS) and nitrogen (RNS) free radical species over intracellular antioxidants It results in oxidation of cellular structures such as membrane lipids and proteins and
mutation of nuclear DNA Maes M (2009) Inflammatory and oxidative and nitrosative
stress pathways underpinning chronic fatigue somatization and psychosomatic symptoms Current Opinions in Psychiatry 22 75ndash83
ROSRNS damage
Membrane oxidation induces permeability changes in mitochondria and this
loss of electron transport function essential requirement of mitochondrial oxidative phosphorylation (ATP)
I Nutraceutici Acidi grassi polinsaturi essenziali (Omega 3
Omega 6) Acido Antranilico Acido ascorbico (o Vitamina C) Acido Folico (o Folacina o Vitamina M) Acido Lipoico (o Acido Tiottico o Vitamina N) Antocianine (o Antociani) Bioflavonoidi o (Flavonoidi o Vitamina C2) Caffeina L-Carnitina Carotenoidi Coenzima Q-10 (o Ubichinone o Vitamina Q) Colina (o Vitamina J) Creatina D-ribosio Ficocianine Fruttosio Glucosammina Inositolo (o Vitamina B7) Isoflavoni Licopene Lievito di birra Maltodestrine Octacosanolo Picnogenolo Policosanoli Proantocianidine (o PAC) Probiotici Resveratrolo Sali minerali (Calcio Cromo Fluoro Fosforo Iodio Magnesio Potassio Ferro Selenio Sodio Zinco) Steroli vegetali (o Fitosteroli) Taurina Teanina Teina Triptofano Vitamine 5-HTP (5-idrossitriptofano)
Lipid replacement therapy
NTFactorreg a lipid replacement oral
supplement containing phospholipids phosphoglycolipids cardiolipids
and other membrane lipids
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Cytokine Dysregulation
Proinflammatory cytokines such as interleukin (IL)-1β IL-6 and tumor necrosis factor (TNF)-α have been evaluated as markers of cancer-related fatigue
Specific cytokines may contribute to fatigue
through more specific pathways IL-1 and IL-6 and TNF-α have been shown to
suppress erythropoiesis TNF has been associated with alterations in
central nervous system neurotransmission interferon-γ can act as chachectins IL-6 have also been associated with depression
Interventions
pharmacological interventions exercise behavioural management use of assistive devices lifestyle management nutritional support complementary or alternative therapy counselling
NCCN Guidelines Activity enhancement
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3 Treatment-Related Fatigue and Exercise in Patients with Cancer A Systematic Review
January 2000 and October 2006 English peer- reviewed nursing and health care journals age 18 or older literature search conducted in October 2006 using the
CINAHLreg Medlinereg Ovidreg and ProQuestreg databases
topics fatigue cancer and exercise Results 10 studies Sample size ranged from 12 to 108 Level of evidence moderate to high
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
focused question ldquoWhat is the relationship
between cancer treatment fatigue and exerciserdquo
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
This systematic review considered the effect of
exercise on fatigue in patients with multiple myeloma breast lung prostate cancers both early and late stages of disease patients receiving chemotherapy or radiation
setting of interventions
home-based exercises (8 ) out-of home exercises (2)
Home-based exercise interventions
walking bicycling or swimming
RESULTS improvement in vigor and reduction in fatigue with a
trend toward improved body esteem Pinto 2005 improved sleep increased lean body weight and less
fatigue with exercise Coleman 2003 progressively increased time in minutes walked per day improved QOL and a significant decrease of fatigue
Courneya 2003 moderated aerobic exercise and resistance training
decreased the overall perception of fatigue Crowley 2003
Out of home exercise interventions Controlled setting with professional instructors with a focus on
muscle strengthening flexibility and endurance Researchers found exercise to be well-tolerated and
feasible in a variety of malignancies No noticeable change in fatigue occurred but reported
bodily pain decreased Losito Murphy amp Thomas 2006 Improved physical and emotional well-being Borst 2005
Participation in a group exercise program was beneficial because patient support increased motivation
Conclusions
Patients with cancer may be challenged to initiate and maintain an exercise program for more than 3 months without unswerving professional support
This support can be made more effective if the
recommended exercise program is regularly adjusted to the patientsrsquo health status and considers shifting hemoglobin levels vital signs respiratory health and subjective feelings that influence the outcomes of exercise
Fatigue and the nutritional approaches
At the organism level cancer-associated fatigue involves the dysregulation of several interrelated physiological
biochemical and psychological systems At the tissue and cellular levels fatigue is
related to reductions in the efficiency of cellular energy systems mainly found in mitochondria
Oxidative stress intracellular excess of reactive oxygen (ROS) and nitrogen (RNS) free radical species over intracellular antioxidants It results in oxidation of cellular structures such as membrane lipids and proteins and
mutation of nuclear DNA Maes M (2009) Inflammatory and oxidative and nitrosative
stress pathways underpinning chronic fatigue somatization and psychosomatic symptoms Current Opinions in Psychiatry 22 75ndash83
ROSRNS damage
Membrane oxidation induces permeability changes in mitochondria and this
loss of electron transport function essential requirement of mitochondrial oxidative phosphorylation (ATP)
I Nutraceutici Acidi grassi polinsaturi essenziali (Omega 3
Omega 6) Acido Antranilico Acido ascorbico (o Vitamina C) Acido Folico (o Folacina o Vitamina M) Acido Lipoico (o Acido Tiottico o Vitamina N) Antocianine (o Antociani) Bioflavonoidi o (Flavonoidi o Vitamina C2) Caffeina L-Carnitina Carotenoidi Coenzima Q-10 (o Ubichinone o Vitamina Q) Colina (o Vitamina J) Creatina D-ribosio Ficocianine Fruttosio Glucosammina Inositolo (o Vitamina B7) Isoflavoni Licopene Lievito di birra Maltodestrine Octacosanolo Picnogenolo Policosanoli Proantocianidine (o PAC) Probiotici Resveratrolo Sali minerali (Calcio Cromo Fluoro Fosforo Iodio Magnesio Potassio Ferro Selenio Sodio Zinco) Steroli vegetali (o Fitosteroli) Taurina Teanina Teina Triptofano Vitamine 5-HTP (5-idrossitriptofano)
Lipid replacement therapy
NTFactorreg a lipid replacement oral
supplement containing phospholipids phosphoglycolipids cardiolipids
and other membrane lipids
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Interventions
pharmacological interventions exercise behavioural management use of assistive devices lifestyle management nutritional support complementary or alternative therapy counselling
NCCN Guidelines Activity enhancement
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3 Treatment-Related Fatigue and Exercise in Patients with Cancer A Systematic Review
January 2000 and October 2006 English peer- reviewed nursing and health care journals age 18 or older literature search conducted in October 2006 using the
CINAHLreg Medlinereg Ovidreg and ProQuestreg databases
topics fatigue cancer and exercise Results 10 studies Sample size ranged from 12 to 108 Level of evidence moderate to high
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
focused question ldquoWhat is the relationship
between cancer treatment fatigue and exerciserdquo
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
This systematic review considered the effect of
exercise on fatigue in patients with multiple myeloma breast lung prostate cancers both early and late stages of disease patients receiving chemotherapy or radiation
setting of interventions
home-based exercises (8 ) out-of home exercises (2)
Home-based exercise interventions
walking bicycling or swimming
RESULTS improvement in vigor and reduction in fatigue with a
trend toward improved body esteem Pinto 2005 improved sleep increased lean body weight and less
fatigue with exercise Coleman 2003 progressively increased time in minutes walked per day improved QOL and a significant decrease of fatigue
Courneya 2003 moderated aerobic exercise and resistance training
decreased the overall perception of fatigue Crowley 2003
Out of home exercise interventions Controlled setting with professional instructors with a focus on
muscle strengthening flexibility and endurance Researchers found exercise to be well-tolerated and
feasible in a variety of malignancies No noticeable change in fatigue occurred but reported
bodily pain decreased Losito Murphy amp Thomas 2006 Improved physical and emotional well-being Borst 2005
Participation in a group exercise program was beneficial because patient support increased motivation
Conclusions
Patients with cancer may be challenged to initiate and maintain an exercise program for more than 3 months without unswerving professional support
This support can be made more effective if the
recommended exercise program is regularly adjusted to the patientsrsquo health status and considers shifting hemoglobin levels vital signs respiratory health and subjective feelings that influence the outcomes of exercise
Fatigue and the nutritional approaches
At the organism level cancer-associated fatigue involves the dysregulation of several interrelated physiological
biochemical and psychological systems At the tissue and cellular levels fatigue is
related to reductions in the efficiency of cellular energy systems mainly found in mitochondria
Oxidative stress intracellular excess of reactive oxygen (ROS) and nitrogen (RNS) free radical species over intracellular antioxidants It results in oxidation of cellular structures such as membrane lipids and proteins and
mutation of nuclear DNA Maes M (2009) Inflammatory and oxidative and nitrosative
stress pathways underpinning chronic fatigue somatization and psychosomatic symptoms Current Opinions in Psychiatry 22 75ndash83
ROSRNS damage
Membrane oxidation induces permeability changes in mitochondria and this
loss of electron transport function essential requirement of mitochondrial oxidative phosphorylation (ATP)
I Nutraceutici Acidi grassi polinsaturi essenziali (Omega 3
Omega 6) Acido Antranilico Acido ascorbico (o Vitamina C) Acido Folico (o Folacina o Vitamina M) Acido Lipoico (o Acido Tiottico o Vitamina N) Antocianine (o Antociani) Bioflavonoidi o (Flavonoidi o Vitamina C2) Caffeina L-Carnitina Carotenoidi Coenzima Q-10 (o Ubichinone o Vitamina Q) Colina (o Vitamina J) Creatina D-ribosio Ficocianine Fruttosio Glucosammina Inositolo (o Vitamina B7) Isoflavoni Licopene Lievito di birra Maltodestrine Octacosanolo Picnogenolo Policosanoli Proantocianidine (o PAC) Probiotici Resveratrolo Sali minerali (Calcio Cromo Fluoro Fosforo Iodio Magnesio Potassio Ferro Selenio Sodio Zinco) Steroli vegetali (o Fitosteroli) Taurina Teanina Teina Triptofano Vitamine 5-HTP (5-idrossitriptofano)
Lipid replacement therapy
NTFactorreg a lipid replacement oral
supplement containing phospholipids phosphoglycolipids cardiolipids
and other membrane lipids
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
NCCN Guidelines Activity enhancement
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3 Treatment-Related Fatigue and Exercise in Patients with Cancer A Systematic Review
January 2000 and October 2006 English peer- reviewed nursing and health care journals age 18 or older literature search conducted in October 2006 using the
CINAHLreg Medlinereg Ovidreg and ProQuestreg databases
topics fatigue cancer and exercise Results 10 studies Sample size ranged from 12 to 108 Level of evidence moderate to high
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
focused question ldquoWhat is the relationship
between cancer treatment fatigue and exerciserdquo
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
This systematic review considered the effect of
exercise on fatigue in patients with multiple myeloma breast lung prostate cancers both early and late stages of disease patients receiving chemotherapy or radiation
setting of interventions
home-based exercises (8 ) out-of home exercises (2)
Home-based exercise interventions
walking bicycling or swimming
RESULTS improvement in vigor and reduction in fatigue with a
trend toward improved body esteem Pinto 2005 improved sleep increased lean body weight and less
fatigue with exercise Coleman 2003 progressively increased time in minutes walked per day improved QOL and a significant decrease of fatigue
Courneya 2003 moderated aerobic exercise and resistance training
decreased the overall perception of fatigue Crowley 2003
Out of home exercise interventions Controlled setting with professional instructors with a focus on
muscle strengthening flexibility and endurance Researchers found exercise to be well-tolerated and
feasible in a variety of malignancies No noticeable change in fatigue occurred but reported
bodily pain decreased Losito Murphy amp Thomas 2006 Improved physical and emotional well-being Borst 2005
Participation in a group exercise program was beneficial because patient support increased motivation
Conclusions
Patients with cancer may be challenged to initiate and maintain an exercise program for more than 3 months without unswerving professional support
This support can be made more effective if the
recommended exercise program is regularly adjusted to the patientsrsquo health status and considers shifting hemoglobin levels vital signs respiratory health and subjective feelings that influence the outcomes of exercise
Fatigue and the nutritional approaches
At the organism level cancer-associated fatigue involves the dysregulation of several interrelated physiological
biochemical and psychological systems At the tissue and cellular levels fatigue is
related to reductions in the efficiency of cellular energy systems mainly found in mitochondria
Oxidative stress intracellular excess of reactive oxygen (ROS) and nitrogen (RNS) free radical species over intracellular antioxidants It results in oxidation of cellular structures such as membrane lipids and proteins and
mutation of nuclear DNA Maes M (2009) Inflammatory and oxidative and nitrosative
stress pathways underpinning chronic fatigue somatization and psychosomatic symptoms Current Opinions in Psychiatry 22 75ndash83
ROSRNS damage
Membrane oxidation induces permeability changes in mitochondria and this
loss of electron transport function essential requirement of mitochondrial oxidative phosphorylation (ATP)
I Nutraceutici Acidi grassi polinsaturi essenziali (Omega 3
Omega 6) Acido Antranilico Acido ascorbico (o Vitamina C) Acido Folico (o Folacina o Vitamina M) Acido Lipoico (o Acido Tiottico o Vitamina N) Antocianine (o Antociani) Bioflavonoidi o (Flavonoidi o Vitamina C2) Caffeina L-Carnitina Carotenoidi Coenzima Q-10 (o Ubichinone o Vitamina Q) Colina (o Vitamina J) Creatina D-ribosio Ficocianine Fruttosio Glucosammina Inositolo (o Vitamina B7) Isoflavoni Licopene Lievito di birra Maltodestrine Octacosanolo Picnogenolo Policosanoli Proantocianidine (o PAC) Probiotici Resveratrolo Sali minerali (Calcio Cromo Fluoro Fosforo Iodio Magnesio Potassio Ferro Selenio Sodio Zinco) Steroli vegetali (o Fitosteroli) Taurina Teanina Teina Triptofano Vitamine 5-HTP (5-idrossitriptofano)
Lipid replacement therapy
NTFactorreg a lipid replacement oral
supplement containing phospholipids phosphoglycolipids cardiolipids
and other membrane lipids
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3 Treatment-Related Fatigue and Exercise in Patients with Cancer A Systematic Review
January 2000 and October 2006 English peer- reviewed nursing and health care journals age 18 or older literature search conducted in October 2006 using the
CINAHLreg Medlinereg Ovidreg and ProQuestreg databases
topics fatigue cancer and exercise Results 10 studies Sample size ranged from 12 to 108 Level of evidence moderate to high
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
focused question ldquoWhat is the relationship
between cancer treatment fatigue and exerciserdquo
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
This systematic review considered the effect of
exercise on fatigue in patients with multiple myeloma breast lung prostate cancers both early and late stages of disease patients receiving chemotherapy or radiation
setting of interventions
home-based exercises (8 ) out-of home exercises (2)
Home-based exercise interventions
walking bicycling or swimming
RESULTS improvement in vigor and reduction in fatigue with a
trend toward improved body esteem Pinto 2005 improved sleep increased lean body weight and less
fatigue with exercise Coleman 2003 progressively increased time in minutes walked per day improved QOL and a significant decrease of fatigue
Courneya 2003 moderated aerobic exercise and resistance training
decreased the overall perception of fatigue Crowley 2003
Out of home exercise interventions Controlled setting with professional instructors with a focus on
muscle strengthening flexibility and endurance Researchers found exercise to be well-tolerated and
feasible in a variety of malignancies No noticeable change in fatigue occurred but reported
bodily pain decreased Losito Murphy amp Thomas 2006 Improved physical and emotional well-being Borst 2005
Participation in a group exercise program was beneficial because patient support increased motivation
Conclusions
Patients with cancer may be challenged to initiate and maintain an exercise program for more than 3 months without unswerving professional support
This support can be made more effective if the
recommended exercise program is regularly adjusted to the patientsrsquo health status and considers shifting hemoglobin levels vital signs respiratory health and subjective feelings that influence the outcomes of exercise
Fatigue and the nutritional approaches
At the organism level cancer-associated fatigue involves the dysregulation of several interrelated physiological
biochemical and psychological systems At the tissue and cellular levels fatigue is
related to reductions in the efficiency of cellular energy systems mainly found in mitochondria
Oxidative stress intracellular excess of reactive oxygen (ROS) and nitrogen (RNS) free radical species over intracellular antioxidants It results in oxidation of cellular structures such as membrane lipids and proteins and
mutation of nuclear DNA Maes M (2009) Inflammatory and oxidative and nitrosative
stress pathways underpinning chronic fatigue somatization and psychosomatic symptoms Current Opinions in Psychiatry 22 75ndash83
ROSRNS damage
Membrane oxidation induces permeability changes in mitochondria and this
loss of electron transport function essential requirement of mitochondrial oxidative phosphorylation (ATP)
I Nutraceutici Acidi grassi polinsaturi essenziali (Omega 3
Omega 6) Acido Antranilico Acido ascorbico (o Vitamina C) Acido Folico (o Folacina o Vitamina M) Acido Lipoico (o Acido Tiottico o Vitamina N) Antocianine (o Antociani) Bioflavonoidi o (Flavonoidi o Vitamina C2) Caffeina L-Carnitina Carotenoidi Coenzima Q-10 (o Ubichinone o Vitamina Q) Colina (o Vitamina J) Creatina D-ribosio Ficocianine Fruttosio Glucosammina Inositolo (o Vitamina B7) Isoflavoni Licopene Lievito di birra Maltodestrine Octacosanolo Picnogenolo Policosanoli Proantocianidine (o PAC) Probiotici Resveratrolo Sali minerali (Calcio Cromo Fluoro Fosforo Iodio Magnesio Potassio Ferro Selenio Sodio Zinco) Steroli vegetali (o Fitosteroli) Taurina Teanina Teina Triptofano Vitamine 5-HTP (5-idrossitriptofano)
Lipid replacement therapy
NTFactorreg a lipid replacement oral
supplement containing phospholipids phosphoglycolipids cardiolipids
and other membrane lipids
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
focused question ldquoWhat is the relationship
between cancer treatment fatigue and exerciserdquo
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
This systematic review considered the effect of
exercise on fatigue in patients with multiple myeloma breast lung prostate cancers both early and late stages of disease patients receiving chemotherapy or radiation
setting of interventions
home-based exercises (8 ) out-of home exercises (2)
Home-based exercise interventions
walking bicycling or swimming
RESULTS improvement in vigor and reduction in fatigue with a
trend toward improved body esteem Pinto 2005 improved sleep increased lean body weight and less
fatigue with exercise Coleman 2003 progressively increased time in minutes walked per day improved QOL and a significant decrease of fatigue
Courneya 2003 moderated aerobic exercise and resistance training
decreased the overall perception of fatigue Crowley 2003
Out of home exercise interventions Controlled setting with professional instructors with a focus on
muscle strengthening flexibility and endurance Researchers found exercise to be well-tolerated and
feasible in a variety of malignancies No noticeable change in fatigue occurred but reported
bodily pain decreased Losito Murphy amp Thomas 2006 Improved physical and emotional well-being Borst 2005
Participation in a group exercise program was beneficial because patient support increased motivation
Conclusions
Patients with cancer may be challenged to initiate and maintain an exercise program for more than 3 months without unswerving professional support
This support can be made more effective if the
recommended exercise program is regularly adjusted to the patientsrsquo health status and considers shifting hemoglobin levels vital signs respiratory health and subjective feelings that influence the outcomes of exercise
Fatigue and the nutritional approaches
At the organism level cancer-associated fatigue involves the dysregulation of several interrelated physiological
biochemical and psychological systems At the tissue and cellular levels fatigue is
related to reductions in the efficiency of cellular energy systems mainly found in mitochondria
Oxidative stress intracellular excess of reactive oxygen (ROS) and nitrogen (RNS) free radical species over intracellular antioxidants It results in oxidation of cellular structures such as membrane lipids and proteins and
mutation of nuclear DNA Maes M (2009) Inflammatory and oxidative and nitrosative
stress pathways underpinning chronic fatigue somatization and psychosomatic symptoms Current Opinions in Psychiatry 22 75ndash83
ROSRNS damage
Membrane oxidation induces permeability changes in mitochondria and this
loss of electron transport function essential requirement of mitochondrial oxidative phosphorylation (ATP)
I Nutraceutici Acidi grassi polinsaturi essenziali (Omega 3
Omega 6) Acido Antranilico Acido ascorbico (o Vitamina C) Acido Folico (o Folacina o Vitamina M) Acido Lipoico (o Acido Tiottico o Vitamina N) Antocianine (o Antociani) Bioflavonoidi o (Flavonoidi o Vitamina C2) Caffeina L-Carnitina Carotenoidi Coenzima Q-10 (o Ubichinone o Vitamina Q) Colina (o Vitamina J) Creatina D-ribosio Ficocianine Fruttosio Glucosammina Inositolo (o Vitamina B7) Isoflavoni Licopene Lievito di birra Maltodestrine Octacosanolo Picnogenolo Policosanoli Proantocianidine (o PAC) Probiotici Resveratrolo Sali minerali (Calcio Cromo Fluoro Fosforo Iodio Magnesio Potassio Ferro Selenio Sodio Zinco) Steroli vegetali (o Fitosteroli) Taurina Teanina Teina Triptofano Vitamine 5-HTP (5-idrossitriptofano)
Lipid replacement therapy
NTFactorreg a lipid replacement oral
supplement containing phospholipids phosphoglycolipids cardiolipids
and other membrane lipids
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Anne-Marie Kuchinski MEDSURG NursingmdashMayJune 2009mdashVol 18No 3
This systematic review considered the effect of
exercise on fatigue in patients with multiple myeloma breast lung prostate cancers both early and late stages of disease patients receiving chemotherapy or radiation
setting of interventions
home-based exercises (8 ) out-of home exercises (2)
Home-based exercise interventions
walking bicycling or swimming
RESULTS improvement in vigor and reduction in fatigue with a
trend toward improved body esteem Pinto 2005 improved sleep increased lean body weight and less
fatigue with exercise Coleman 2003 progressively increased time in minutes walked per day improved QOL and a significant decrease of fatigue
Courneya 2003 moderated aerobic exercise and resistance training
decreased the overall perception of fatigue Crowley 2003
Out of home exercise interventions Controlled setting with professional instructors with a focus on
muscle strengthening flexibility and endurance Researchers found exercise to be well-tolerated and
feasible in a variety of malignancies No noticeable change in fatigue occurred but reported
bodily pain decreased Losito Murphy amp Thomas 2006 Improved physical and emotional well-being Borst 2005
Participation in a group exercise program was beneficial because patient support increased motivation
Conclusions
Patients with cancer may be challenged to initiate and maintain an exercise program for more than 3 months without unswerving professional support
This support can be made more effective if the
recommended exercise program is regularly adjusted to the patientsrsquo health status and considers shifting hemoglobin levels vital signs respiratory health and subjective feelings that influence the outcomes of exercise
Fatigue and the nutritional approaches
At the organism level cancer-associated fatigue involves the dysregulation of several interrelated physiological
biochemical and psychological systems At the tissue and cellular levels fatigue is
related to reductions in the efficiency of cellular energy systems mainly found in mitochondria
Oxidative stress intracellular excess of reactive oxygen (ROS) and nitrogen (RNS) free radical species over intracellular antioxidants It results in oxidation of cellular structures such as membrane lipids and proteins and
mutation of nuclear DNA Maes M (2009) Inflammatory and oxidative and nitrosative
stress pathways underpinning chronic fatigue somatization and psychosomatic symptoms Current Opinions in Psychiatry 22 75ndash83
ROSRNS damage
Membrane oxidation induces permeability changes in mitochondria and this
loss of electron transport function essential requirement of mitochondrial oxidative phosphorylation (ATP)
I Nutraceutici Acidi grassi polinsaturi essenziali (Omega 3
Omega 6) Acido Antranilico Acido ascorbico (o Vitamina C) Acido Folico (o Folacina o Vitamina M) Acido Lipoico (o Acido Tiottico o Vitamina N) Antocianine (o Antociani) Bioflavonoidi o (Flavonoidi o Vitamina C2) Caffeina L-Carnitina Carotenoidi Coenzima Q-10 (o Ubichinone o Vitamina Q) Colina (o Vitamina J) Creatina D-ribosio Ficocianine Fruttosio Glucosammina Inositolo (o Vitamina B7) Isoflavoni Licopene Lievito di birra Maltodestrine Octacosanolo Picnogenolo Policosanoli Proantocianidine (o PAC) Probiotici Resveratrolo Sali minerali (Calcio Cromo Fluoro Fosforo Iodio Magnesio Potassio Ferro Selenio Sodio Zinco) Steroli vegetali (o Fitosteroli) Taurina Teanina Teina Triptofano Vitamine 5-HTP (5-idrossitriptofano)
Lipid replacement therapy
NTFactorreg a lipid replacement oral
supplement containing phospholipids phosphoglycolipids cardiolipids
and other membrane lipids
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
setting of interventions
home-based exercises (8 ) out-of home exercises (2)
Home-based exercise interventions
walking bicycling or swimming
RESULTS improvement in vigor and reduction in fatigue with a
trend toward improved body esteem Pinto 2005 improved sleep increased lean body weight and less
fatigue with exercise Coleman 2003 progressively increased time in minutes walked per day improved QOL and a significant decrease of fatigue
Courneya 2003 moderated aerobic exercise and resistance training
decreased the overall perception of fatigue Crowley 2003
Out of home exercise interventions Controlled setting with professional instructors with a focus on
muscle strengthening flexibility and endurance Researchers found exercise to be well-tolerated and
feasible in a variety of malignancies No noticeable change in fatigue occurred but reported
bodily pain decreased Losito Murphy amp Thomas 2006 Improved physical and emotional well-being Borst 2005
Participation in a group exercise program was beneficial because patient support increased motivation
Conclusions
Patients with cancer may be challenged to initiate and maintain an exercise program for more than 3 months without unswerving professional support
This support can be made more effective if the
recommended exercise program is regularly adjusted to the patientsrsquo health status and considers shifting hemoglobin levels vital signs respiratory health and subjective feelings that influence the outcomes of exercise
Fatigue and the nutritional approaches
At the organism level cancer-associated fatigue involves the dysregulation of several interrelated physiological
biochemical and psychological systems At the tissue and cellular levels fatigue is
related to reductions in the efficiency of cellular energy systems mainly found in mitochondria
Oxidative stress intracellular excess of reactive oxygen (ROS) and nitrogen (RNS) free radical species over intracellular antioxidants It results in oxidation of cellular structures such as membrane lipids and proteins and
mutation of nuclear DNA Maes M (2009) Inflammatory and oxidative and nitrosative
stress pathways underpinning chronic fatigue somatization and psychosomatic symptoms Current Opinions in Psychiatry 22 75ndash83
ROSRNS damage
Membrane oxidation induces permeability changes in mitochondria and this
loss of electron transport function essential requirement of mitochondrial oxidative phosphorylation (ATP)
I Nutraceutici Acidi grassi polinsaturi essenziali (Omega 3
Omega 6) Acido Antranilico Acido ascorbico (o Vitamina C) Acido Folico (o Folacina o Vitamina M) Acido Lipoico (o Acido Tiottico o Vitamina N) Antocianine (o Antociani) Bioflavonoidi o (Flavonoidi o Vitamina C2) Caffeina L-Carnitina Carotenoidi Coenzima Q-10 (o Ubichinone o Vitamina Q) Colina (o Vitamina J) Creatina D-ribosio Ficocianine Fruttosio Glucosammina Inositolo (o Vitamina B7) Isoflavoni Licopene Lievito di birra Maltodestrine Octacosanolo Picnogenolo Policosanoli Proantocianidine (o PAC) Probiotici Resveratrolo Sali minerali (Calcio Cromo Fluoro Fosforo Iodio Magnesio Potassio Ferro Selenio Sodio Zinco) Steroli vegetali (o Fitosteroli) Taurina Teanina Teina Triptofano Vitamine 5-HTP (5-idrossitriptofano)
Lipid replacement therapy
NTFactorreg a lipid replacement oral
supplement containing phospholipids phosphoglycolipids cardiolipids
and other membrane lipids
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Home-based exercise interventions
walking bicycling or swimming
RESULTS improvement in vigor and reduction in fatigue with a
trend toward improved body esteem Pinto 2005 improved sleep increased lean body weight and less
fatigue with exercise Coleman 2003 progressively increased time in minutes walked per day improved QOL and a significant decrease of fatigue
Courneya 2003 moderated aerobic exercise and resistance training
decreased the overall perception of fatigue Crowley 2003
Out of home exercise interventions Controlled setting with professional instructors with a focus on
muscle strengthening flexibility and endurance Researchers found exercise to be well-tolerated and
feasible in a variety of malignancies No noticeable change in fatigue occurred but reported
bodily pain decreased Losito Murphy amp Thomas 2006 Improved physical and emotional well-being Borst 2005
Participation in a group exercise program was beneficial because patient support increased motivation
Conclusions
Patients with cancer may be challenged to initiate and maintain an exercise program for more than 3 months without unswerving professional support
This support can be made more effective if the
recommended exercise program is regularly adjusted to the patientsrsquo health status and considers shifting hemoglobin levels vital signs respiratory health and subjective feelings that influence the outcomes of exercise
Fatigue and the nutritional approaches
At the organism level cancer-associated fatigue involves the dysregulation of several interrelated physiological
biochemical and psychological systems At the tissue and cellular levels fatigue is
related to reductions in the efficiency of cellular energy systems mainly found in mitochondria
Oxidative stress intracellular excess of reactive oxygen (ROS) and nitrogen (RNS) free radical species over intracellular antioxidants It results in oxidation of cellular structures such as membrane lipids and proteins and
mutation of nuclear DNA Maes M (2009) Inflammatory and oxidative and nitrosative
stress pathways underpinning chronic fatigue somatization and psychosomatic symptoms Current Opinions in Psychiatry 22 75ndash83
ROSRNS damage
Membrane oxidation induces permeability changes in mitochondria and this
loss of electron transport function essential requirement of mitochondrial oxidative phosphorylation (ATP)
I Nutraceutici Acidi grassi polinsaturi essenziali (Omega 3
Omega 6) Acido Antranilico Acido ascorbico (o Vitamina C) Acido Folico (o Folacina o Vitamina M) Acido Lipoico (o Acido Tiottico o Vitamina N) Antocianine (o Antociani) Bioflavonoidi o (Flavonoidi o Vitamina C2) Caffeina L-Carnitina Carotenoidi Coenzima Q-10 (o Ubichinone o Vitamina Q) Colina (o Vitamina J) Creatina D-ribosio Ficocianine Fruttosio Glucosammina Inositolo (o Vitamina B7) Isoflavoni Licopene Lievito di birra Maltodestrine Octacosanolo Picnogenolo Policosanoli Proantocianidine (o PAC) Probiotici Resveratrolo Sali minerali (Calcio Cromo Fluoro Fosforo Iodio Magnesio Potassio Ferro Selenio Sodio Zinco) Steroli vegetali (o Fitosteroli) Taurina Teanina Teina Triptofano Vitamine 5-HTP (5-idrossitriptofano)
Lipid replacement therapy
NTFactorreg a lipid replacement oral
supplement containing phospholipids phosphoglycolipids cardiolipids
and other membrane lipids
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Out of home exercise interventions Controlled setting with professional instructors with a focus on
muscle strengthening flexibility and endurance Researchers found exercise to be well-tolerated and
feasible in a variety of malignancies No noticeable change in fatigue occurred but reported
bodily pain decreased Losito Murphy amp Thomas 2006 Improved physical and emotional well-being Borst 2005
Participation in a group exercise program was beneficial because patient support increased motivation
Conclusions
Patients with cancer may be challenged to initiate and maintain an exercise program for more than 3 months without unswerving professional support
This support can be made more effective if the
recommended exercise program is regularly adjusted to the patientsrsquo health status and considers shifting hemoglobin levels vital signs respiratory health and subjective feelings that influence the outcomes of exercise
Fatigue and the nutritional approaches
At the organism level cancer-associated fatigue involves the dysregulation of several interrelated physiological
biochemical and psychological systems At the tissue and cellular levels fatigue is
related to reductions in the efficiency of cellular energy systems mainly found in mitochondria
Oxidative stress intracellular excess of reactive oxygen (ROS) and nitrogen (RNS) free radical species over intracellular antioxidants It results in oxidation of cellular structures such as membrane lipids and proteins and
mutation of nuclear DNA Maes M (2009) Inflammatory and oxidative and nitrosative
stress pathways underpinning chronic fatigue somatization and psychosomatic symptoms Current Opinions in Psychiatry 22 75ndash83
ROSRNS damage
Membrane oxidation induces permeability changes in mitochondria and this
loss of electron transport function essential requirement of mitochondrial oxidative phosphorylation (ATP)
I Nutraceutici Acidi grassi polinsaturi essenziali (Omega 3
Omega 6) Acido Antranilico Acido ascorbico (o Vitamina C) Acido Folico (o Folacina o Vitamina M) Acido Lipoico (o Acido Tiottico o Vitamina N) Antocianine (o Antociani) Bioflavonoidi o (Flavonoidi o Vitamina C2) Caffeina L-Carnitina Carotenoidi Coenzima Q-10 (o Ubichinone o Vitamina Q) Colina (o Vitamina J) Creatina D-ribosio Ficocianine Fruttosio Glucosammina Inositolo (o Vitamina B7) Isoflavoni Licopene Lievito di birra Maltodestrine Octacosanolo Picnogenolo Policosanoli Proantocianidine (o PAC) Probiotici Resveratrolo Sali minerali (Calcio Cromo Fluoro Fosforo Iodio Magnesio Potassio Ferro Selenio Sodio Zinco) Steroli vegetali (o Fitosteroli) Taurina Teanina Teina Triptofano Vitamine 5-HTP (5-idrossitriptofano)
Lipid replacement therapy
NTFactorreg a lipid replacement oral
supplement containing phospholipids phosphoglycolipids cardiolipids
and other membrane lipids
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Conclusions
Patients with cancer may be challenged to initiate and maintain an exercise program for more than 3 months without unswerving professional support
This support can be made more effective if the
recommended exercise program is regularly adjusted to the patientsrsquo health status and considers shifting hemoglobin levels vital signs respiratory health and subjective feelings that influence the outcomes of exercise
Fatigue and the nutritional approaches
At the organism level cancer-associated fatigue involves the dysregulation of several interrelated physiological
biochemical and psychological systems At the tissue and cellular levels fatigue is
related to reductions in the efficiency of cellular energy systems mainly found in mitochondria
Oxidative stress intracellular excess of reactive oxygen (ROS) and nitrogen (RNS) free radical species over intracellular antioxidants It results in oxidation of cellular structures such as membrane lipids and proteins and
mutation of nuclear DNA Maes M (2009) Inflammatory and oxidative and nitrosative
stress pathways underpinning chronic fatigue somatization and psychosomatic symptoms Current Opinions in Psychiatry 22 75ndash83
ROSRNS damage
Membrane oxidation induces permeability changes in mitochondria and this
loss of electron transport function essential requirement of mitochondrial oxidative phosphorylation (ATP)
I Nutraceutici Acidi grassi polinsaturi essenziali (Omega 3
Omega 6) Acido Antranilico Acido ascorbico (o Vitamina C) Acido Folico (o Folacina o Vitamina M) Acido Lipoico (o Acido Tiottico o Vitamina N) Antocianine (o Antociani) Bioflavonoidi o (Flavonoidi o Vitamina C2) Caffeina L-Carnitina Carotenoidi Coenzima Q-10 (o Ubichinone o Vitamina Q) Colina (o Vitamina J) Creatina D-ribosio Ficocianine Fruttosio Glucosammina Inositolo (o Vitamina B7) Isoflavoni Licopene Lievito di birra Maltodestrine Octacosanolo Picnogenolo Policosanoli Proantocianidine (o PAC) Probiotici Resveratrolo Sali minerali (Calcio Cromo Fluoro Fosforo Iodio Magnesio Potassio Ferro Selenio Sodio Zinco) Steroli vegetali (o Fitosteroli) Taurina Teanina Teina Triptofano Vitamine 5-HTP (5-idrossitriptofano)
Lipid replacement therapy
NTFactorreg a lipid replacement oral
supplement containing phospholipids phosphoglycolipids cardiolipids
and other membrane lipids
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Fatigue and the nutritional approaches
At the organism level cancer-associated fatigue involves the dysregulation of several interrelated physiological
biochemical and psychological systems At the tissue and cellular levels fatigue is
related to reductions in the efficiency of cellular energy systems mainly found in mitochondria
Oxidative stress intracellular excess of reactive oxygen (ROS) and nitrogen (RNS) free radical species over intracellular antioxidants It results in oxidation of cellular structures such as membrane lipids and proteins and
mutation of nuclear DNA Maes M (2009) Inflammatory and oxidative and nitrosative
stress pathways underpinning chronic fatigue somatization and psychosomatic symptoms Current Opinions in Psychiatry 22 75ndash83
ROSRNS damage
Membrane oxidation induces permeability changes in mitochondria and this
loss of electron transport function essential requirement of mitochondrial oxidative phosphorylation (ATP)
I Nutraceutici Acidi grassi polinsaturi essenziali (Omega 3
Omega 6) Acido Antranilico Acido ascorbico (o Vitamina C) Acido Folico (o Folacina o Vitamina M) Acido Lipoico (o Acido Tiottico o Vitamina N) Antocianine (o Antociani) Bioflavonoidi o (Flavonoidi o Vitamina C2) Caffeina L-Carnitina Carotenoidi Coenzima Q-10 (o Ubichinone o Vitamina Q) Colina (o Vitamina J) Creatina D-ribosio Ficocianine Fruttosio Glucosammina Inositolo (o Vitamina B7) Isoflavoni Licopene Lievito di birra Maltodestrine Octacosanolo Picnogenolo Policosanoli Proantocianidine (o PAC) Probiotici Resveratrolo Sali minerali (Calcio Cromo Fluoro Fosforo Iodio Magnesio Potassio Ferro Selenio Sodio Zinco) Steroli vegetali (o Fitosteroli) Taurina Teanina Teina Triptofano Vitamine 5-HTP (5-idrossitriptofano)
Lipid replacement therapy
NTFactorreg a lipid replacement oral
supplement containing phospholipids phosphoglycolipids cardiolipids
and other membrane lipids
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
At the organism level cancer-associated fatigue involves the dysregulation of several interrelated physiological
biochemical and psychological systems At the tissue and cellular levels fatigue is
related to reductions in the efficiency of cellular energy systems mainly found in mitochondria
Oxidative stress intracellular excess of reactive oxygen (ROS) and nitrogen (RNS) free radical species over intracellular antioxidants It results in oxidation of cellular structures such as membrane lipids and proteins and
mutation of nuclear DNA Maes M (2009) Inflammatory and oxidative and nitrosative
stress pathways underpinning chronic fatigue somatization and psychosomatic symptoms Current Opinions in Psychiatry 22 75ndash83
ROSRNS damage
Membrane oxidation induces permeability changes in mitochondria and this
loss of electron transport function essential requirement of mitochondrial oxidative phosphorylation (ATP)
I Nutraceutici Acidi grassi polinsaturi essenziali (Omega 3
Omega 6) Acido Antranilico Acido ascorbico (o Vitamina C) Acido Folico (o Folacina o Vitamina M) Acido Lipoico (o Acido Tiottico o Vitamina N) Antocianine (o Antociani) Bioflavonoidi o (Flavonoidi o Vitamina C2) Caffeina L-Carnitina Carotenoidi Coenzima Q-10 (o Ubichinone o Vitamina Q) Colina (o Vitamina J) Creatina D-ribosio Ficocianine Fruttosio Glucosammina Inositolo (o Vitamina B7) Isoflavoni Licopene Lievito di birra Maltodestrine Octacosanolo Picnogenolo Policosanoli Proantocianidine (o PAC) Probiotici Resveratrolo Sali minerali (Calcio Cromo Fluoro Fosforo Iodio Magnesio Potassio Ferro Selenio Sodio Zinco) Steroli vegetali (o Fitosteroli) Taurina Teanina Teina Triptofano Vitamine 5-HTP (5-idrossitriptofano)
Lipid replacement therapy
NTFactorreg a lipid replacement oral
supplement containing phospholipids phosphoglycolipids cardiolipids
and other membrane lipids
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Oxidative stress intracellular excess of reactive oxygen (ROS) and nitrogen (RNS) free radical species over intracellular antioxidants It results in oxidation of cellular structures such as membrane lipids and proteins and
mutation of nuclear DNA Maes M (2009) Inflammatory and oxidative and nitrosative
stress pathways underpinning chronic fatigue somatization and psychosomatic symptoms Current Opinions in Psychiatry 22 75ndash83
ROSRNS damage
Membrane oxidation induces permeability changes in mitochondria and this
loss of electron transport function essential requirement of mitochondrial oxidative phosphorylation (ATP)
I Nutraceutici Acidi grassi polinsaturi essenziali (Omega 3
Omega 6) Acido Antranilico Acido ascorbico (o Vitamina C) Acido Folico (o Folacina o Vitamina M) Acido Lipoico (o Acido Tiottico o Vitamina N) Antocianine (o Antociani) Bioflavonoidi o (Flavonoidi o Vitamina C2) Caffeina L-Carnitina Carotenoidi Coenzima Q-10 (o Ubichinone o Vitamina Q) Colina (o Vitamina J) Creatina D-ribosio Ficocianine Fruttosio Glucosammina Inositolo (o Vitamina B7) Isoflavoni Licopene Lievito di birra Maltodestrine Octacosanolo Picnogenolo Policosanoli Proantocianidine (o PAC) Probiotici Resveratrolo Sali minerali (Calcio Cromo Fluoro Fosforo Iodio Magnesio Potassio Ferro Selenio Sodio Zinco) Steroli vegetali (o Fitosteroli) Taurina Teanina Teina Triptofano Vitamine 5-HTP (5-idrossitriptofano)
Lipid replacement therapy
NTFactorreg a lipid replacement oral
supplement containing phospholipids phosphoglycolipids cardiolipids
and other membrane lipids
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
ROSRNS damage
Membrane oxidation induces permeability changes in mitochondria and this
loss of electron transport function essential requirement of mitochondrial oxidative phosphorylation (ATP)
I Nutraceutici Acidi grassi polinsaturi essenziali (Omega 3
Omega 6) Acido Antranilico Acido ascorbico (o Vitamina C) Acido Folico (o Folacina o Vitamina M) Acido Lipoico (o Acido Tiottico o Vitamina N) Antocianine (o Antociani) Bioflavonoidi o (Flavonoidi o Vitamina C2) Caffeina L-Carnitina Carotenoidi Coenzima Q-10 (o Ubichinone o Vitamina Q) Colina (o Vitamina J) Creatina D-ribosio Ficocianine Fruttosio Glucosammina Inositolo (o Vitamina B7) Isoflavoni Licopene Lievito di birra Maltodestrine Octacosanolo Picnogenolo Policosanoli Proantocianidine (o PAC) Probiotici Resveratrolo Sali minerali (Calcio Cromo Fluoro Fosforo Iodio Magnesio Potassio Ferro Selenio Sodio Zinco) Steroli vegetali (o Fitosteroli) Taurina Teanina Teina Triptofano Vitamine 5-HTP (5-idrossitriptofano)
Lipid replacement therapy
NTFactorreg a lipid replacement oral
supplement containing phospholipids phosphoglycolipids cardiolipids
and other membrane lipids
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
I Nutraceutici Acidi grassi polinsaturi essenziali (Omega 3
Omega 6) Acido Antranilico Acido ascorbico (o Vitamina C) Acido Folico (o Folacina o Vitamina M) Acido Lipoico (o Acido Tiottico o Vitamina N) Antocianine (o Antociani) Bioflavonoidi o (Flavonoidi o Vitamina C2) Caffeina L-Carnitina Carotenoidi Coenzima Q-10 (o Ubichinone o Vitamina Q) Colina (o Vitamina J) Creatina D-ribosio Ficocianine Fruttosio Glucosammina Inositolo (o Vitamina B7) Isoflavoni Licopene Lievito di birra Maltodestrine Octacosanolo Picnogenolo Policosanoli Proantocianidine (o PAC) Probiotici Resveratrolo Sali minerali (Calcio Cromo Fluoro Fosforo Iodio Magnesio Potassio Ferro Selenio Sodio Zinco) Steroli vegetali (o Fitosteroli) Taurina Teanina Teina Triptofano Vitamine 5-HTP (5-idrossitriptofano)
Lipid replacement therapy
NTFactorreg a lipid replacement oral
supplement containing phospholipids phosphoglycolipids cardiolipids
and other membrane lipids
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Lipid replacement therapy
NTFactorreg a lipid replacement oral
supplement containing phospholipids phosphoglycolipids cardiolipids
and other membrane lipids
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Ellithorpe R R Settineri R amp Nicolson G L (2003) Reduction of fatigue by use of a dietary supplement containing glycophospholipids Journal of the American Nutraceutical Association 6(1) 23ndash28
NTFactor in patients with severe chronic fatigue
reduce their fatigue by approximately 405 in 8 weeks
405
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Nicolson G L Ellithorpe et al Lipid replacement therapy with a glycophospholipidndash antioxidantndashvitamin formulation significantly reduces fatigue within one week Journal of the American Nutraceutical Association 13(1) 11ndash15 2010
NTFactor plus vitamins minerals and other supplements
resulted in a 368 reduction in fatigue within 1 week
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Safety Tolerability and Symptom Outcomes Associated with L-Carnitine Supplementation in Patients with Cancer Fatigue and Carnitine Deficiency A Phase III Study Ricardo A Cruciani 2006 Journal of Pain and Symptom Management
L-carnitine a micronutrient
important for the processing of long-chain fatty acids and energy production in mammalian cells
Dose escalation proceeded through all dose
levels (250 750 1250 1750 2250 2750 and 3000 mgdayrespectively)
mild nausea no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Pharmacologic Treatment of Cancer-Related Fatigue Jennifer K Carroll The Oncologist 20071243-51
L-carnitine three studies open-label prospective designs with 12ndash50
participants Treatment with l-carnitine (500ndash600 mgday) for 1ndash4
weeks RESULTS increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life measures
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Efficacy of l-carnitine administration on fatigue nutritional status oxidative stress and related quality of life in 12 advanced cancer patients undergoing anticancer therapy Giulia Gramignano Nutrition Volume 22 February 2006
12 patients advanced tumors (50 at stage IV) mean age 60 y range 42ndash73 antineoplastic treatment L-Carnitina was administered orally at 6 gd for 4 wk outcome measures fatigue and quality of life in
relation to oxidative stress nutritional status and laboratory variables (reactive oxygen species glutathione peroxidase and proinflammatory cytokines)
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Giulia Gramignano Nutrition Volume 22 February 2006
RESULTS Fatigue decreased significantly Nutritional variables (lean body mass and appetite)
increased significantly Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not significantly
Proinflammatory cytokines did not change significantly
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Reversing mitochondrial dysfunction fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy Clin Exp Metastasis (2008) 25161ndash169 Garth L Nicolson AElig Kenneth A Conklin
Chemotherapy can displace important mitochondrial cofactors such as CoQ10
The concurrent administration of CoQ10 during chemotherapy can affect both acute and chronic cardiotoxicity caused by anthracyclines
Acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors such as coenzyme Q10
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Neuro Endocrinol Lett 2005 Dec26(6)745-51 In chronic fatigue syndrome the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes M Mihaylova I Leunis JC
omega3 poly-unsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA) CFS was accompanied by increased levels of omega6
PUFAs linoleic acid arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs) ie oleic acid
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
ω6-PUFA ω3-PUFA
Acido Linoleico Acido Linolenico
Acido Arachidonico Acido Eicosapentaenoico e decosaesaenoico
Lipoossigenasi Cicloossogenasi
LT Serie 5
Prostanoidi Serie 3
Diminuzione attivazione piastrine Vasodilatazione
Inibizione cascata infiammazione
Fosfolipidi di membrana
Ac Arachidonico libero
Lipoossigenasi
Cicloossogenasi LT
Serie 4 Prostanoidi
Serie 2
Fosfolipasi A2 e C
Prostanoidi Serie 3
PG serie 2
TX Serie 2
Immuno- soppressione Radicali Liberi Carcinogenesi
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Neuro Endocrinol Lett 2005 Dec26(6)745-51 Maes M Mihaylova I Leunis JC
Results decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS
The results suggest that patients with CFS should
respond favourably to treatment with omega3 PUFAs such as EPA and DHA
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Serotonin and central nervous system fatigue nutritional considerations J Mark Davis Am J Clin Nutr 200072(suppl)573Sndash8S
Increases in brain 5-HT concentration have been associated with increased physical and perhaps mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Cochrane Database of Systematic Reviews 2012
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Types of participants
Adults 18 years or older Advanced progressive illness Clinically significant fatigue andor weight loss in the
latter stages of illness degenerative neurological conditions such as
multiple sclerosis Parkinsonrsquos disease and dementia
irreversible organ failure cancer with distant metastasis acquired immune deficiency syndrome
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Cancer - identified five systematic reviews (116 studies with 17342 participants) bull pharmacological interventions eicosapentaenoic acid (EPA) amantadina carnitinaeritropoietina bull non pharmacological interventions exercise physical training medically assisted hydration psychosocial interventions
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Types of outcome measure
Primary outcomes 1 Clinically significant improvements in fatigue 2 Improvements in quality of life 3 Withdrawals due to adverse events
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Cancer fatigue Pharmacological interventions RESULTS
Dewey 2007 (five studies 587 participants) failed to provide sufficient evidence of a benefit to
the use of EPA (ac Eicosapentaenoico) over placebo for the management of fatigue in advanced cancer
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Cancer fatigue Pharmacological interventions RESULTS Minton 2008 (51 studies 10296 participants) small but significant improvement in fatigue over
placebo with the psychostimulant drug methylphenidate
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Cancer fatigue Pharmacological interventions RESULTS
Glaspy 2010 Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or placebo
they are no longer recommended in practice for this use especially if haemoglobin concentration is above 12 gdL
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Cancer fatigue Pharmacological interventions RESULTS
No benefits over placebo were seen for fatigue with the use of the antidepressant drug paroxetine nor with progestational steroids
Megestrol acetate can provide a small statistically
significant weight gain for people with cancer versus placebo
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Cancer fatigue Non pharmacological interventions RESULTS Cramp 2008 (28 studies 2083 participants) supported the use of exercise in the management
of cancer related fatigue No recommendations can be made for specific
exercise interventions that might best manage fatigue in advanced stages of cancer
The optimal management of fatigue is likely to be different for those in the advanced stages of
a non curative illness as compared with those who are in the early stages of chronic disease
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Cancer fatigue Non pharmacological interventions RESULTS
Goedendorp 2009 (27 studies with 3324 participants) For people undergoing cancer treatment at any
disease stage found Insufficient evidence that psychosocial
interventions were beneficial for fatigue management
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it
Irsquom so Tired Biological and Genetic Mechanisms of Cancer related Fatigue Andrea Barsevick PhD Qual Life Res 2010 December 19(10) 1419ndash1427 As the science continues
to progress toward individualized medicine understanding the genetic dimensions of CRF will become increasingly important
in order to identify persons at risk for this debilitating symptom as well as targets
for intervention to alleviate it