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The editor has compiled this formulary as a list of treatment regimens, which are intended to be a guide to baseline chemotherapy only. It is neither a legal nor a

prescriptive document and should not be utilised in anyway as a formal guide to prescribing.

Author: North Wales Cancer NetworkEditor: Tracy Parry, Lead Network PharmacistVersion: 2.1Approved by: C&D NHS Trust D&T, NEWT D&T, NWWT D&T

committeesDate approved:Review date: March 2010

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North Wales Cancer Network

Chemotherapy Protocols -2008/9

INTRODUCTION 3

BREAST CANCER 3

OESOPHAGEAL AND OESOPHAGO-GASTRIC CANCER 3

PANCREATIC CANCER 3

ANAL CANCER 3

COLORECTAL CANCER 3

OVARIAN CANCER 3

ENDOMETRIAL CANCER 3

CERVICAL CANCER 3

SMALL CELL LUNG CANCER 3

NON-SMALL CELL LUNG CANCER 3

MESOTHELIOMA CHEMOTHERAPY REGIMENS 3

HEAD AND NECK CANCER 3

BLADDER CANCER 3

CHOLANGIOCARCINOMA 3

RENAL CANCER 3

PROSTATE CANCER 3

TESTICULAR CANCER 3

MALIGNANT MELANOMA 3

SARCOMAS 3

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GASTRO-INTESTINAL STROMAL TUMOURS 3

APPENDIX I 3

PREPARATION OF A CLINICAL CASE 3PHARMACY ASSESSMENT 3CAPACITY ASSESSMENT (DAY TREATMENT UNIT) 3PRESENTATION TO THE NETWORK FORMULARY GROUP 3COMMISSIONING ASSESSMENT 3FURTHER WORK 3D+T COMMITTEES 3OTHER TRUST COMMITTEES 3APPEAL MECHANISM 3TABLE 1 MEMBERSHIP OF NETWORK FORMULARY GROUP 3

APPENDIX II 3

APPENDIX III 3

APPENDIX IV 3

APPENDIX IV 3

APPENDIX VI 3

APPENDIX VII 3

HIGHLY EMETOGENIC REGIMENS 3MODERATELY EMETOGENIC REGIMENS 3LOW EMETOGENIC REGIMENS 3DELAYED EMESIS 3EMESIS LEADING TO ADMISSION 3ANTICIPATORY EMESIS 3

APPENDIX VIII 3

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INTRODUCTIONThis list of protocols for the drug treatment of cancer has been compiled, with the active contribution of the oncology clinicians and the lead oncology pharmacists in the three trusts in North Wales, with the aim of:

Identifying the core regimen used for the most common forms of cancer Informing Trusts and commissioners of the baseline utilisation of chemotherapy Acting as an agreed dispensing formulary for pharmacists in terms of the diseases and

application of drugs therein Providing uniform access to cancer treatment for patients across North Wales.

The editor has compiled this formulary as a list of treatment regimens, which are intended to be a guide to baseline chemotherapy only. It is neither a legal nor a prescriptive document and should not be utilised in anyway as a formal guide to prescribing.

This list contains the regimens, which are available for use during the year beginning April 1st 2008 to March 31st 2009.

The formulary largely concentrates on regimens used as first and second line. The formulary recognises that third line or individualised use of chemotherapy is more difficult to standardise and this therefore is not included.

Future inclusions

It is hoped that future versions will include sections on:

Haemato-oncology chemotherapy Treatment and prophylaxis of neutropenic sepsis Use of blood products Use of growth factors Extravasation policy

New drugs

The formulary will be reviewed annually .The North Wales Cancer Network formulary group will oversee the revision and implementation of the formulary across North Wales. New submissions to the formulary will be scrutinised by the group following the process in Appendix I.

Inevitable situations will arrive that are not covered by the standard North Wales Cancer network regimens. These may include expensive drugs or combinations prior to a NICE appraisal or not in the NICE or AWMSG appraisal programme.

Consultants who wish to use a non-protocol regimen should apply to their local Drugs and Therapeutic Committee for clinical approval. Once achieved they should then refer to their Directorate or Division to achieve funding.

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If funding is unavailable within the Directorate or Division then a submission can be made to individual commissioners but should emanate from the Directorate or Divisional leads not the individual clinician.

Resource Issues.

All the regimens within this formulary should be funded and this includes all NICE drugs approved up to the point of publication December 2009.

However though all the regimens are funded and therefore available it cannot be automatically assumed that all the regimens can be delivered. Clinicians are advised that they must ensure that the regimen in question is deliverable within the identified clinical environment before they offer it to the patient.

In light of this both clinicians and managers are advised to use this formulary as a basis for identifying which chemotherapy regimen should be available to patients in North Wales. In doing so, these regimens should be available in all three Trusts assuming clinical governance and capacity parameters are met.

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BREAST CANCER

Neo-adjuvant

EC/DOCETAXEL

Patient group: Standard 1st line regimen.

Chemotherapy: EC x 4 cycles followed by Docetaxel x 4 cycles

EC

Patient Group: For patients with locally advanced disease, or to allow less radical surgery in patients with operable tumours.If limited response after 2 to 3 cycles, consider switching to Docetaxel

Chemotherapy: Epirubicin 75mg/m2 i.v. bolus over 3-5 minutes Day 1Cyclophosphamide 600mg/m2 i.v. bolus over 3-5 minutes Day 1

Repeated at 21 day intervals for 4-6 cycles

Anti-emetics: High emetic potential

Investigations:

Weight, FBC, U&E’s, LFT’s before each cycle LV ejection fraction prior to first cycle if patient has history of cardiac problems.

Risk of cardiomyopathy increases with cumulative epirubicin dose of > 900mg/m2

Where renal/hepatic function is abnormal, treatment is at consultant physician discretion.

Dose Modifications:

Epirubicin - Moderate liver impairment (bilirubin: 1.4-3 mg/100ml) give 50% of the dose, severe impairment (bilirubin> 3 mg/100 ml) give 25% of the dose.

Additional Information: Red discolouration of urine may occur for 1-2 days after administration.

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DOCETAXEL

Pre-medication: Dexamethasone 8mg po twice daily for 3 days starting the day before treatment. Required for all cycles.

Chemotherapy: Docetaxel 100mg/m2 i.v. infusion over 60 mins Day 1

Repeat every 21 days for 4 cycles

Additional Medication: Ciprofloxacin 500mg po twice daily for 7 days starting on day 5

Anti-emetic: Moderate emetic potential

Investigations:

Weight, FBC, U&E’s, LFT’s before each cycle. Where renal/hepatic function is abnormal, treatment is at consultant physician

discretion.

Dose modification:

Neutrophils < 1.0 x 109/L defer dosePlatelets < 100 x 109/L defer doseAST or ALT > 1.5 x upper limit normal reduce dose by 25%

> 3.5 x upper limit normal discontinue

Non-haematological toxicities (excluding alopecia):if necessary delay treatment by one or more weeks until recovery to grade 0 or 1; if recovery takes longer than one week or if toxicity of grade 3+ is documented during chemotherapy, the dose should be reduced by 20% in all subsequent cycles.

Docetaxel: If ALT/AST > 1.5 x ULN and ALP 2.5 x ULN give 75% of dose. If bilirubin > 22μmol/L +/- ALT/AST> 3.5 x ULN with ALP > 6 x ULN contraindicated.

1. P Piedbois et al Annals of Oncology 2007 18(1):52-57 2. von Minckwitz G, Raab G, Caputo A, et al. (2005) Doxorubicin with cyclophosphamide followed by docetaxel every 21 days compared with doxorubicin and docetaxel every 14 days as preoperative treatment in operable breast cancer: the GEPARDUO study of the German

Breast Group. J Clin Oncol 23:2676–2685

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EC/DOCETAXEL/TRASTUZUMAB

Patient group: Patients with locally advanced breast cancer that are HER2 positive

(T3N1 or T4; any T + N2 or N3 or + ipsilateral supraclavicular node involvement) ECOG PS 0-1 and have a satisfactory LVEF.

Anti-emetics: High emetic potential (cycles 1-4) and moderately emetogenic (cycles 5-8)

Additional Medication: Prophylactic ciprofloxacin 500mg po twice daily for 7 days starting on day

5 of the cycle. (For cycles 5-8 inclusive)

Investigations:

Weight, FBC, U&E’s, LFT’s and renal function before each cycle LV ejection fraction prior to first cycle and then as per cardiac guidelines. Where renal/hepatic function is abnormal, treatment is at consultant

physician discretion.

Dose Modifications:

Epirubicin: Moderate liver impairment (bilirubin: 1.4-3 mg/100ml) give 50% of the dose,

severe impairment (bilirubin> 3 mg/100 ml) give 25% of the dose.

Pre-medication: Dexamethasone 8mg po twice daily for 3 days starting the day before treatment with Docetaxel (cycle 5,6,7and 8)

Chemotherapy: Epirubicin 75mg/m2 i.v. bolus over 3-5 minutes Day 1Cyclophosphamide 600mg/m2 i.v. bolus over 3-5 minutes Day 1Repeated at 21 day intervals for 4 cycles

Followed by:Docetaxel 100mg/m2 i.v. infusion over 60 mins Day 1 cycle 5Trastuzumab 8mg/kg (loading dose) in 250ml sodium chloride 0.9% infusion over 90 minutes.Docetaxel 100mg/m2 i.v. infusion over 60 mins Day 1 cycle 6,7 &8Trastuzumab 6mg/kg (loading dose) in 250ml

sodium chloride 0.9% infusion over 90 minutes.Repeated at 21 day intervals

Surgery followed by:Trastuzumab 8mg/kg (loading dose) in 250ml Day 1 cycle 9sodium chloride 0.9% infusion over 90 minutes.

Trastuzumab 6mg/kg (loading dose) in 250ml Day 1 cycle 10 - 22sodium chloride 0.9% infusion over 90 minutes.

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Docetaxel: Neutrophils < 1.0 x 109/L defer dose

Platelets < 100 x 109/L defer doseAST or ALT > 1.5 x upper limit normal reduce dose by 25%

> 3.5 x upper limit normal discontinue


If ALT/AST > 1.5 x ULN and ALP 2.5 x ULN give 75% of dose. If bilirubin > 22μmol/L +/- ALT/AST> 3.5 x ULN with ALP > 6 x ULN contraindicated.

1. Gianni L, Eiermann. W, et al Neo-adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer: primary efficacy analysis of the NOAH trial. San Antonio Breast Cancer Symposium 2008. Abstract 31.

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AdjuvantEPI-CMF (E-CMF)

Patient group: Epi-CMF is standard for all breast patients except node positive tumours who are offered FEC/Docetaxel

Chemotherapy: Epirubicin 100mg/m2 i.v. bolus over 3-5 minutes Day 1

Repeated at 21 day intervals for 4 cycles

Followed by CMF 4 cycles (Classical Bonnadonna) Anti-emetic: High emetic potential

Investigations: Weight, FBC, U&E’s, LFT’s before each cycle LV ejection fraction prior to first cycle if patient has history of cardiac problems.



Dose Modifications: Epirubicin - Moderate liver impairment (bilirubin: 1.4-3 mg/100ml) give 50%

of the dose, severe impairment (bilirubin> 3 mg/100 ml) give 25% of the dose.

Additional Information: Red discolouration of urine may occur for 1-2 days after administration.

Chemotherapy: CMF*Cyclophosphamide 100mg/m2 po Days 1 to 14Methotrexate 40mg/m2 i.v. bolus Days 1 and 85-fluorouracil 600mg/m2 i.v. bolus Days 1 and 8

*for patients unable to tolerate oral cyclophosphamide, substitute i.v. cyclophosphamide 600mg/m2 days 1 and 8

Repeated at 28 day intervals to a total 4 cycles if Epi-CMF and 6 cycles if CMF ALONE

Additional Medication: Folinic acid rescue not normally required unless patients

develop signs of methotrexate toxicity, then 15mg p.o. 6 hourly x 6 doses starting 24 hours post methotrexate with subsequent cycles.

Anti-emetic High emetic potential

Investigations: Weight, FBC, U&E’s, LFT’s before each cycle and FBC on day 8.

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Where renal/hepatic function is abnormal, treatment is at consultant physician discretion, but methotrexate is hazardous in the presence of renal insufficiency and presence of third space fluids.

Dose modification:

WBC ≤3.0 x 109/L and neutrophils ≤1.0 x 109/L or platelets 100 x 109/L:- delay day 1 treatment by one week (EPI)- cancel day 8 treatment but continue oral cyclophosphamide if possible.

(CMF)Grade 3 mucositis (EPI)- reduce dose of epirubicin by 20%Neutropenic sepsis (EPI)- reduce dose of epirubicin and/or cyclophosphamide by 20%

or consider G-CSF support to maintain ≥ 85% dose intensity

Cyclophosphamide: Not recommended in patients with bilirubin >17μmol/L or serum transaminases or ALP 2-3 x ULNGFR (ml/min) Dose>50 100%10-50 75%<10 50%

Methotrexate: If bilirubin 53-84 μmol/L or AST> 180 give 75% of dose, if bilirubin >85 μmol/L omit.Cr Cl (ml/min) Dose>80 100%60 65%45 50%<30 Contraindicated

Additional therapy and information:

Patients on sequential chemotherapy who require adjuvant radiotherapy should have this after epirubicin and during CMF (between cycles 1 & 2) or at the discretion of the clinical oncologist.Patients may or may not have adjuvant hormonal therapy upon completion of chemotherapy.

1. Bonnadonna G et al. JAMA 1995; 273(7): 542-72. National Breast Cancer Study of Epirubicin + CMF vs Classical CMP Adjuvant Therapy, CRC BR3014

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FEC 75

Patient group: PS 0-1Older patientsUnsuitable for Epi-CMF

Chemotherapy:5-fluorouracil 600mg/m2 i.v. bolus over 3-5 minutes Day 1Epirubicin 75mg/m2 i.v. bolus over 3-5 minutes Day 1Cyclophosphamide 600mg/m2 i.v. bolus over 3-5 minutes Day 1

Repeat at 21-day intervals for 6 cyclesAdditional Medication: Prophylactic ciprofloxacin 500mg po twice daily days 8 - 14

Anti-emetic: High emetic potential

Investigations: Weight, FBC, U&E’s, LFT’s before each cycle. LV ejection fraction prior to first cycle if patient has history of cardiac problems.



Dose Modifications:

Epirubicin: Moderate liver impairment (bilirubin: 1.4-3 mg/100ml) give 50% of the dose, severe impairment (bilirubin> 3 mg/100 ml) give 25% of the dose.


Additional Information: Red discolouration of urine may occur for 1-2 days after administration

1. Early Breast Cancer Trialists Collaborative Group. Lancet 1998; 352: 930-422. Levine MN, Bramwell VH, Pritchard KL et al. J Clin Oncol 1998; 16: 2651-83 .Bonneterre J et al. Epirubicin increases long-term survival in adjuvant chemotherapy with poor-prognosis, node positive, early

breast cancer: 10-year follow-up results of the French Adjuvant Study group 05 randomised trial. JCO 2005; 23: 2686 – 26934. French Adjuvant Study Group. Benefit of a high-dose epirubicin regimen in adjuvant chemotherapy for node-positive breast cancer

patients with poor prognostic factors: 5 year follow-up results of French Adjuvant Study Group 05 randomized trial. JCO 2001; 19: 602 – 611

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FEC/DOCETAXEL

Patient group: As per NICE guidance High risk Node positive PS 0 – 1

Chemotherapy: 5-fluorouracil 500mg/m2 i.v. bolus over 3-5 minutes Day 1Epirubicin 100mg/m2 i.v. bolus over 3-5 minutes Day 1Cyclophosphamide 500mg/m2 i.v. bolus over 3-5 minutes Day 1


Repeat at 21-day intervals for 3 cycles

followed by


Chemotherapy: Docetaxel 100mg/m2 i.v. infusion over 60 minutes Day 1

Repeat for 3 cycles at 21-day intervals

Additional Medication: Prophylactic ciprofloxacin 500mg po twice daily for 7 days starting day 5


Investigations: Weight, FBC, U&E’s, LFT’s before each cycle. LV ejection fraction prior to first cycle if patient has history of cardiac problems.



Dose Modifications:

Neutrophils < 1.0 x 109/L defer dosePlatelets < 100 x 109/L defer doseAST or ALT > 1.5 x upper limit normal reduce dose by 25%

> 3.5 x upper limit normal discontinue Epirubicin: Moderate liver impairment (bilirubin: 1.4-3 mg/100ml) give 50% of

the dose, severe impairment (bilirubin> 3 mg/100 ml) give 25% of the dose.

Cyclophosphamide: Not recommended in patients with bilirubin >17μmol/L or serum transaminases or ALP 2-3 x ULN

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GFR (ml/min) Dose>50 100%10-50 75%<10 50%

Docetaxel: If ALT/AST > 1.5 x ULN and ALP 2.5 x ULN give 75% of dose. If bilirubin > 22μmol/L +/- ALT/AST> 3.5 x ULN with ALP > 6 x ULN contraindicated.Non-haematological toxicities (excluding alopecia):if necessary delay treatment by one or more weeks until recovery to grade 0 or 1; if recovery takes longer than one week or if toxicity of grade 3+ is documented during chemotherapy, the dose should be reduced by 20% in all subsequent cycles.

1. Roche H et al.Breast Cancer Res Treat, 2004; abstract 270; 88 supl 1:S16

TRASTUZAMAB14

Patient profile: Women with primary breast cancer who Over expressing HER-2 (3+ on IHC or FISH +) Completed (neo)adjuvant chemotherapy within the preceding 6 weeks After completion of adjuvant radiotherapy LVEF measured by echocardiography or MUGA ≥ 55% ER+ women to be receiving appropriate hormonal therapy Willing to undergo cardiac monitoring and regular follow up No history of allergy to mice or mouse proteins

Chemotherapy: Trastuzumab Initial dose: 8mg/kg i.v. infusion over 90 minutes Subsequent dose: 6mg/kg

Repeat every 21 days for 18 doses. Reload if dose delayed by > 7 days.

NB: Patients should be observed for at least 6 hours after the start of the first infusion and for 2 hours after the start of the subsequent infusions for symptoms like fever and chills or other infusion-related symptoms. These symptoms are usually mild to moderate in severity, and occur infrequently with subsequent Herceptin infusions. Interruption of the infusion may help control such symptoms. The infusion may be resumed when symptoms abate.

Anti-emetic: Low emetic potential

Investigations: Weight, FBC, U&E and LFT before each cycle LVEF before treatment and then 3 monthly

Dose Modifications:No reductions in the dose of Herceptin were made during clinical trials

1.National Institute for Health and Clinical Excellence.bTrastuzumab for the adjuvant treatment of early stage HER2-positive Breast Cancer. TA107; August 20062. SPC Herceptin

TCH

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Patient group: High-risk breast cancer in the adjuvant setting where anthracycline in contraindicated.HER2 +ve


Chemotherapy: Docetaxel 75mg/m2 i.v. infusion over 60 minutes Day 1Carboplatin AUC 6 i.v. infusion over 60 minutes Day 1


Trastuzumab loading dose: 8mg/kg i.v. infusion over 90 minutes Day 1Maintenance: 6mg/kg


Repeat every 21 days for 18 dosesAdditional Medication: Prophylactic ciprofloxacin 500mg po twice daily days 5 - 14


Investigations: LV ejection fraction prior to first cycle Cardiac function should be monitored after 3 months during treatment. Weight, U&E’s, FBC, creatinine clearance, LFT’s before each cycle Where renal/hepatic function is abnormal, treatment is at consultant

physician discretion

Dose modifications: Carboplatin: Adjust dose using Calvert formula. Contraindicated if Cr Cl <

20ml/min Neutrophils < 1.0 x 109/L defer dose

Platelets < 100 x 109/L defer doseAST or ALT > 1.5 x upper limit normal reduce dose by 25%

> 3.5 x upper limit normal discontinue Non-haematological toxicities (excluding alopecia):if necessary delay treatment by

one or more weeks until recovery to grade 0 or 1; if recovery takes longer than one week or if toxicity of grade 3+ is documented during chemotherapy, the dose should be reduced by 20% in all subsequent cycles.

1. BCIRG06 data

TC

Patient group: Operable Stage I to III invasive breast cancer.

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Adjuvant chemotherapy for patients in whom an anthracycline based regimen (TAC or FEC-T) is contra-indicated or who have a second primary breast cancer previously treated with an anthracycline and are HER2 negative. PS 0-1


Chemotherapy: Docetaxel 75mg/m2 i.v. infusion over 60 minutes Day 1Cyclophosphamide 600mg/m2 i.v. bolus over 3-5 minutes Day 1

Repeat every 21 days for 6 cyclesAdditional Medication: Prophylactic ciprofloxacin 500mg po twice daily days 5 – 14.

Consider G-csf support if necessary.


Investigations: U&E, renal function, LFT, FBC, at start of each cycle Where renal/hepatic function is abnormal, treatment is at consultant


Toxicities: Hypersensitivity - infusion related reaction, Anaemia, Thrombocytopenia, Febrile neutropenia, Asthenia, Myalgia, Arthralgia, Stomatitis, Diarrhoea, Nausea, Vomiting, Phlebitis, Oedema, Fever and Infection.

Dose modifications:Neutrophils < 1.0 x 109/L defer dosePlatelets < 100 x 109/L defer doseAST or ALT > 1.5 x upper limit normal reduce dose by 25%

> 3.5 x upper limit normal discontinueFebrile neutropenia:1st occasion – 100% dose with GCSF support. If GCSF support already being provided or a second occurrence then give 75% dose plus GCSF support.



Cyclophosphamide: Not recommended in patients with bilirubin >17μmol/L or serum transaminases or ALP 2-3 x ULN

GFR (ml/min) Dose>50 100%10-50 75%<10 50%

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1. Jones SE et al Docetaxel With Cyclophosphamide Is Associated With an Overall Survival Benefit Compared With Doxorubicin and Cyclophosphamide: 7-Year Follow-Up of US Oncology Research Trial 9735 J Clin Oncol 2009

HORMONAL TREATMENTSWomen with oestrogen-receptor-positive tumours should be offered hormone treatment.

Adjuvant18

All clinicians prescribing adjuvant therapy should have access to Adjuvant! Online in the multidisciplinary meeting and in the clinic to give a prediction of absolute benefit.

Pre-menopausal women should have tamoxifen at a dose of 20 mg a day for at least 5 years. This remains the gold standard for pre-menopausal women. There is no evidence to support the continued use of tamoxifen after five years. Tamoxifen provides protection against bone fractures in postmenopausal women and it lowers serum cholesterol levels. However, long-term use of tamoxifen may be associated with vaginal bleeding, endometrial thickening, and increased risk of endometrial cancer and thromboembolic events.

Post-menopausal women should have tamoxifen at a dose of 20 mg a day for at least 5 years or an aromatase inhibitor (check Adjuvant Online for absolute benefit) .Anastrazole 1-mg tablet taken orally once daily for 5 years is an alternative to tamoxifen. Letrozole and exemestane are also options when patients have received prior tamoxifen and there is an indication to switch to an aromatase inhibitor.

When considering aromatase inhibitors a discussion with the patient regarding absolute benefit, balanced with potential side effects should take place. Side effects reported with Al include increase in the number of fractures due to osteoporosis, arthralgia and myalgia and potential cardiac problems. There are however fewer incidences of gynaecological side effects and thromboembolic events than with tamoxifen.

Primary Hormone Therapy

Primary hormone therapy is not a substitute for the established methods of surgery and radiotherapy, and should only be used first-line if the patient is very infirm or refuses surgery. Surgery with or without radiotherapy remains the treatment of choice for the majority of elderly patients.The indications for primary hormone therapy are:

Selected postmenopausal ER positive patients with operable breast cancer >4 cm size who express a strong desire to avoid masectomy, and in whom primary chemotherapy is considered unsuitable.

Patients with any tumour who are truly unfit for surgery or primary chemotherapy.

Patients who refuse surgery and in whom primary chemotherapy is considered unsuitable.

Patients with T4 breast cancer and in whom primary chemotherapy is considered unsuitable.

It is recommended that aromatase inhibitors are used in the first instance as these have proven to be more effective than tamoxifen.

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Anastrazole 1mg daily or letrozole 2.5mg daily should be used as first line therapy for patients who require primary hormone therapy.

Relapse following the use of either letrozole or anastrozole in either the adjuvant setting or as first line therapy, exemestane (or tamoxifen if not previously used) should be prescribed.

1. NICE Technology Appraisal 1122. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the

randomised trials. Lancet 351; 1451-1467, 1998 3. Phase 111 study of Letrozole versus tamoxifen as first line therapy of advanced breast cancer in

postmenopausal women: analysis of survival and update of efficacy from the International Letrozole breast Cancer group. J Clin Onc; 21(11), 2003, 2101-2109

4. Bonneterre J, Budzar A, Nabholtz JM et al. Anastrozole is superior to tamoxifen as first line therapy in hormone receptor advanced breast carcinoma.\Cancer 92:2247-2258, 2001

5. Nabholtz JM, Buzdar A, Pollak M, et al. Anastrozole is superior to Tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenterrandomized trial. J Clin Oncl, 2000 November; 18(22): 3758-3767

6. Buzdar A, Jonat W, Howell A, et al. Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: results of overview analysis of two phase III trials. J Clin Oncol, 1996 July; 14(7): 2000-2011

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Metastatic/Advanced disease

EC

Patient group: Standard chemotherapyAnthracycline naive

Chemotherapy: Epirubicin 75mg/m2 i.v. bolus over 3-5 minutes Day 1Cyclophosphamide 600mg/m2 i.v. bolus over 3-5 minutes Day 1

Repeat at 21-day intervals to a maximum of 6 cycles

Anti-emetics: Moderate emetic potential

Investigations: Weight, FBC, U&E’s, LFT’s before each cycle LV ejection fraction prior to first cycle if patient has history of cardiac problems.



Dose Modifications:




1. Fisher B et al. J Clin Oncol 1990; 8: 2483-962. UKCCCR ABO1 Breast Cancer trial (1996)

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EPIRUBICIN

Patient group: For patients with compromised liver or marrow function due to tumour infiltration.Combination therapy inappropriate

Chemotherapy: Epirubicin 20mg/m2 i.v. bolus over 3-5 minutes Day 1

Repeat weekly until evidence of non-response, disease progression or limited by cardiotoxicity risk


Investigations: Weight, FBC, U&E’s, LFT’s before each cycle. LV ejection fraction prior to cycle 1 if history of cardiac problems. Risk of

cardiomyopathy increases with cumulative epirubicin dose of > 900mg/m2

Normal limits for administration apply with the exception of patients with marrow infiltration. Treatment may be continued at lower platelet and neutrophil counts at treating physician’s discretion.

Dose Modifications:



1. Twelves CJ. Et al. British Journal of Cancer, 1989; 60(6): 938-412. Gasparini G. et al. Am J Clin Oncol 1991; 14(1): 38-443. Twelves CJ. Et al. Annals of Oncology 1991 2(9): 663-64. Jeonsuu H et al. J Clin Oncol, 1008; 16(12): 3720-30

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DOCETAXEL/CAPECITABINE

Patient group: Younger patient, NICE TA 62PS 0-1


Chemotherapy: Docetaxel 75mg/m2 i.v. infusion over 60 minutes on Day 1Capecitabine 1250mg/m2 p.o. twice daily Day 1-14Doses should be rounded to the nearest 150mg. Tablets should be swallowed with water within 30 minutes after a meal.

Repeat every 21 days. Max 6 -8 cycles.


Additional Medication: loperamide with detailed instructions on when and how to take them

Investigations: Weight, U&E’s, FBC, creatinine clearance, LFT’s before each cycle

Dose modifications: Capecitabine: CrCl (ml/min) Dose

>50 100%10-50 75%<10 50%


For grade 2 toxicity or higher: No recovery from toxicity within 2 weeks, discontinue docetaxel Capecitabine doses missed should not be replaced Toxicity > grade 2 still present at end of 3 week cycle should have a further delay of 1

week Doses that have been reduced in a previous cycle should not be increased

subsequently First event grade 2: delay until recovery (maximum 2 weeks) Second event grade 2: delay until recovery and restart at 75% capecitabine dose and

docetaxel at 55mg/m2

First event grade 3: delay until recovery and restart at 75% capecitabine dose and docetaxel 55mg/m2

Third event grade 2, second event grade 3, or any 4 event: discontinue docetaxel and restart capecitabine at 50% of starting dose.Further events, any grade: discontinue both drugs.

1. National Institute for Health and Clinical Excellence. Technology Apraisal no. 62 May 20032. O’Shaughnessy L et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline

pretreated patients with advanced breast cancer. J.Clin. Oncol. 2002;20(12):2812-28233. Wright TL, Twelves CJ. Eur J Cancer; 2002; 38(15): 1957-6

PACLITAXEL/GEMCITABINE

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Patient group: Less myelosuppressive than docetaxel/capecitabine Usually given after an anthracycline containing regimen PS = 0, 1, 2 May also be given third line after a vinorelbine containing regimen.

Pre-medication: To be given 30 minutes before paclitaxelDexamethasone 20mg i.v.Ranitidine 50mg i.v.Chlorphenamine 10mg i.v.

Chemotherapy: Paclitaxel 175mg/m2 i.v infusion over 3 hours Day 1

Gemcitabine 1250 mg/m2 i.v. infusion over 30-60 minutes Day 1 + 8

Repeat at 21-day intervals

Anti-emetic: Moderate emetic potential

Investigations: Weight, FBC, U&E, LFTs prior to each cycle Where renal/hepatic function are abnormal, treatment is at consultant


Dose Modifications:

Day 1: if WBC<3.0 x 109/L, or neutrophils<1.5 x 109/L or platelets<150 x 109/L, delay treatment one week

Day 8: if WBC<2.0 x 109/L or neutrophils<1.0 x 109/L or platelets<75 x 109/L, omit treatment

If grade 4 haematological toxicity occurs then reduce dose by 25% for subsequent cycles

Peripheral neurotoxicity may occur and severity < grade 3 is an indication to stop treatment.

1. National Institute for Health and Clinical Excellence. Technology Appraisal no.116 January 20072. Joensuu H et al. J Clin Oncol; 1998: 16(12): 3720-304. Smorenburg CH et al. Eur J Cancer; 2001; 37(18): 2310-235. Albain KS et al. Proceedings ASCO, 2004. 23:abstract 50165.6. Seidman AD et al. Proceedings ASCO 2004. 23 abstract 512.

PACLITAXEL (weekly)24

Patient group: 2nd or 3rd line therapyHeavily pre-treated patientsPS < 2

Pre-medication: To be given 30 minutes before paclitaxel:Dexamethasone 20mg i.v. Ranitidine 50mg i.v.Chlorphenamine 10mg i.v.

Chemotherapy: Paclitaxel 90mg/m2 i.v. infused over 1 hr Day 1

Repeat weekly for 12 to 18 cycles depending on tolerability and response.


Investigations: FBC, U&E, Creatinine clearance, LFT’s prior to each cycle Patients with abnormal hepatic function may be treated cautiously Where renal/hepatic function is abnormal, treatment is at consultant physician

discretion. Normal limits for administration apply with the exception that for patients with

marrow infiltration, treatment may be continued at lower platelet and neutrophil levels at treating physician’s discretion.

Dose modifications:Neutrophils <0.8 x 109/L omit dosePlatelets <75 x 109/L omit doseAST or ALT >1.5 x upper limit normal reduce dose by 25%

>3.5 x upper limit normal discontinueGrade 3 Neurotoxicity discontinue

1. Seidman AD, Hudis CA, Albanel , ,et al: Dose-density therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer. L Clin Oncol 16:3353-61,1998

2. Perez EA, Vogel CL, Irwin DH, et al: Multicentre phase II trial of weekly paclitaxel in women with metastatic breast cancer. L Clin Oncol 19:4216-23, 2001

3. Waintraub SE et al. Phase II study to evaluate the efficacy of weekly paclitaxel in patients with metastatic breast cancer who have failed prior anthracyclines +/- taxane therapy.. Proc Am Soc Clin Oncol, 1999;18:135a, abstract 515

DOCETAXEL (3 weekly) Patient profile: 2nd or 3rd line

25

Heavily pre-treated patientsPS < 2


Chemotherapy: Docetaxel 100mg/m2 i.v.infusion over 60 minutes Day 1

Repeat every 3 weeks for 6 - 8 cycles or until evidence of stable disease, metastatic progression, or limited toxicities.

Additional Medication: Prophylactic ciprofloxacin 500mg po twice daily days 5 – 14


Investigations: Weight, FBC, U&E’s, LFT’s before each cycle Where renal/hepatic function is abnormal, treatment is at consultant


Dose modifications : Neutrophils < 0.8 x 109/L omit dose Platelets <75 x 109/L omit dose If ALT/AST > 1.5 x ULN and ALP 2.5 x ULN give 75% of dose. If bilirubin >

22μmol/L +/- ALT/AST> 3.5 x ULN with ALP > 6 x ULN contraindicated.

Non-haematological toxicities (excluding alopecia); if necessary delay treatment by 1 or more weeks until recovery to grade 0 or 1; if recovery takes longer than 1 week or if toxicity of grade 3+ is documented during chemotherapy, the dose should be reduced by 20% in subsequent cycles.

1. Ravdin PM, Valero V. Review of Docetaxel (Taxotere), a Highly Active New Agent for the Treatment of Metastatic Breast Cancer. Semin Oncol, 1995; 22: 17-21

2. Nabholtz JM, Senn HJ, Bezwoda WR, et al. Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. J Clin Oncol 1999;17:1413-24.

26

CAPECITABINE

Patient group: 2nd or 3rd line MBCNot fit for combination chemotherapy (NICE)

Chemotherapy: 1250mg/m2 p.o. twice daily for 14 days Doses should be rounded to the nearest 150mg. Tablets should be swallowed with water within 30 minutes after a meal.

Repeat every 21 days for up to 8 cycles or until disease progression

Additional Medication: Loperamide with detailed instructions on when and how to take them

Anti-emetics: Low emetic potential

Investigations: Weight, FBC, U&E’s, LFT’s before each cycle. Where renal/hepatic function is abnormal, treatment is at consultant


Dose modifications: If WBC is <3.0x109/L or neutrophils <1.0 x 109/L or platelets <100 x 109/L, then

delay treatment by one week.

Renal insufficiency Creatinine Clearance 30 – 50mL/min reduce capecitabine by 75%If CC<30mL/min, omit capecitabine.

Toxicity Grade Immediate action Dose adjustment for next cycle/dose Grade 2 1st appearance Interrupt until resolved to grade 0-1 100%

2nd appearance Interrupt until resolved to grade 0-1 75%3rd appearance Interrupt until resolved to grade 0-1 50%4th appearance Discontinue treatment N/AGrade 3 1st appearance Interrupt until resolved to grade 0-1 75%

2nd appearance Interrupt until resolved to grade 0-1 50%3rd appearance Discontinue treatment N/A

1. SmPC Xeloda June 20092. NICE CG Breast Cancer (Advanced) February 2009.

27

VINORELBINE (IV/Oral)

Patient group: Not fit for combination chemotherapyor previous problems with capecitabine or 5 fluorouracil.

Chemotherapy Vinorelbine 30mg/ m2(maximum 60mg) i.v. bolus Day 1 and 8

Or

Vinorelibine 60mg/m2 p.o. once daily Day 1and 8 Taken orally as a single dose, swallowed with water without chewing or sucking the capsule. Take with food.

21-day cycle for 6 cycles

Anti-emetics: Low emetic potential (moderate for oral vinorelbine)

Investigations: Weight, FBC, U&E, LFT’s before each cycle Calculated creatinine clearance (should be >30mL/min)

Dose modifications:For IV Vinorelbine

Bilirubin >2.5 x ULN reduce vinorelbine dose by 50%Bilirubin >5 x ULN reduce vinorelbine dose by 75%Bilirubin >10 x ULN omit vinorelbine

Oral Vinorelbine See IV dose modifications and for any administration planned to be given at 80mg/m², if the neutrophil count is below 500/mm3 or more than once between 500 and 1000 / mm3 the administration should be delayed until recovery and the dose reduced from 80 to 60mg/m2 per week during the 3 following administrations.

1. Degardin M et al. Ann Oncol 1994; 5: 423-62. Romero A et al. J Clin Oncol 1994; 12:336-413. AWMSG Advice No: 1007 – October 20074. SPC Navelbine 30mg Capsules.eMC Nov 2007

VX (VIN/CAP)

28

Patient group: Restricted Use. 3rd line in patients with aggressive disease and in whom taxanes or anthracyclines are contraindicated. Alternative to NICE approved docetaxel/capecitabine. PS 0-1

Chemotherapy: Vinorelbine 60mg/m2 po daily (increasing to 80mg/m2) Day 1 & 8Taken orally as a single dose, swallowed with water without chewing or sucking the capsule. Take with food.

Capecitabine 1250mg/m2 p.o. twice daily Day 1-14Doses should be rounded to the nearest 150mg. Tablets should be swallowed with water within 30 minutes after a meal.

Repeat every 4 weeks for up to 8 cycles depending on response.

Additional Medication: Loperamide 2mg prn. Maximum of 8 in 24hrs.


Investigations: Weight, FBC, U&E, LFT’s before each cycle

Dose modifications:Vinorelbine Bilirubin >2.5 x ULN reduce vinorelbine dose by 50%Bilirubin >5 x ULN reduce vinorelbine dose by 75%Bilirubin >10 x ULN omit vinorelbine

If the neutrophil count is below 500/mm3 or more than once between 500 and 1000 / mm3 the administration should be delayed until recovery and the dose reduced from 80 to 60mg/m2 per week during the 3 following administrations.

Capecitabine : Creatinine Clearance 30 – 50mL/min reduce capecitabine by 75%If CC<30mL/min, omit capecitabine.

Toxicity Grade Immediate action Dose adjustment for next cycle/dose Grade 2 1st appearance Interrupt until resolved to grade 0-1 100%



1. SmPC Xeloda June 2009.2. Gil-Delgado M, et al. Oral vinorelbine in combination with capecitabine in advanced breast cancer. Proc Am Soc Clinical Oncol

2006; 24 (18s part 1): 105863. Lorusso V, et al. Oral vinorelbine plus capecitabine (oral vincap) combination in patients with advanced breast cancer (ABC). A

phase II st udy of the GIOM (Gruppo Oncologico dell’Italia Meridionale). Ann Oncol 2006; 17 (Suppl 7): vii15 – vii17

29

4. Nole F, et al. Phase II study of an all-oral regimen combining oral vinorelbine with capecitabine as first-line chemotherapy (CT) of metastatic breast cancer (MBC). Eur J Cancer 5 (4): 218 (Abstract 2114)

HER2 positive tumours

30

PACLITAXEL/TRASTUZUMAB

Patient group: First line therapy with HER2 positive diseasePS 1-2Care within close proximity to anthracycline therapy (<6 months)

WeeklyPre medication: to be given 30 minutes before paclitaxel:

Dexamethasone 20mg ivRanitidine 50mg ivChlorphenamine 10mg iv

Chemotherapy: Paclitaxel 90mg/m2 i.v. infusion over 1 hour Day 1Trastuzumab 4mg/kg i.v. infusion over 90 minutes Day 1Trastuzumab maintenance dose 2mg/kg


Treatment repeated weekly for 12-18 cycles depending on response and tolerability.

Three weeklyPre medication: to be given 30 minutes before paclitaxel:

Dexamethasone 20mg ivRanitidine 50mg ivChlorphenamine 10mg iv

Chemotherapy: Paclitaxel 175mg/m2 i.v. infusion over 3 hours Day 1Trastuzumab 8mg/kg i.v. infusion over 90 minutes Day 1

Trastuzumab 6mg/kg (starting second cycle)

Repeated every 21-days for 6 cycles depending on response and tolerability. Herceptin should be continued until progressive disease depending on response and tolerability.


Investigations: Prior to first course, assessment of cardiac function using cardiac echo or

MUGA scan is mandatory, and also at 3 monthly intervals during therapy. Weight, FBC, U&E’s, LFT’s, tumour markers prior to each course.

Dose modifications:

Neutrophils <1.0 x 109/lL omit dose

31

Platelets <100 x 109/L omit dose Grade 3 neurotoxicity discontinue

1. Norton L Proc ASCO 1999; 18:127A2. Slamon D, Proc ASCO 1998; 17:98A3. Seidman A. J Clin Oncol 1998; 16:1-104 Gelman K. Proc ASCO 2001 20:69a abstract 2715. National Institute for Health and Clinical Excellence. Technology appraisal no. 34 March 2002

TRASTUZUMAB (weekly)

Patient group: For patients not appropriate for paclitaxel/combined treatmentPrior treatment or disease progression on taxol single agent.

32

Chemotherapy: Trastuzumab loading dose: 4mg/kg i.v. infusion over 90 minutes Day 1

Trastuzumab maintenance dose;2mg/kg i.v. infusion over 90 minutes Day 1


Repeat weekly until evidence of stable disease, or metastatic progression.


Investigations: Prior to 1st course FBC, U&E’s, LFT’s, tumour markers ECG, ECHO Prior to each course, FBC, U&E’s LFT’s, tumour markers. Cardiac function should be monitored after 3 months during treatment.

Dose modifications: Not needed for trastuzumab alone

1. Vogel CL et al. J Clin Oncol 2000; 20:719-262. Slalom DJ et al; New Engl Med 2001; 334:783-923. Cobleigh MA et al. J Clin Oncol 1999; 17: 2639-484 Balsega J et al. J Clin Oncol; 14: 737-445 National institute for Health and Clinical Excellence. Guidance for the use of trastuzumab for the treatment of

advanced breast cancer. Technology Appraisal no.32 March 2002

DOCETAXEL/TRASTUZUMAB (3 weekly)

Patient group: 1st line therapy for patients with HER2

33

PS 0 – 1Paclitaxel allergy/intolerance

Pre-medication: Dexamethasone 8mg twice daily for 3 days starting day before treatment. Required for all cycles.

Chemotherapy: Docetaxel 100 mg/m2 i.v. infusion over 60 minutes Day 1Trastuzumab 8mg/kg i.v. infusion over 90 minutes Day 1cycle 1 (capped at 750mg)Trastuzumab dose 6mg/kg cycle 2 onwards (capped at 600mg)


Repeat at 21-day intervals for 6 cycles or until disease progression


Investigations: Prior to 1st course FBC, U&E’s, LFT’s, tumour markings ECG, ECHO Prior to each course, FBC, U&E’s LFT’s, tumour markings. Cardiac function should be monitored after 3 months during treatment.

Dose Modifications:

Neurotoxicity or cutaneous Reaction Grade 3 or 4 toxicity reduce Docetaxel to 75mg/m2

Hepatic Dysfunction AST/ALT Alk Phosp Bilirubin Dose of Docetaxel

Mild-moderate > 1.5 ULN > 2.5 x ULN Reduce to 75mg/m2

Severe > 3 > 6 x ULN > ULN Stop docetaxel

1. Extra JM et al, San Antonie Breast Cancer Smyposium 2003; abstr 2172. Leyland-Jones B et al, J Clin Oncol, 2003 Nov 1; 21(21): 3965-713. Filippo Montemurro Oncology 2004;66:38-45

VINORELBINE/TRASTUZUMAB

Patient group: Prior treatmentReaction to taxane

34

Chemotherapy: Trastuzumab 8mg/kg i.v. infusion over 90 minutes Day 1 Trastuzumab 6mg/kg cycle 2 onwardsVinorelbine 30mg/m2 i.v. bolus Days 1 and 8


Treatment is repeated every 21 days until disease progression


Investigations: Prior to 1st course FBC, U&E’s, LFT’s, tumour markings ECG, ECHO Prior to each course, FBC, U&E’s LFT’s, tumour markings. Cardiac function should be monitored after 3 months during

Dose modifications:

Neutrophila <1.0x109/L omit vinorelbine, and reduce subsequent doses by 25%

Platelets < 75x109/L omit vinorelbine and reduce subsequent doses by 25%

AST or ALT >5xULN reduce vinorelbine by 50%Bilirubin 3-5 x ULN reduce vinorelbine by 50%Bilirubin 5-10 x ULN reduce vinorelbine by 75%Bilirubin >10 x ULN omit vinorelbine

1. Chan A, Untch M, Petruzelka L et al. Multinational phase II study of navelbine (N) and herceptin (H) as first-line therapy for HER2-overexpressing metastatic breast cancer (HER2+ MBC). San Antonio Breast Cancer Symposium 2002: abstr 434. 2. CCO Practice Guidelines: The Role of Trastuzumab (Herceptin) in the Treatment of Women with HER2/neu-overexpressing Metastatic Breast Cancer 3.CCO Practice Guideline: Vinorelbine in stage IV breast cancer. 4.Leyland-Jones B, Gelmon K, Ayoub JP, et al. Pharmacokinetics, safety, and efficacy of trastuzumab administered every three weeks in combination with paclitaxel. J Clin Oncol. 2003 Nov 1; 21(21):3965-71. Chan A et al, San Antonio Breast Cancer Symposium 2002; abstr 434

LAPATANIB

Patient group: PS 0 -2 ErbB2 and HER2 positive metastatic diseasePrior therapy with anthracycline and taxanesNon cerebral relapse on trastuzumab

35

Suitable for treatment with CapecitabineNo significant cardiac history.

Chemotherapy: Lapatanib 1250mg OD (as a single dose) continuouslyTo be taken at least one hour before, or at least one hour after food.

Capecitabine 2000mg/m2 /daily with or after food Days 1-14

Repeat every 3 weeks and assess response after 2-3 cycles. Continue for 8 cycles or until disease progression.


Additional Medication: Loperamide 2mg prn. Maximum of 8 in 24hrs.

Investigations: Prior to 1st course FBC, U&E’s, LFT’s, ECHO Prior to each course, FBC, U&E’s LFT’s Cardiac function should be monitored after 3 months

Dose modifications: Renal insufficiency

Creatinine Clearance 30 – 50mL/min reduce capecitabine by 75%If CC<30mL/min, omit capecitabine. No adjustment is needed for Lapatanib in mild to moderate renal impairment.

Hepatotoxicity Lapatanib dosing should be discontinued if changes in liver function are severe and patients should not be retreated.

Capecitabine dose –reduction scheduleToxicity Grade Immediate action Dose adjustment for next

cycle/dose Grade 2 1st appearance Interrupt until resolved to grade 0-1 100%



Additional information: Avoid Grapefruit juice during treatment with Lapatanib. Avoid co-administration with verapamil, cyclosporine, erythromycin, ritonavir,

saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone, rifampicin, rifabutin, carbamazepine, phenytoin or Hypericum perforatum [St John's wort], quinidine.

Avoid drugs that alter the pH of the stomach (H2 blockers and PPIs)

1. SPC Tyverb™ GlaxoSmithKline UK www.emc.medicines.org.uk [accessed January 21 2010]2. SPC Xeloda™ Roche products Ltd www.emc.medicines.org.uk [accessed January 21 2010]

36

http://www.emc.medicines.org.uk/


3. Cameron D, Casey M, Press M, et al A phase III randomised comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat 2008;

4. Geyer GE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. New Engl J Med 2006; 355: 2733-2743

5. Sherrill B , Amonkar MM, Stein S et al. Lapatininb plus capecitabine for Erb-B2 (Her-2) positive advanced breast or metastatic breast cancer: a summary of Q-TwiST analysis from registrations study EGF100151. Br J Cancer 2008;99:711-715

Bisphosphonates

Patient group: PS 0 – 2Symptomatic/extensive bone pain/metastases

37

Pre-treatment: Pre-treatment dental screening is recommended due to the risk of ostenonecrosis of the jaw.

Bisphosphonate: Ibandronic acid 6mg i.v. in 100mL 0.9% sodium chloride over 15 minutes

Repeat at 28 day intervals (ensure patient adequately hydrated)

OR

Ibandronic acid 50mg po dailyCalcium Supplements: Patients should have their serum calcium measured every four

weeks and calcium with vitamin D e.g. Adcal D3 forte tablets, prescribed as necessary.

Dose modifications:

Dose modification for impaired renal function:Creatinine Clearance (ml/min)

Dosage / Infusion time Infusion Volume

50 6mg / 15 minutes 100ml

30 - 50 6mg / 1 hour 500ml

<30 2mg / 1 hour 500ml

1. Body JJ, Diel IJ, Lichinitzer M, et al Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies. Br J Cancer 2004;90:1133-7.

2. Ibandronic acid (Bondronat®) for the treatment of bone metastases London Cancer New Drugs Group—APC/DTC Briefing July 2008

OESOPHAGEAL AND OESOPHAGO-GASTRIC CANCER

Adjuvant38

No proven role.

Neo-adjuvant

CISPLATIN/5FU

Patient group: Standard first line, prior to surgery for operable oesophageal cancerPS 0-1CrCl > 50mL/min

Hydration: Please refer to appendix and Trust protocol

Chemotherapy: Cisplatin 80mg/m2 i.v. infusion over 2 hours Day 15-fluorouracil 1000mg/m2 i.v. infusion over 24 hours Days 1- 4

Urine output should be maintained above 100mL/hr throughout treatment. If output falls below 400mL in any 4 hour period, then give furosemide 20mg iv or 40mg po repeated as necessary. Alternately, mannitol may be used.

Repeat at 21-day cycles for two cycles onlyAdditional Medication: Ciprofloxacin 500mg PO BD for 7 days starting day 8 of cycle.


Investigations: Weight, FBC, U&E’s, LFT’s before each cycleCreatinine clearance prior to each cycle and administer cisplatin according to guidelines.

Dose modifications: CrCl > 50mL/min full dose cisplatin40-50mL/min reduce cisplatin 50%<40mL/min omit cisplatin

1.Walsh T et al, N Eng J Med 1996; 335: 452-72.Herskovic A et al N Eng J Med 1992; 326: 1593-83.Wobst et al Ann Oncol 1998; 9(9): 951-62

5FU/FA + XRT CHEMORADIATION

Patient profile: Gastro-oesophageal cancer Selected cases only, patients with high risk of occurrence High risk/toxicity

39

CYCLE 1:Calcium Levofolinate 25mg i.v. bolus Day 1- 55-Fluorouracil 425mg/m2 i.v. bolus Day 1- 5

CYCLE 2: With Week 1 radiotherapy (to begin 4 weeks after cycle 1):

Calcium Levofolinate 25mg i.v. bolus Day 1- 45-Fluorouracil 400mg/m2 i.v. bolus Day 1- 4

CYCLE 3 with Week 5 radiotherapy:


CYCLE 4 & 5 (one month after completion of radiotherapy):


NBCalcium Levofolinate 25mg= 50mg Folinic acid

1. Macdonald JS et al. 36th ASCO Annual Meeting May 2000

CHEMO-RADIATION PROTOCOL

Patient group: May be offered for oesophageal cancer as an alternative to surgery if MDT decides appropriate


Chemotherapy: Treatment is given with week 1 and week 5 of radiotherapy

Cisplatin 80mg/m2 i.v. infusion over 2 hours Day 1 and 295 fluorouracil 1000mg/m2/day continuous infusion Days 1-4 + 29-32

Urine output should be maintained above 100mL/hr throughout treatment. If output falls below 400mL in any 4 hour period, then give furosemide 20mg iv or 40mg po repeated as necessary. Alternately, mannitol may be used.

40


Investigations: Weight, FBC, U&E’s, LFT’s before each cycle Creatinine clearance prior to each cycle and administer cisplatin

according to guidelines.

Dose modifications: CrCl >50mL/min full dose cisplatin40-50mL/min reduce cisplatin 50%<40mL/min omit cisplatin

1. Weaver A et al. Am J Surg 1984; 148: 525-92. Munro AJ Br J Cancer 1995; 71: 83-913. Ervin TJ et al. J Clin Oncol 1987; 5: 10-20 4. Herskovic A,Martz K, Al-Sarraf M et al, N Eng J Med 1992; 326:1593-85. Al-Sarraf M, Martz K, Herskovic MA et al J Clin Oncol 1997; 15: 277-84

ECF

Patient group: Standard for operable gastric or oesophago-gastric cancer


Chemotherapy: Epirubicin 50mg/m2 i.v. bolus over 3-5 minutes Day 1Cisplatin 60mg/m2 i.v. infusion over 2 hours Day 15 fluorouracil 200mg/m2/day continuous infusion and continue until 3 weeks after last cycle (unless disease is progressing)

Check urine output and give furosemide 20mg iv or 40mg po if output falls below 100mLhr or 400mL in any 4-hour period. Alternately, mannitol infusion may be used.

Repeat every 21-days 3 cycles pre-op and 3 cycles post-op

41


Investigations: Weight, FBS, U&E’s, LFT’s before each cycle Calculate creatinine clearance before each cycle. LV ejection fraction prior to first cycle if patient has history of cardiac problems.




Dose modifications: Epirubicin - Moderate liver impairment (bilirubin: 1.4-3 mg/100ml) give

50% of dose, severe impairment (bilirubin> 3 mg/100 ml) give 25% of dose

If WBC < 3.0 x 109Ll or platelets <100 x 109/L prior to next cycle then delay chemotherapy by one week (but continue 5FU). If 2 week delay needed, reduce doses by 25%. If > 2 week delay, reduce dose by 50%

Patients developing plantar-palmar erythema should receive pyridoxine 50mg po tds continuously.

If grade 3 or grade 3 mucositis reduce 5FU dose by 25% If grade 2 neuropathy or creatinine clearance < 50mL/min, change

cisplatin to carboplatin (AUC = 5) and increase treatment cycle to 28 days.

1. Walters JS et al. Br J Cancer 1999; 80: 269-72

ECX

Patient group: For patients who are fit enough for ECF regime but for whom a central venous line is inadvisable or contraindicated.Patient choice.


Chemotherapy: Capecitabine 1250mg/m2/day p.o.in 2 divided doses continuouslyDoses should be rounded to the nearest 150mg. Tablets should be swallowed with water within 30 minutes after a meal.

Epirubicin 50mg/m2 i.v. bolus over 3-5 minutes Day 1Cisplatin 60mg/m2 i.v. infusion over 2 hours Day 1

Urine output should be maintained above 100ml/hr throughout treatment. If output falls below 400mls in any 4 hour period, then give furosemide 20mg iv or 40mg po Repeated as necessary.Alternately, mannitol may be used.

42

Repeat every 21-days 3 cycles pre-op and 3 cycles post-op


Ciprofloxacin 500mg PO BD for seven days starting on day 8 of each cycle.


Investigations: LV ejection fraction prior to cycle 1 if history of cardiac problems Risk of



Weight, FBS, U&E’s, LFT’s before each cycle Calculate creatinine clearance before each cycle.


Dose modifications: CrCl >50mL/min full dose cisplatin, full dose capecitabine

40-50mL/min reduce cisplatin 50%, and capecitabine 25%<40mL/min omit cisplatin, and capecitabine.

Hand & foot syndrome or diarrhoea grade 3 or 4: Stop capecitabine until toxicity has resolved. Restart with 25% dose reduction.

Platelets 50 - 74 x 109/L or neutrophils 0.5 – 0.9 x 109/LStop capecitabine, delay epirubicin and cisplatin until recovery.Restart capecitabine at full dose and reduce epirubicinBy 25% on subsequent cycles

Platelets 25 – 49 x 109/L or neutrophils <0.5 x 109/LStop capecitabine and delay epirubicin cisplatin until recoveryRestart capecitabine at full doseReduce epirubicin by 50% on subsequent cycles

Platelets <25 x 109/L or neutrophils <0.5 x 109/LStop capecitabine & delay cisplatin until recovery

Restart capecitabine at full dosOmit epirubicin from subsequent cycles.

1. A Randomised controlled trial comparing standard chemotherapy followed by resection in patients with respectable adenocarcinoma of the oesophagus. (OE05)

43

Advanced /Metastatic disease

ECF

Patient group: Standard 1st line regimen for oesophageal and oesophago-gastric cancer


Chemotherapy: Epirubicin 50mg/m2 i.v. bolus over 3-5 minutes Day 1Cisplatin 60mg/m2 i.v. infusion over 2 hours Day 15 fluorouracil 200mg/m2/day continuous infusion and continue until 3 weeks after last cycle (unless disease is progressing)

Check urine output and give furosemide 20mg iv or 40mg po if output falls below 100ml/hr or 400mL over any 4 hour period. Alternately, mannitol infusion may be used.

Repeated every 21 days for 4 – 8 cycles


44

Investigations: Weight, FBS, U&E’s, LFT’s before each cycle Calculate creatinine clearance before each cycle. LV ejection fraction prior to first cycle if patient has history of cardiac problems.




Dose modifications: Epirubicin - Moderate liver impairment (bilirubin: 1.4-3 mg/100ml) give 50% of

dose, severe impairment (bilirubin> 3 mg/100 ml) give 25% of dose If WBC < 3.0 x 109/L or platelets <100 x 109/L prior to treatment then delay

chemotherapy by one week (but continue 5FU). If 2 week delay needed, reduce doses by 25%. If > 2 week delay, reduce dose by 50%


If grade 3 or grade 3 mucositis reduce 5FU dose by 25% If grade 2 neuropathy or creatinine clearance < 50mL/min, change cisplatin to

carboplatin (AUC = 5) and increase treatment cycle to 28 days.

1. Walters JS et al. Br J Cancer 1999; 80: 269-722. Findlay M et al. Ann Oncol. 1994; 5: 609-15

ECX

Patient group: For patients who are fit enough for ECF regime but for whom a central venous line is inadvisable or contraindicated.Patient choice.


Chemotherapy: Capecitabine 1250mg/m2/day p.o.in 2 divided doses for up to 24 weeks

Doses should be rounded to the nearest 150mg. Tablets should be swallowed with water within 30 minutes after a meal.

Epirubicin 50mg/m2 i.v. bolus over 3-5 minutes Day 1Cisplatin 60mg/m2 i.v. infusion over 2 hours Day 1

Urine output should be maintained above 100ml/hr throughout treatment. If output falls below 400mls in any 4 hour period, then give furosemide 20mg iv or 40mg po. Repeated as necessary.Alternately, mannitol may be used.

45

Repeat every 21 days No more than 2 cycles unless response is seen. Maximum of 8 cycles


Ciprofloxacin 500mg PO BD for seven days starting on day 8 of each cycle.







Dose modifications: Epirubicin - Moderate liver impairment (bilirubin: 1.4-3 mg/100ml) give 50%

of dose, severe impairment (bilirubin> 3 mg/100 ml) give 25% of dose CrCl >50mL/min full dose cisplatin, full dose capecitabine

40-50mL/min reduce cisplatin 50%, and capecitabine 25%<40mL/min omit cisplatin, and capecitabine.

Hand & foot syndrome or diarrhoea grade 3 or 4: Stop capecitabine until toxicity has resolved. Restart with 25% dose reduction.

Platelets 50 - 74 x 109/L or neutrophils 0.5 – 0.9 x 109/LStop capecitabine, delay epirubicin and cisplatin until recovery.Restart capecitabine at full dose and reduce epirubicinBy 25% on subsequent cycles

Platelets 25 – 49 x 109/L or neutrophils <0.5 x 109/LStop capecitabine and delay epirubicin cisplatin until recoveryRestart capecitabine at full doseReduce epirubicin by 50% on subsequent cycles

Platelets <25 x 109/L or neutrophils <0.5 x 109/LStop capecitabine & delay cisplatin until recovery

Restart capecitabine at full dosOmit epirubicin from subsequent cycles.

1. Sumpter, K et al. Br J Cancer 2005; 92: 1976 – 19832. Cunningham, D et al. Proc ASCO 2006 Abstract LBA40173. Cunningham, D et al. NEJM 2006; 355: 11 – 204. A Randomised controlled trial comparing standard chemotherapy followed by resection in patients with respectable

adenocarcinoma of the oesophagus. (OE05)

46

E-CARBO F

Patient profile: Patients with poor renal function PS<2

Chemotherapy: Epirubicin 50mg/m2 i.v. bolus over 3-5 minutes Day 1Carboplatin AUC 5 i.v. infusion Day 1Fluorouracil 200mg/m2/day continuous infusion and continue until 3 weeks after last cycle.

Repeated on a 21 day cycle for a maximum of 8 cycles.





Weight, FBS, U&E’s, LFT’s before each cycle47

Calculate creatinine clearance before each cycle.


Dose modifications:

Epirubicin - Moderate liver impairment (bilirubin: 1.4-3 mg/100ml) give 50% of dose, severe impairment (bilirubin> 3 mg/100 ml) give 25% of dose

Adjust carboplatin dose using Calvert formula If WBC<3.0 x 109/L or platelets, 100 x 109/Ll, then Delay chemotherapy

by 1 week (but continue 5FU). If week 2 delay needed, reduce dose by 25%. If 2 week delay reduce dose by 50%.


If grade 3 or grade 3 mucositis, reduce 5FU dose by 25%.

1. Webb A et al J Clin Oncol 1997; 15: 261-7

E-CARBO-X

Patient profile: For patients who may not be able to tolerate ECF,Poor renal function (CCl calc < 50mls/min)Patient choice.

Chemotherapy: Epirubicin 50mg/m2 i.v. bolus over 3-5 minutes Day 1Carboplatin AUC 5 i.v. infusion Day 1Capecitabine 1250mg/m2/day p.o.in 2 divided doses continuouslyDoses should be rounded to the nearest 150mg. Tablets should be swallowed with water within 30 minutes after a meal.

Repeated on a 21-day cycle for up to 8 cycles.



Investigations:

48

LV ejection fraction prior to cycle 1 if history of cardiac problems Risk of cardiomyopathy increases with cumulative epirubicin dose of > 900mg/m2




Dose modifications: Epirubicin - Moderate liver impairment (bilirubin: 1.4-3 mg/100ml) give

50% of dose, severe impairment (bilirubin> 3 mg/100 ml) give 25% of dose

Adjust carboplatin dose using Calvert formula Platelets <100 x 109/L or/neutrophils 0.5 – 0.9 x 109/LStop treatment until

neutrophils >1.0 x 109/L. Restart capecitabine at full dose. Reduce epirubicin & carboplatin by 25%.

Neutrophils <0.5 x 109/L: Stop treatment until neutrophils > 1.0 x 109/L. Restart capecitabine at full dose. Reduce dose of epirubicin and carboplatin by 50%.

Hand and foot syndrome or diarrhoea grade 3 or 4: Stop capecitabine until toxicity has resolved. Restart with 25% dose reduction.

1. Real –2 Trial. A phase II/III randomised trial comparing ECF with EEF, ECX and EEX in patients with advanced oesophago-gastric cancer.

2. Ross PJ, Rao S, Cunningham D. Pathol Oncol Res, 1998. 4(2): 87-953. Evans TR et al. Ann Oncology 2002 13(9): 1469-784. Calvert AH et al, Carboplatin dodage: prospective evaluation of a simple formula based on renal function. L Clin

Oncol: 1989: 7(11) 1748-56

49

PANCREATIC CANCER

Adjuvant

5FU/FA

Patient profile: Standard first line regimen. Patient preference.

Chemotherapy: Post-operative chemotherapy should be started no later than 8 weeks after surgery

5-fluorouracil 425mg/m2 i.v. bolus Days 1 to 5Folinic acid 50mg i.v. bolus Days 1 to 5

(Calcium Levofolinate 25mg)

Repeat at 28-day intervals for a maximum of 6 cycles.


Investigations: Weight, FBC, U&E’s, LFT’s before each cycle.

Dose modifications:

For patients over 70 years reduce fluorouracil dose to 370mg/m2

1. John P. Neoptolemos et al A Randomized Trial of Chemoradiotherapy and Chemotherapy after Resection of Pancreatic Cancer NEJM Volume 350:1200-1210 March 18, 2004 Number 12

Advanced50

GEMCITABINE

Patient profile: Standard first line (NICE standard)PS 0-1

Chemotherapy: Induction: Gemcitabine 1000mg/m2 i.v. infusion over 30 minutes weekly for 7 weeks followed by a 1 week break

Maintenance:Gemcitabine 1000mg/m2 i.v. infusion over 30 minutes days 1,8 and 15

Maintenance treatment is repeated every 28 days for up to 6 cycles


Investigations: Weight, FBC, U&E’s, LFT,s before each cycle

NB: transaminases my rise during gemcitabine therapy. Where renal/hepatic function is abnormal, treatment is at consultant


Dose modifications: If WBC is <3.0x109/L or neutrophils <1.0 x 109/L or platelets <100 x 109/L,

then delay treatment by one week.

1. National Instutie for Health and Clinical Excellence: Technology appraisal no 25: 20012. Burris HA et al. J Clin Oncol 1997 15(6): 2404-133. Rothenburg ML et at. Ann Oncol; 1996 7(4) 347-53

51

ANAL CANCER

Radical Chemoradiation

FuMi/XRT

Patient profile : PS 0-2T 1 – 4 N 1 – 3

Chemotherapy: XRT for 5 weeksMitomycin C 12mg/m2 i.v. bolus (max 20mg) Day 15-fluorouracil 1000mg/m2 / 24 hours i.v infusion Days 1- 45-fluorouracil 1000mg/m2/ 24 hours for 4 days during final week of XRT

Anti-emetics: High emetic potential (day 1)

Investigations: Weight, FBC, U&E’s, LFT’s prior to each cycle.

Dose modifications:

For patients with significant concurrent illness and those aged over 80, a reduced dose regimen was recommended: 5-fluorouracil 750 mg/m2 on days 1–4 and mitomycin 10 mg/m2

1.Cummings BJ et al. Int J Radiat Biol Phys 1991; 21: 11115-252.UKCCCR Anal Cancer Trial. Lancet 1996; 348: 1049-54

Adjuvant

No proven role

52

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T1B-3Y9H2FY-20&_user=5761894&_coverDate=10%2F19%2F1996&_rdoc=8&_fmt=full&_orig=browse&_srch=doc-info(%23toc%234886%231996%23996510965%23151926%23FLA%23display%23Volume)&_cdi=4886&_sort=d&_docanchor=&_ct=69&_acct=C000010758&_version=1&_urlVersion=0&_userid=5761894&md5=5bf1fa1d940cfc5172e02605689bf37e#bib2%23bib2

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T1B-3Y9H2FY-20&_user=5761894&_coverDate=10%2F19%2F1996&_rdoc=8&_fmt=full&_orig=browse&_srch=doc-info(%23toc%234886%231996%23996510965%23151926%23FLA%23display%23Volume)&_cdi=4886&_sort=d&_docanchor=&_ct=69&_acct=C000010758&_version=1&_urlVersion=0&_userid=5761894&md5=5bf1fa1d940cfc5172e02605689bf37e#bib2%23bib2

Advanced/Metastatic diseaseCISPLATIN/5FU

Patient profile: If prior FuMi chemotherapy given


Chemotherapy: Cisplatin 60mg/m2 i.v. infusion over 2 hours Day 1 5 fluorouracil 1000mg/m2/day continuous infusion Days 1 - 4

Check urine output and give furosemide 20mg iv or 40mg po if output falls below 100ml/hr.Alternately, mannitol infusion may be used.

Repeat at 21-day intervals for max 4 courses.


Investigations: Weight, Creatinine clearance, U&E’s, FBC, LFT’s prior to each cycle.

Dose Modifications:

Creatinine clearance cisplatin dose> 50 mL / min 100%40 – 50 mL / min 75%< 40 mL / min no further cisplatin

Consider changing to carboplatin in renal impairment.

1. Rich T Oncology 1999; 13 (10 supp 5): 131-42. Stafford s, Martenson J Oncology 1998; 12(3): 373-73. Myerson RJ Rays 1997; 22(3): 393-94. ACT-II The second UK phase III anal cancer trial: A trial of chemoradiation & maintenance therapy for patients with anal cancer.

53

COLORECTAL CANCERNeo-adjuvant

CAPECITABINE + XRT

Patient profile: Rectal threatening mesorectal fasciaDown staging pre-operativelyFailed venous catheterisationReceiving anticoagulants

Chemotherapy: Capecitabine 825mg/m2 p.o. twice daily Mon to Fri during XRTDoses should be rounded to the nearest 150mg. Tablets should be swallowed with water within 30 minutes after a meal.





Dose modifications: If WBC is <3.0x109/L or neutrophils <1.0 x 109/L or platelets <100 x 109/L,

then delay treatment by one week. Renal insufficiency Creatinine Clearance 30 – 50mL/min reduce capecitabine by 75%If CC<30mlL/min, omit capecitabine.

Dose modification for stomatitis, diarrhoea or palmar-plantar syndrome due to capecitabine.Grade 1st Occurrence 2nd Occurrence 3rd Occurrence 4th Occurrence1 Continue Continue Continue Continue2 – 3 Stop until recovery

to grade 0 – 1Restart at 75%

Stop until recoveryto grade 0 – 1Restart at 75%

Stop Stop

4 Stop until recoveryTo grade 0 – 1If in patient’s interestto continue, restart at 50%. Otherwise stop

Stop Stop Stop

1.I. Chau A multidisciplinary approach using twelve weeks of neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation (CRT) and total mesorectal excision (TME) for MRI defined poor risk rectal cancer 2005 Gastrointestinal Cancers Symposium ASCO

54

http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Virtual+Meeting?&vmview=vm_meeting_tracks_view&confID=36

http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Virtual+Meeting?&vmview=vm_meeting_tracks_view&confID=36

5FU (CI) WITH OR WITHOUT XRT

Patient profile: Rectal threatening mesorectal fasciaDown staging pre-operatively

Chemotherapy: 5 Fluorouracil 200mg/m2/d continuous i.v. infusion days 1 to 35 with XRT

OR

5 Fluorouracil 300mg/m2/d continuous i.v. infusion days 1 to 35 when given without XRT


Investigations: Weight, FBC. U&E’s, LFT’s

Dose modifications:Treatment delays and dose reduction required for ≥ grade 2 diarrhoea or mucositis

1. Lokich JJ et al. J Clin Oncol 1989; 7: 425-322. O’Connell et al. N Engl J Med 1994; 331: 502-7

55

Adjuvant

CAPECITABINE

Patient profile: High risk Dukes B and Dukes C


Repeat every 21 days for 8 cycles.





Dose modifications: If WBC is <3.0x109/L or neutrophils <1.0 x 109/L or platelets <100 x 109/L, then






Stop Stop


Stop Stop Stop

1. NICE Technology Appraisal 100. April 20062. Hoff PM et al. J Clin Oncol, 2001; 19(8): 2282-923. Twelves C. Eur J Cancer, 2002; 38 Suppl 2: 15-204. Scheithaurer W et al. Ann Oncol, 2003; 14(12): 1735-435. Twelves C et al. Eur J Cancer, 2001; 37(5): 597-6046. Reddy GK, Clin Colorectal Cancer, 2004; 4(2): 87-8

56

5FU/FA

Patent profile: High risk Dukes B & Dukes CPatient choice

Chemotherapy: 5 fluorouracil 370mg/m2 i.v. bolus (over 5 minutes) Day 1Calcium Levofolinate 25mg i.v. bolus Day 1(Folinic acid 50mg)

Repeated weekly for 24 - 30 weeks


Investigations: Weight, FBC, U&E’s, LFT’s monthly Where renal/hepatic function is abnormal, treatment is at consultant


Dose modifications:Treatment delays and dose reduction required for ≥ grade 2 diarrhoea or

mucositis5-fluorouracil dose may be reduced to 300mg/m2 if patients are having

concurrent pelvic radiotherapy.

1. QASAR 1 –a UKCCR study of adjuvant chemotherapy for colorectal cancer

57

MODIFIED DE GRAMONT

Patient profile: Stage III (Dukes’C) colon cancer.PS = 0,1 or 2

Chemotherapy: Calcium levofolinate 175mg i.v. infusion over 2 hours Day 1(Folinic acid 350mg)5-fluorouracil 400mg/m2 i.v. bolus Day 15-fluorouracil 2800mg/m2 i.v. infusion over 46 hours Day 1

Repeat at 14-day intervals for 6 cycles.





Dose modifications:

Treatment delays and dose reduction required for ≥ grade 2 diarrhoea or mucositis

1. De Gramont A. et al, J Cancer Clin Oncol, 1988; 24(9); 1499-5032. SL Cheeseman et al British Journal of Cancer (2002) 87, 393 – 3993. Seymour MT et al. Annals Oncol 1998, 9(Suppl 4): 474. MRC Trial - CR08

OXALIPLATIN/ MODIFIED DE GRAMONT (OxMdG)

58

Patient profile: Stage III (dukes’C) colon cancer.

Chemotherapy: Oxaliplatin 85mg/m2 i.v. infusion over 2 hours Day 1Calcium levofolinate 175mg i.v. infusion over 2 hours Day 1(Folinic acid 350mg)5-fluorouracil 400mg/m2 i.v. bolus Day 15-fluorouracil 2400mg/m2 i.v. infusion over 46 hours Day 1






Dose modifications:

Neurological symptoms (paraesthesia, dysaesthesia) oxaliplatin dosage adjustment should be based on the duration and severity of these symptoms. Oxaliplatin dose should be reduced from 85 to 75mg/m2 (adjuvant setting).

If grade 4 diarrhoea, grade 3-4 neutropenia (neutrophils < 1.0x109/L), grade 3-4 thrombocytopenia (platelets < 50x109/L) occur, the dose of oxaliplatin should be reduced from 85 to 75 mg/m² (adjuvant setting), in addition to any 5-fluorouracil dose reductions required.

1. National Institute for Health and Clinical Excellence. Technology Appraisal Guidance 100. Capecitabine and oxaliplatin in the adjuvant treatment of stage III (Dukes’ C) colon cancer April 2006

Advanced Metastatic Disease59

CETUXIMAB + OXMdG/IrMdG

Patient Profile: 1st line for metastatic colorectal cancer (NICE)PS 0 – 1 KRAS wild type Primary surgery with curative intent has been carried out. The metastatic disease is confined to the liver and is unresectable

(including PET/CT assessment) The patient is fit enough to undergo potentially curative resection (as

confirmed by the hepatobiliary surgical team)

Pre-medication: Chlorphenamine IV 10mg or 8mg po 30-60 minutes prior to CetuximabAtropine s/c 0.24mg prior to irinotecan

Chemotherapy: Cetuximab 400mg/m2 IV infusion over 2 hours Day 1 Cetuximab 250mg/m2 IV infusion over 1 hour Weekly for 16 wks

INCOMBINATION WITHOxMdG Oxaliplatin 85mg/m2 i.v. infusion over 2 hours Day 1

Calcium Levofolinate 175mg i.v. infusion over 2 hours Day 1(Folinic acid 350mg)5-fluorouracil 400mg/m2 i.v. bolus Day 15-fluorouracil 2400mg/m2 i.v. infusion over 46 hours Day 1


ORIrMdG Irinotecan 180mg/m2 i.v. infusion over 90 minutes Day 1

Ca Levofolinate 175mg i.v. infusion over 2 hours Day 1(Folinic acid 350mg)5-fluorouracil 400mg/m2 i.v. bolus over 15 minutes Day 15-fluorouracil 2400mg/m2 i.v infusion over 46 hours Day 1

Repeat at 14-day intervals for 6 cycles then review


Additional Medication: OxMdG - Loperamide with detailed instructions on when and how to take

them IrMdG -Patients on irinotecan can suffer from potentially fatal delayed diarrhoea especially when associated with fever. All patients should be prescribed loperamide and Ciprofloxacin (500mg bd for 7 days) to be taken if instructed.



60

Dose modifications:

Oxaliplatin - Neurological symptoms (paraesthesia, dysaesthesia) oxaliplatin dosage adjustment should be based on the duration and severity of these symptoms. Oxaliplatin dose should be reduced from 85 to 75 mg/m2 (adjuvant).


Irinotecan -A dose reduction of 15 to 20 % should be applied for irinotecan and/or 5FU when haematological toxicity (neutropenia grade 4, febrile neutropenia (neutropenia grade 3-4 and fever grade 2-4), thrombocytopenia and leukopenia (grade 4)), non haematological toxicity (grade 3-4).

1. NICE TA 176 Cetuximab 1st line for colorectal cancer. www.nice.org.uk [accessed 21 January 2010]2. SPC Erbitux™ .Merck Serono. www.emc.medicines.org.uk [accessed 21 January 2010]

OXALIPLATIN/ MODIFIED DE GRAMONT (OxMdG)

Patient profile: PS 0 – 1 61


http://www.nice.org.uk/

Standard 1st line, alternative to FOLFIRI

Chemotherapy: Oxaliplatin 85mg/m2 i.v. infusion over 2 hours Day 1Calcium Levofolinate 175mg i.v. infusion over 2 hours Day 1(Folinic acid 350mg)5-fluorouracil 400mg/m2 i.v. bolus Day 15-fluorouracil 2400mg/m2 i.v. infusion over 46 hours Day 1

Repeat at 14 day intervals for 4 cycles. If evidence of response/clinical benefit, continue for up to 12 cycles





Dose modifications:

Neurological symptoms (paraesthesia, dysaesthesia) oxaliplatin dosage adjustment should be based on the duration and severity of these symptoms. Oxaliplatin dose should be reduced from 85 to 75 mg/m2 (adjuvant).


1. National Institute for Health and Clinical Excellence. Technology Appraisal 33. Irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer. August 2005.2. Giacchetti S, et al. J Clin Oncol. 2000; 18(1): 136-3 De Gramont A, et al. J Clin Oncol. 2000; 18(16) 2938-29474. Giacchetti S, et al. Ann Oncol. 1999; 10(6): 663-669

XelOx

Patient profile: Standard 1st line 62

Failed venous catheterisation

Chemotherapy: Oxaliplatin 130mg/m2 i.v. infusion over 2 hours Day 1

Capecitabine 1000mg/m2 p.o. twice daily Day 1-14Doses should be rounded to the nearest 150mg. Tablets should be swallowed with water within 30 minutes after a meal.



Anti-emetics: High emetic potential during Oxaliplatin administration


physician discretion.Dose modifications:

If WBC is <3.0x109/L or neutrophils <1.0 x 109/L or platelets <100 x 109/L, then delay treatment by one week.

Renal insufficiency Creatinine Clearance 30 – 50mLls/min reduce capecitabine by 75%If ClCr <30mL/min, omit capecitabine.

Neurological symptoms (paraesthesia, dysaesthesia) oxaliplatin dosage adjustment should be based on the duration and severity of these symptoms. Oxaliplatin dose should be reduced from 85 to 65 mg/m2 (metastatic setting).

Other If grade 4 diarrhoea, grade 3-4 neutropenia (neutrophils < 1.0x109/L), grade 3-4 thrombocytopenia (platelets < 50x109/L) occur, the dose of oxaliplatin should be reduced from 85 to 65 mg/m² (metastatic setting) or 75 mg/m² (adjuvant setting), in addition to any 5-fluorouracil dose reductions required.




Stop Stop


Stop Stop Stop

1. Cassidy J. et al. J Clin Oncol. 2004; 22(11): 2084-912. National Institute for Health and Clinical Excellence. Technology Appraisal 93. Irinotecan, oxaliplatin and raltitrexed for the

treatment of advanced colorectal cancer. August 2005.

IRINOTECAN/MODIFIED DE GRAMONT (IrMdG)

Patient Profile: PS 0 – 1, alternative to OxMdG

63

Neuropathy risk/poor renal function

Pre-medication: Atropine s/c 0.24mg prior to irinotecan (SPC states 0.25mg s/c)

Chemotherapy: Irinotecan 180mg/m2 i.v. infusion over 90 minutes Day 1 Ca Levofolinate 175mg i.v. infusion over 2 hours Day 1(Folinic acid 350mg)5-fluorouracil 400mg/m2 i.v. bolus over 15 minutes Day 15-fluorouracil 2400mg/m2 i.v infusion over 46 hours Day 1

Repeat at 14-day intervals for 6 cycles then review

Additional Medication: Patients on irinotecan can suffer from potentially fatal delayed diarrhoea

especially when associated with fever. All patients should be prescribed loperamide (4mg stat. then 2mg 2hourly for max. 48 hrs) and Ciprofloxacin (500mg bd for 7 days) to be taken if instructed.


Investigations Weight, FBC, U&E’s, LFT’s before each cycle Where renal/hepatic function is abnormal, treatment is at consultant


Dose modifications: A dose reduction of 15 to 20 % should be applied for irinotecan and/or

5FU when applicable: haematological toxicity (neutropenia grade 4, febrile neutropenia

(neutropenia grade 3-4 and fever grade 2-4), thrombocytopenia and leukopenia (grade 4)),

non haematological toxicity (grade 3-4)

1. National Institute for Health and Clinical Excellence. Technology Appraisal 93. Irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer. August 2005.2. Douillard JY et al Pro ASCO 1999; 18: 233a, abstract 8993. Saltz LB et al Pro ASCO 1999; 18: 233a, abstract 898

Modified de Gramont

Patient profile: Unfit for combination therapy

64

Chemotherapy: Ca Levofolinate 175mg i.v. infusion over 2 hours Day 1(Folinic acid 350mg)5-fluorouracil 400mg/m2 i.v. bolus Day 15-fluorouracil 2800mg/m2 i.v. infusion over 46 hours Day 1

Repeat at 14 day intervals for 4 cycles. If evidence of response/clinical benefit, continue for up to 12 cycles




Dose modifications:

Treatment delays and dose reduction required for ≥ grade 2 diarrhoea or mucositis

1. De Gramont A. et al, J Cancer Clin Oncol, 1988; 24(9); 1499-5032. SL Cheeseman et al British Journal of Cancer (2002) 87, 393 – 3994. Seymour MT et al. Annals Oncol 1998, 9(Suppl 4): 47

CAPECITABINE

Patient profile: Unfit for combination therapy

65

As per NICE guidance


Repeat at 21 days from day 1, for 8 cycles.





Dose modifications:

If WBC is <3.0x109/L or neutrophils <1.0 x 109/L or platelets <100 x 109/L, then delay treatment by one week.





Stop Stop


Stop Stop Stop

1. National Instittute for Health and Clinical Excellence, Technology appraisal no. 61: 20032. Hoff PM et al. J Clin Oncol 2001; 19 2282-923. Van Cutsem E et al Eur J Clin Oncol 2001; 19: 4097-1064 Twelves C. Eur J Cancer 2002; 38: 515-5205. Callidy J et al. Anals Oncol 2002; 13: 566-75

UFT

Patient Profile: Unfit for combination therapy As per NICE guidance

66

Chemotherapy: Tegafur 300 mg/m2 (with uracil 672 mg/m2) p.o., combined with oral FA 90 mg/day, given in three divided doses one hour before or one hour after meals (preferably every 8 hours)

28 days followed by 7 days off (35 day cycle).

BSA (m2 )Uftoral

(capsules/day)

Daily schedule

(number of capsules)

Morning Midday Evening

< 1.17 3 1 1 1

1.17 - 1.49 4 2 1 1

1.50 - 1.83 5 2 2 1

> 1.83 6 2 2 2




Dose modifications:

(CTC) Grade Toxicity

Uftoral Dose Modification †

Non-Haematologic Toxicity (including diarrhoea)

0 - 1 No change

2 Therapy withheld until toxicity resolves to grade 1. No change in subsequent dose

3 - 4 Therapy withheld until toxicity resolves to grade 1. Decrease subsequent dose by 1 capsule/day. Dose reduction maintained for ongoing cycle and remainder of therapy

67

Haematologic Toxicity (based on granulocyte or platelet count)

0 - 1 No change

2 - 4 Therapy withheld until granulocytes 1500/mm3 and platelets 100,000/mm3

Haematologic Toxicity: Retreatment

0 - 2 No change

3 - 4 Decrease subsequent dose by 1 capsule/day. Dose reduction maintained for ongoing cycle and remainder of therapy

1. National Instittute for Health and Clinical Excellence, Technology appraisal no. 61: 20032. SPC Uftoral capsules

68

MITOMYCIN + 5FU

Patient Profile: 3rd line PS < 2

Chemotherapy: Mitomycin–C 7mg/m2 i.v. bolus (max 14mg) Day 1

Repeat every 6 weeks, Maximum 4 doses of Mitomycin

5- fluorouracil 300mg/m2/day continuous infusion in pump(7 day supply)

Anti-emetics: Moderate emetic potential for Mitomycin administration.



Dose modification: Treatment delays and dose reduction required for ≥ grade 2

diarrhoea or mucositis

1. Ross et al. Annals Oncol 1997; 8: 95-10012. MRC Trial - CR083. S. A Grumett et al The role of mitomycin C in the treatment of patients with advanced colorectal cancer resistant to 5-fluorouracil-folinic acid chemotherapy. Annals of Oncology 2001 12;4:575

69

MITOMYCIN + CAPECITABINE (MX)

Patient profile 3rd linePS < 2Failed venous catheterisation

Chemotherapy: Mitomycin-C 7mg/m2 i.v. bolus (Max 14mg) Day 1

Repeat every 6 weeks for 4 cycles

Capecitabine 1250 mg/m2 p.o. twice daily for 14 days

Doses should be rounded to the nearest 150mg. Tablets should be swallowed with water within 30 minutes after a meal.

Repeat at intervals of 21 days


Anti-emetics: Moderate emetic potential for mitomycin administration.

Investigations: Weight, FBC, U&E’s LFT’s before each cycle Where renal/hepatic function is abnormal, treatment is at consultant


Dose modifications: If WBC is <3.0x109/l or neutrophils <1.0 x 109/l or platelets <100 x 109/l, then


Renal insufficiency Creatinine Clearance 30 – 50mls/min reduce capecitabine by 75%If CC<30mls/min, omit capecitabine.

Grade 1st Occurrence 2nd Occurrence 3rd Occurrence 4th Occurrence1 Continue Continue Continue Continue2 – 3 Stop until recovery



Stop Stop


Stop Stop Stop

70

Dose modification for stomatitis, diarrhoea or palmar-plantar syndrome due to capecitabine.

1. Ross et al. Ann Oncol 1997; 8: 95-10012. Rao S et al Phase II study of capecitabine and mitomycin C as first-line treatment in patients with advanced colorectal cancer. Br J Cancer 2004;91:839-843.3. Chester JD et al. Protracted infusional 5-fluorouracil (5-FU) with bolus mitomycin in 5-fluorouracil resistant colorectal cancer. Ann Oncol 2000;11:235-237.

71

OVARIAN CANCER

Adjuvant

CARBOPLATIN

Patient profile: Stage 1 a/bPoorly differentiated

Chemotherapy: Carboplatin AUC 6 i.v. infusion over 1 hour Day 1(or AUC 5 for measured Creatinine Clearance)

Repeated at 21-day intervals for a maximum of 6 cycles


Investigations: Weight, FBC, U&E’s, LFT’s before each cycle. Measure creatinine before first cycle and re-calculate using serum

creatinine before each cycle thereafter

Dose Modifications:Dose for 1st course is based on creatinine clearance. On subsequent courses check serum creatinine, if it has changed by 10% recalculate

clearance using Calvert formula

FBC on day of treatment:

WBC>2.5x109/L(neuts>1.5x109/L)

WBC 2.5-2.0x109/L(neuts>1.5-1.0x109/L)

WBC<2.0x109/L(neuts<1.0x109/L)

Pls > 75x109/L 100% Reduce carboplatin to AUC=5 or 4 if CCmeas

Delay 1 week, then reduce carboplatin to AUC=5 or 4 if CCmeas

Pls <75x109/L Delay 1 week then reduce Carboplatin to AUC=5 or4 if CC meas

Delay 1 week then reduce Carboplatin to AUC=5 or4 if CC meas


1. Taylor A et al. J Clin Onc, 1994; 12: 2066-702. Harper P. Seminars in Oncology 1997; 24(5 suppl 15):S15-25

72

CARBOPLATIN/PACLITAXEL

Patient profile: Stage 1C or high risk of recurrence

Pre-medication: To be given 30 minutes before paclitaxel;Chlorphenamine 10mg i.vDexamethasone 20mg i.v.Ranitidine 50mg i.v.

Chemotherapy: Paclitaxel 175mg/m2 i.v infusion over 3 hours Day 1Carboplatin AUC 6 (calculated) i.v. infusion over 1 hour Day 1



Investigations: Weight, CA125, FBC, U&E’s, LFT’s before each cycle. Calculate creatinine clearance before each cycle.

Dose modifications: If WBC<3.5x109/l (neutrophils <1.5x109/l) or platelets <100x109/l then delay treatment for 1 week

If neutropenia is prolonged (more than 7 days) of severe neuropathy occurs then reduce paclitaxel dose by 20%.

Carboplatin: Dose for 1st course is based on creatinine clearance. On subsequent courses check serum creatinine, if it has risen by 10% recalculate clearance using Calvert formula.


WBC>2.5x109/L(neuts>1.5x109/L)

WBC 2.5-2.0x109/L(neuts>1.5-1.0x109/L)

WBC<2.0x109/L(neuts<1.0x109/L)

Pls > 75x109/L 100% Reduce carboplatin to AUC=5 or 4 if CCmeas


Pls <75x109/L Delay 1 week then reduce Carboplatin to AUC=5 or4 if CC meas



1. Harper P. Seminars in Oncology 1997; 24(5 suppl 15): S15-252. Anon. The Lancet 1998; 352: 1571-6

73

Metastatic/Advanced disease


Patient Profile: Stage 2PS ≤ 2

Pre-medication: To be given 30 minutes before paclitaxelChlorphenamine 10mg i.vDexamethasone 20mg i.v.Ranitidine 50mg i.v.

Chemotherapy: Paclitaxel 175mg/m2 i.v infusion over 3 hours Day 1Carboplatin AUC 6 (calculated) i.v. infusion over 1 hour Day 1

Repeat at 21-day intervals.


Investigations: Weight, CA125, FBC, U&E’s, LFT’s before each cycle. Calculate creatinine clearance before each cycle.

Dose modifications: If WBC<3.5x109/l (neutrophils <1.5x109/l) or platelets <100x109/l then delay treatment for 1 week

If neutropenia is prolonged (more than 7 days) of severe neuropathy occurs then reduce Paclitaxel dose by 20%.

Carboplatin: Dose for 1st course is based on creatinine clearance. On subsequent courses check serum creatinine, if it has risen by 10% recalculate clearance using Calvert formula


WBC>2.5x109/l(neuts>1.5x109/l)

WBC 2.5-2.0x109/l(neuts>1.5-1.0x109/l)

WBC<2.0x109/l(neuts<1.0x109/l)

Pls > 75x109/l 100% Reduce carboplatin to AUC=5 or 4 if CCmeas


Pls <7.5x109/l Delay 1 week then reduce Carboplatin to AUC=5 or4 if CC meas



1. McGuire WP, et al. N Engl J Med. 1997; 334: 1-62. Piccart MJ, et al.J Natl Cancer Inst. 2000; 9: 699-7083. Colombo N. Proc Am Soc Clin Oncol.2000; 19:A15004. Neijt et al. Proc Am Soc Clin Oncol.1997; 16:A3525. DuBois A et Al. Proc Am Soc Clin Oncol.1998; 17:A3616. Ozols RF. Et al. Proc Am Soc Clin Oncol.1999; 18:A1373

74

CARBOPLATIN/DOCETAXEL

Patient profile: Patients allergic to paclitaxel

Pre-medication: Dexamethsone 8mg po twice a day for 3 days starting day before chemotherapy is due.

Chemotherapy: Docetaxel 75mg/m2 i.v. infusion over 1 hour Day 1Carboplatin AUC 5 i.v. infusion over 1 hour Day 1

Repeated every 21 days.


Investigations: Weight, CA125,FBC, U&E’s, LFT’s before each cycle. Calculate creatinine clearance before each cycle.

Dose modification:

Docetaxel: Neutrophils < 1.0 x 109/L defer dosePlatelets < 100 x 109/L defer doseAST or ALT > 1.5 x ULN reduce dose by25%

> 3.5 x ULN discontinue


Carboplatin: Dose for 1st course is based on creatinine clearance. On subsequent courses check serum creatinine, if it has risen by 10% recalculate clearance using Calvert formula

1. Vasey P et al J Natl Cancer Inst 2004 Nov 17; 96(22): 1682-21

75

LIPOSOMAL DOXORUBICIN

Patient profile: PS ≤ 2Platinum resistant/refactory2nd line after platinum/taxane failure (NICE)

Chemotherapy: Liposomal Doxorubicin 50mg/m2 iv infusion (1mg/minute) Day 1 If no reaction, give subsequent doses over 60 minutes.

Repeat every 28 days. Max 6 cycles.


Investigations: CA125, weight, FBC, U&E’s, LFT’s before each cycle. ECG/LVEF before treatment and regularly throughout treatment

Dose modifications: Impaired hepatic function : Dose reduction should be considered in patients

with raised bilirubin above 4x upper limit of normal. For mlelosupression : Delay treatment until neutrophils >1.5x109/L and

platelets >150x109/L.Reduce dose by 25% if grad 4 myelosupression occurs. For stomatitis or palmar-plantar syndrome : Delay treatment until toxicity has

recoverd to grade 1 or better.If a 2 week delay is required for recovery, reduce dose by 25%.If grade 3 or 4 toxicity is still apparent at 6 weeks then stop treatment.

1. National Institute for Health and Clinical Excellence Technology Appraisal no. 91. Ovarian Cancer (advanced) – paclitaxel, pegylated liposomal doxorubicin hydrochloride and topotecan (review)

2. SPC Caelyx

76

TOPOTECAN

Patient profile: PS 0 – 1Resistant/refractory to platinum-based combination therapy and after Liposomal doxorubicin failure (NICE)

Chemotherapy: Topotecan 1.5mg/m2 i.v infusion over 30 minutes Days 1 to 5

Repeat every 21 days until disease progression

OR Weekly Schedule

Topotecan 4mg/m2 i.v. infusion over 30 minutes Days 1, 8 and 15



Investigations: CA125, weight, FBC, U&E’s, LFT’s prior to each cycle.

Dose Modifications:Neutrophils < 1.0 x 109/l defer treatmentPlatelets <100 x 109/l defer treatmentHb < 9g d/l defer treatmentCrCl < 41-60mls/min 75% of doseCrCl < 40mls/min 50% of dose

1. National Institute for Health and Clinical Excellence Technology Appraisal no. 91. Ovarian Cancer (advanced) – paclitaxel, pegylated liposomal doxorubicin hydrochloride and topotecan (review)

2. SPC Hycamtin3. Sehouli, J et al. Topotecan weekly versus routine 5-day schedule in patients with platinum resistant ovarian cancer (TOWER): A

randomised, two-stage phase II study of the North-Eastern German Society of Gynaecological Oncology (NOGGO). JCO 2007 ASCO Annual Meeting Proceedings Part 1, Vol 25, No. 18S, 2007: 5526

4. Vandenput, I et al. Effectiveness of weekly topotecan in patients with recurrent epithelial ovarian cancer. Int J Gynecol Cancer 2007, 17: 83 – 87

5. Morris, R et al. Topotecan weekly bolus chemotherapy for relapsed platinum-sensitive ovarian and peritoneal cancers. Gynecologic Oncology 2008; 109: 346 - 352

PACLITAXEL77

Patient profile: Relapse after single agent Carboplatin

Pre-medication: to be administered 30 minutes before chemotherapyDexamethasone 20mg iv Ranitidine 50 mg iv Chlorphenamine 10mg iv

Chemotherapy: Paclitaxel 175mg/m2 i.v. infusion over 3 hours Day 1



Investigations: Weight, CA125, FBC, U&E’s LFT’s before each cycle.

Dose modifications: If WBC<3.5x109/L (neutrophils <1.5x109/L) or platelets <100x109/L then

delay treatment for 1 week

If neutropenia is prolonged (more than 7 days) of severe neuropathy occurs then reduce dose by 20%.

No anticipatory dose reduction is needed for frail or elderly patients.

1. National Institute for Health and Clinical Excellence Technology Appraisal no. 91. Ovarian Cancer (advanced) – paclitaxel, pegylated liposomal doxorubicin hydrochloride and topotecan (review)2. Trimble EL et al. J Clin Oncol 1993; 11: 2405-103. Eisenhauer EA et al. J Clin Oncol 1994; 12: 2654-66

78

ENDOMETRIAL CANCER

Adjuvant


Patient profile: Adjuvant P/S 0-1

Pre-medication: To be given 30 minutes prior to paclitaxel:Chlorphenamine 10mg i.vDexamethasone 20mg i.v.Ranitidine 50mg i.v.

Chemotherapy: Carboplatin AUC 6 (calculated) i.v. infusion over 1 hour Day 1Paclitaxel 175mg/m2 i.v infusion over 3 hours Day 1

Repeat every 21 days for 4 cycles after operation and before radiotherapy


Investigations: Weight, FBC, U&E’s, UFT’s before each cycle Creatinine clearance should be calculated before each cycle

Dose modifications: If WBC<3.5x109/L (neutrophils <1.5x109/L) or platelets <100x109/L then

delay treatment for 1 week

If neutropenia is prolonged (more than 7 days) of severe neuropathy occurs then reduce Paclitaxel dose by 20%.

FBC on day of treatment WBC > 2.5x109/L(neuts > 1.0x109/L )

WBC < 2.5x109/L(neuts < 1.0x109/L)

Platelets >75x109/l Carboplatin 100%Paclitaxel 100%

Delay 1 week then reduceCarboplatin to AUC=5 Paclitaxel 75%

Platelets < 75x109/l Delay 1 week then reduceCarboplatin to AUC=5Paclitaxel 100%

Delay 1 week then reduceCarboplatin to AUC=5Paclitaxel 75%

1. Kwon Js, Elit L, Finn M et al. A compariaon of two prophylactic regimens for hypersensitivityrecations to paclitaxel. Gynecol Oncol 2002 Mar; 84(3): 420-5.2. Hoskins PJ, Swenerton KD, Pike JA, et al. Paclitaxel and carboplatin, alone with irradiation, inadvanced or recurrent endometrial cancer: a phase II study. J Clin Oncol 2001; 19(20): 4048-4053.3. Weber B, Mayer F, Bougnoux P, Lesimple T, Joly F, Fabbro M, et al. What is the bestchemotherapy regimen in recurrent or advanced endometrial carcinoma? Preliminary results.

79

[abstract]. Proc Am Soc Clin Oncol 2003;22.

Metastatic/Advanced

CARBOPLATIN

Patient profile: FitPS 2

Chemotherapy: Carboplatin AUC 6 (or 5 for measured CrCl) Day 1i.v. infusion over 1 hour

21-day intervals for a maximum of 6 cycles


Investigations: Weight, FBC, U&E’s, LFT’s before each cycle. Measure creatinine before first cycle and re-calculate using serum

creatinine before each cycle thereafter

Dose modifications: Adjust dose using Calvert formula

If WBC<3.5x109/L (neutrophils <1.5x109/L) or platelets <100x109/L then delay treatment for 1 week

1. Burke TW et al Gynecol Oncol 1993; Dec; 51(3): 397-4002. Muggia FM et al Semin Oncol 1994; Apr; 21(2 suppl 2): 35-42

80

Mixed Mullerian

DOXORUBICIN

Patient profile: PS 1 - 2

Chemotherapy: Doxorubicin 75mg/m2 i.v. bolus over 3-5 minutes Day 1

Repeat at 21-day intervals for 6 cycles at depending on response


Investigations: Weight, FBC, U&E’s LFT’s before each cycle Maximum cumulative dose: 450-550mg/m2

Consider LV ejection fraction if history of cardiac disease.

Dose modifications:

Doxorubicin dosage must be reduced if hepatic function is impairedBilirubin (μmol/L) Dose 20-50 75%51-85 50%>85 omit

1. Omura GA, Major FJ, Blessing JA, Sedlacek TV, Thigpen JT, Creasman WT, et al. A randomized study of adriamycin with and without dimethyl triazenoimidazole carboxamide in advanced uterine sarcomas. Cancer 1983;52:626-32.

2. Muss HB, Bundy B, DiSaia PJ, Homesley HD, Fowler WC, Jr., Creasman W, et al. Treatment of recurrent or advanced uterine sarcoma. A randomized trial of doxorubicin versus doxorubicin and cyclophosphamide (a phase III trial of the Gynecologic Oncology Group). Cancer 1985;55:1648-53.

3. Cancer Care Ontario Practice Guidelines. Systemic Therapy for Advanced, Recurrent, or Metastatic Uterine Sarcoma Evidence Summary Report #4-12

81

CISPLATIN

Patient profile: PS 1 - 2

Hydration: Please refer to appendix and Trust protocol for details

Chemotherapy: Cisplatin 80mg/m2 i.v. infusion over 2 hours Day 1

Urine should be maintained above 100ml/l/hr throughout treatment. If output falls below 400ml in any 4 hour period, then give furosemide 20mg i.v. repeated as necessaryAlternatively mannitol may be used.

Repeat at 21-day intervals. Maximum of 6 cycles


Investigations: Weight. U&E’s, FBC, LFT’s before each cycle Calculate creatinine clearance before each cycle

Dose modifications : If WBC < 3.5 x 109/l or platelets < 100 x 109/l delay treatment by one week.

Creatinine clearance Cisplatin dose

> 50 mL / min 100%40 – 50 mL/ min 75%< 40 mL / min no further cisplatin

1. Clatterbridge Centre for Oncology - Chemotherapy Protocols April 20001 Thigpen T et al, Semin Oncol 1994; 21: 114-1182. Thigpen T et al. J Clin Oncol 1991; 9: 1962-6

82

CERVICAL CANCER

CISPLATIN

Patient profile: In combination with radical radiotherapyBulky 1B, 2B or 3BNormal liver/renal/haematology


Chemotherapy Cisplatin 40 mg/m2 (max 70mg) i.v. infusion over 2 hours Day 1


Repeat weekly for a maximum of 6 weeks.


Investigations: Weight, FBC, U&E’s, LFT’s before each cycle. Calculate creatinine clearance before each cycle

Dose modifications:

Reduce dose to 30mg/m2 if radiotherapy treatment fields large.

Creatinine clearance cisplatin dose

> 50 mL / min 100%40 – 50 mL / min 75%< 40 mL / min no further cisplatin

1. Rose PG, Bundy BN. J Clin Oncol 2002; 20: 891-32. Green JA. Lancet. 2001; 358: 781-63. Morris M, et al. N Eng J Med. 1999; 340: 1137-434. Rose PG, et al. N Eng J Med. 1999; 340: 1144-53

83

TOPOTECAN/CISPLATIN

Patient profile: Recurrent disease after radiotherapy and for patients with Stage IVB disease in platinum naïve patients PS0/1.


Chemotherapy: Topotecan 0.75 mg/m2/day i.v. infusion over 30 minutes Days 1-3Cisplatin 50 mg/m2 i.v. infusion over 2 hours Day 1

Urine should be maintained above 100mL/hr throughout treatment. If output falls below 400mL in any 4 hour period, then give furosemide

20mg i.v. repeated as necessary .Alternatively mannitol may be used.

Repeat every 21 days for 4 – 6 cycles or until disease progression


Investigations: Weight, FBC, U & E’s LFT’s before each cycle Calculate creatinine clearance before each cycle

Dose modifications:

Neutrophils < 1.0 x 109/L defer treatmentPlatelets <100 x 109/L defer treatmentHb < 9g dL defer treatment

Severe neutropenia (neutrophil count less than 0.5 x 109/L) for 7 days or more, or severe neutropenia associated with fever or infection or who have had treatment delayed due to neutropenia the dose should be reduced by 20% to 0.6 mg/m2/day for subsequent courses (or subsequently down to 0.45 mg/m2/day if necessary).

Creatinine clearance Cisplatin dose


1. AWMSG Final Appraisal IV Topotecan for Cervical Cancer Advice No: 0208 – February 2008 2. Long HJ, Bundy BN, Grendys EC, et al. Randomized phase III trial of cisplatin with or without topotecan in carcinoma of

the uterine cervix: a Gynecologic Oncology Group study. J Clin Oncol 2005; 23: 4626–33. 3. SPC Hycamtin 2009

84

MCarbo

This is a modification of the BMCarbo regimen where bleomycin is omitted due to pulmonary toxicity

Patient profile: If renal function inadequate for cisplatin (in MC)

Chemotherapy: Mitomycin-C 10mg/m2 i.v. bolus over 3-5 minutes Day 1 (cycles 1 & 3 only)Carboplatin AUC 6 i.v. infusion over 1 hour Day 1(AUC of 5 is used for measured clearance)

Repeated every 21 days for a maximum of 4 courses.


Investigations: Weight, Creatine clearance, FBC, U&E’s, LFT’s before each cycle.

Dose Modifications:

If WBC < 3.5 x 109/L or platelets < 100 x 109/Ldelay treatment by one week.

Adjust dose using Calvert formula

85

LUNG CANCER

SMALL CELL LUNG CANCER

Adjuvant

CARBOPLATIN + ETOPOSIDE

Patient profile: For rare cases of resected small cell lung cancer

Chemotherapy: Carboplatin AUC 5iv. infusion over 1 hour Day 1Etoposide 100mg/m2 iv. infusion over 1 hour Day 1Etoposide 200mg/m2 po daily Day 2 + 3(Round down to nearest 50mg)



Prophylactic antibiotics: Ciprofloxacin 250mg bd and Fluconozole 50mg od on days 8 to 14 during first

cycle and subsequent cycles if risk of infection.

Investigations:1. Weight, FBC, U&E’s, LFT’s, Creatinine Clearance before each cycle.

Dose modifications: If WBC > 3.5 x 109/L and platelets >100 x 109/L give full dose. If below these

levels, delay for 1 week. If WBC < 1.0 or platelets <25 or if neutropenic sepsis occurs at any time, reduce dose by 25% for subsequent doses.

Renal Impairment CrCl 41 - 60 mL/min REDUCE Carboplatin using calvert formulaCrCl 15 - 40 mL/min REDUCE Carboplatin doseusing calvert formula and

REDUCE Etoposide to 75% doseCrCl < 10-15 mL/min OMIT Carboplatin and REDUCE Etoposide to 50% dose or

OMIT Etoposide

Hepatic Impairment If Bilirubin 1-2 x ULN REDUCE Etoposide to 50% doseIf Bilirubin 2-4x ULN REDUCE Etoposide to 25% doseIf Bilirubin > 4 x ULN STOP treatment with Etoposide

1. Smith IE, Evans BD, Gore ME, et al. Carboplatin (Paraplatin; JM8) and etoposide (VP-16) as first-line combination therapy for small-cell lung cancer. J Clin Oncol. 1987 Feb; 5(2): 185-9.

86

Advanced disease

CARBOPLATIN + ETOPOSIDE

Patient profile: Standard regimenPS ≤ 2

Chemotherapy: Carboplatin AUC 5 iv. infusion over 1 hour Day 1Etoposide 100mg/m2 iv. infusion over 1 hour Day 1Etoposide 200mg/m2 po daily Day 2 + 3(round down to nearest 50mg)



Prophylactic antibiotics: Ciprofloxacin 250mg bd and Fluconozole 50mg od on days 8 to 14 during first

cycle and subsequent cycles if risk of infection.

Investigations: Weight, FBC, U&E’s, LFT’s, Creatinine Clearance before each cycle. Where renal/hepatic function is abnormal, treatment is at consultant


Dose modifications: If WBC > 3.5 x 109/L and platelets >100 x 109/L give full dose. If below these levels,

delay for 1 week. If WBC < 1.0 or platelets <25 or if neutropenic sepsis occurs at any time, reduce dose by 25% for subsequent doses.

Renal Impairment CrCl 41 - 60 mL/min REDUCE Carboplatin using calvert formulaCrCl 15 - 40 mL/min REDUCE Carboplatin doseusing calvert formula and

REDUCE Etoposide to 75% doseCrCl < 10-15 mL/min OMIT Carboplatin and REDUCE Etoposide to 50%

dose or OMIT Etoposide

Hepatic Impairment If Bilirubin 1-2 x ULN REDUCE Etoposide to 50% doseIf Bilirubin 2-4x ULN REDUCE Etoposide to 25% doseIf Bilirubin > 4 x ULN STOP treatment with Etoposide

1. Cancer Care Ontario Clinical Practice Guideline Chemotherapy for Relapsed Small Cell Lung Cancer: Evidence-Based Series #7-17:

2. Skarlos DV et al. Ann Oncol 1994; 5: 601-7

87

TOPOTECAN IV/ORAL

Patient profile: 2nd line therapy in patients fit for further chemotherapy.PS ≤2

Chemotherapy: Topotecan 1.5mg/m2 /day i.v.infusion over 30 minutes Days 1-5

ORTopotecan 2.3 mg/m2 / day orally Days 1-5(rounded to the nearest o.25mg capsule)

Repeat at 21-day intervals until disease progression


Investigations: CT chest before treatment and after 2-3 cycles Weight, FBC, U&E’s, LFT’s before each cycle Where renal/hepatic function is abnormal, treatment is at consultant


Toxicities: Neutropenia, fever, thrombocytopenia, anaemia, nausea, vomiting, diarrhoea, abdominal pain, constipation, stomatitis, dyspepsia, alopecia, rash, fatigue, asthenia, malaise, anorexia, infection and sepsis.

Dose modifications:

Neutrophils < 1.0 x 109/L defer treatmentPlatelets <100 x 109/L defer treatmentHb < 9g dL defer treatmentCrCl < 41-60mLs/min 75% of doseCrCl < 40mLs/min 50% of dose

Oral Topotecan:Severe neutropenia associated with fever or infection, or who have had treatment delayed due to neutropenia, the dose should be reduced by 0.4 mg/m2/day to 1.9 mg/m2/day (or subsequently down to 1.5 mg/m2/day if necessary).For patients who experience grade 3 or 4 diarrhoea, the dose should be reduced by 0.4 mg/m2/day for subsequent courses.

1. AWMSG Final Appraisal for IV Topotecan for SCLC Advice No: 0108 – February 20082. SmPC Hycamtin capsules June 2009.3. O'Brien ME, Ciuleanu TE, Tsekov H, et al. Phase III Trial comparing supportive care alone with supportive care with

oral topotecan in patients with relapsed small-cell lung cancer. J Clin Oncol 2006; 24(34): 5441-5447 4. Eckardt JR, von Pawel J, Pujol J et al. Phase III study of oral compared with intravenous Topotecan as second-line

therapy in small-cell lung cancer. J Clin Oncol 2007; 25(15): 2086-92.

88

NON-SMALL CELL LUNG CANCER

Adjuvant

CISPLATIN/VINORELBINE

Patient profile: Postoperative adjuvant treatment for fitter younger patientsPS 0 – 1 stage lc-llb


Chemotherapy: Vinorelbine 30mg/m2 i.v. infusion over 5-10 minutes Days 1 & 8 (max 60mg)Cisplatin 80mg/m2 i.v. infusion over 2 hours Day 1


Repeat 21-day intervals for 4 cycles

Anti-emetics: High emetic potential day 1

Investigations: Weight, Creatine Clearance, FBC, U&E’s, LFT’s before each cycle Where renal/hepatic function is abnormal, treatment is at consultant physician

discretion.

Dose Modifications: If WBC < 3.5 x 109/L or platelets < 100 x 109/L delay treatment by one week. Hepatic Impairment If Bilirubin 35 – 50 µmol/L REDUCE Vinorelbine to 50% doseIf Bilirubin >50 µmol/L REDUCE Vinorelbine to 25% dose



1. Arriagada R, Bergman B, Dunant A, et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small- cell lung cancer. NEJM. 2004; 350(4): 351-60.

2. Douillard JY, Rosell R, Delena M, et al. ANITA: Phase III adjuvant vinorelbine and cisplatin versus observation in completely resected (stage I-III) non-small-cell lung cancer (NSCLC) patients: final results after 70 month median follow-up. On behalf of the Adjuvant Navelbine Internation Trialist Assoication (abstract). J Clin Oncol. 2005; 23:A7013.

3. Winton T, Livington D, Johnson D et al. Vinorelbine plus cisplatin as compared with oberservation in resected non small cell lung cancer. NEJM 2005; 352: 2589-2587,

89

CARBOPLATIN/VINORELBINE

Patient profile: Alternative to Vin/ CisPS 0 – 1 stage lc - llb

Chemotherapy: Carboplatin AUC 5 i.v. infusion over 1 hour Day 1(AUC = 4 if measured clearance used)Vinorelbine 30mg/m2 i.v. infusion over 5-10 minutes Days 1 & 8(max 60mg)

Repeat 21-28 day intervals for 4 cycles


Investigations: Weight, Creatine Clearance, FBC, U&E’s, LFT’s before each cycle Where renal/hepatic function is abnormal, treatment is at consultant physician

discretion.

Dose Modifications:

Hepatic impairment If Bilirubin 35 – 50 µmol/L REDUCE Vinorelbine to 50% doseIf Bilirubin >50 µmol/L REDUCE Vinorelbine to 25% dose

Renal Impairment Reduce dose of Carboplatin according to calvert formula

1. Santomaggio C, et al. Carboplatin and vinorelbine in the treatment of advanced non-small-cell lung cancer. A multicenter phase II study. Am J Clin Oncol 1998;21(1):67-71

2. Couture F, Vincent M, Sehdev S, et al. Carboplatin and vinorelbine (‘CarNavel”) : A prospective phase II evaluation of 2 doses of carboplatin in advanced non-small cell lung cancer (S-NSCLC). Proc. ASCO 2003. (Abstract no. 2715)

3. Chetiyawardana, Nov 2002, Data from Pierre Fabre.

90

Metastatic/AdvancedGEMCITABINE/CARBOPLATIN

Patient profile: 1st line for advanced Squamous cell (adenocarcinoma and large cell –see Pem/Cis)PS ≤ 2

Chemotherapy: Carboplatin AUC 5 i.v. infusion over 1 hour Day 1Gemcitabine 1250mg/m2 i.v. infusion over 30 mins Days 1 + 8

Repeat 21 days from day 1. Assess response after 2 cycles. Max 4 cycles.

Additional Medication: Ciprofloxacin 500mg po twice daily, days 8- 14

Anti-emetics: Day 1: Moderate emetic potentialDay 8: Low emetic potential

Investigations: Weight, FBC, U&E’s, Creatinine Clearance, LFT’s before each cycle Where renal/hepatic function is abnormal, treatment is at consultant


Dose modifications:Gemcitabine 1000mg/m2 if PS > 1

Day 1: Neutophils <1.5x109/L or platelets <100x109/L defer treatment one week.

Day 8: Neutrophils <1.0x109/L or platelets <75x109/L then cancel day 8 gemcitabine.

1. National Institute for Health and Clinical Excellence, Guidance on the use of decetaxel, paclitaxel, gemcitabine and vinorelbine for the treatment of non-small cell lung cancer. 2001; National Institute for health and clinical excellence; London.2. Scagliotte GV. Et al. J Clin Oncol.2002. 20(21): 4285-913. Zatloukal P & Petruzelka L. Lung Cancer, 2002; 38 Suppl 2: S33-64. Kortsik C et al. Lung Cancer; 2003. 40(1): 85-905. Rudd RM et al. Proceedings of the Americal Society of Clinical Oncology, 2002: Abstract 11646. Cockcroft D & Gault MH. 1976; Nephron 16: 31-41

91

PEMETREXED/CISPLATIN

Patient profile: Stage III or IV NSCLC (histology confirmed as Adenocarcinoma or large cell)

PS 0-1Cr Cl= >45ml/minBilirubin ≤ 1.5 x ULNALT, AST and Alkaline Phosphatase ≤ 3 x ULN (or ≤ 5 x ULN if liver metastases present)

Pre medication: Dexamethasone 4mg bd po for 3 days starting day prior to chemo, to reduce severity of skin reactions

Chemotherapy: Day 1Pre-hydration 1 Litre of sodium chloride 0.9% with

20mmol potassium and 8mmol magnesium over 1 hour.

Pemetrexed 500mg/m2 in 100ml sodium chloride 0.9% infusion over 10 minutes

Hydration Mannitol 20% 100ml over 15 minutes

Cisplatin 75mg/m2 in 1000ml sodium chloride 0.9% infusion over 2 hrs.

Post-hydration 1Litre of sodium chloride 0.9% with 40mmol potassium and 8mmol magnesium over 2 hours.

500ml sodium chloride 0.9% with potassium 10mmol over 1 hour or ask patient to drink 500ml of water before discharge.

Urine should be maintained above 100ml/l/hr throughout treatment. If output falls below 400ml in any 4 hour period, then give furosemide 20mg i.v. repeated as necessary. Alternatively mannitol may be used.

AdditionalMedication: Vitamin B12 injection 1 week before and with the first dose of

pemetrexed and with every 3 cycles thereafter. Folic acid 400micrograms orally daily starting 1 week before pemetrexed, continuing until 21 days after the last dose.Ciprofloxacin 500mg po twice daily, days 8- 14



Investigations: Weight, Creatinine clearance, FBC, U&E’s, LFT’s before each cycle

92

Chest X-ray and CT Scan at baseline and after every two cycles Where renal/hepatic function is abnormal, treatment is at consultant physician

discretion.

Dose Modifications:Myelosuppression: Delay treatment until neutrophils >1.5x109/L and platelets >150x109/LNon-haematological toxicity: delay treatment until symptoms recovered and modify subsequent doseRenal impairmentCreatinine clearance cisplatin dose> 50 mL / min 100%40 – 50 mL / min 75%< 40 mL / min no further Cisplatin

Dose modification for Haematological toxicity

Dose of Pemetrexed (mg/m2 )

Dose for Cisplatin (mg/m2 )

Nadir ANC <0.5 x 103 and nadir platelets 50 x103

75% of previous dose 75% of previous dose

Nadir platelets <50 x103 regardless of nadir ANC 75% of previous dose 75% of previous dose

Nadir platelets <50 x103 with bleeding , regardless of nadir ANC 50% of previous dose 100% of previous dose

Dose Modification Table for Non-Haematologic Toxicities



Any Grade 3 or 4 toxicities except mucositis


Any diarrhoea requiring hospitalisation (irrespective of grade) or Grade 3 or 4 diarrhoea


Grade 3 or 4 mucositis 50% of previous dose 100% of previous dose

1. Pemetrexed for the first-line treatment of non-small-cell lung cancer. NICE TA 181. www.nice.org.uk2. SPC Alimta. Eli Lilly & co Ltd. emc.medicines.org.uk [ accessed 15 October 09]

93

ERLOTINIB

Patient profile: 2nd line treatment in advanced NSCLC for patients that meet the following criteria:

Adenocarcinoma ECOG PS 0-1 Non-Smoker +/- female

Chemotherapy: Erlotinib 150 mg p. o. daily 1hour before or 2 hours after food

Continuous therapy until disease progression

AdditionalMedication: Loperamide 2mg PRN for diarrhoea

Emollient e.g. Diprobase cream for skinAvoid strong sunlight. Use sun block SPF 15 or above.


Investigations: Weight, FBC, U & Es, LFT’s before each cycle In patients who do not develop rash within the first 4 – 8 weeks of

treatment, further treatment should be re-assessed

Dose modifications: When dose adjustment is necessary, reduce in 50 mg steps.

1. National Institute for Health and Clinical Excellence TA1622. SPC Tarceva 20083. Shepherd FA et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005 Jul 14; 353(2):123-32.

94

DOCETAXEL

Patient profile: 2nd line treatment. Alternative to ErlotinibPS = 0 or 1

Pre-medication: Dexamethasone 8mg p.o. twice daily for 3 days starting day before chemotherapy.

Chemotherapy: Docetaxel 75mg/m2 i.v. infusion over 1 hour Day 1



Investigations: Weight, FBC, U&E,s, LFT’s before each cycle

Dose modifications: Neutrophils < 1.0 x 109/L defer dose Platelets < 100 x 109/L defer dose AST or ALT > 1.5 x ULN reduce dose by 25% > 3.5 x ULN discontinue


4. National Institute for Health and Clinical Excellence, Guidance on the use of decetaxel, paclitaxel, gemcitabine and vinorelbine for the treatment of non-small cell lung cancer. 2001; National Institute for health and clinical excellence; London

5. Shepherd FA. Et al. J Clin Oncol. 2000; 18: 2094-1036. Fossella F. Eur J Cancer. 2001; 37 (suppl 6): S154 (Abstract)7. Roszkowski K. et al. 2000; Lung Cancer; 27: 145-7

95

MESOTHELIOMA CHEMOTHERAPY REGIMENS

MVP

Patient profile: Standard treatment, MS01 trial


Chemotherapy: Mitomycin C 6mg/m2 i.v. bolus over 3-5 minutes Day 1Vinblastine 6mg/m2 i.v. bolus over 3-5 minutes Day 1(Max dose 10mg)Cisplatin 50mg/m2 i.v. infusion over 2 hours Day 1

Urine should be maintained above 100ml/l/hr throughout treatment. If output falls below 400ml in any 4 hour period, then give furosemide 20mg i.v. repeated as necessary .Alternatively mannitol may be used.



Investigations: Weight, creatinine clearance, FBC, U&E’s, LFT’s before each cycle


Dose modifications:

Hepatic Impairment If Bilirubin 1-2.5 x ULN REDUCE Vinblastine to 50% doseIf Bilirubin >2.5 x ULN REDUCE Vinblastine to 25% dose



1. Ellis PA et al. Brit J Cancer 1995; 71: 366-702. Non-small cell lung cancer collaborative group BMJ 1995; 311: 899-9093. Middleton GW et al. Ann Oncol. 1998; 9: 269-73

96

PEMETREXED/CISPLATIN

Patient profile: Advanced disease, not suitable for surgery PS 0-1

Pre medication: Dexamethasone 4mg bd po for 3 days starting day prior to chemo, to reduce severity of skin reactions


Chemotherapy: Pemetrexed 500mg/m2 i.v. infusion over 10 minutes Day 1Cisplatin 75mg/m2 i.v. infusion over 2 hours Day 1


AdditionalMedication: Folic acid 400mcg po daily starting a week before chemo,

supplementation must continue during the full course of therapy and for 21 days after the last dose of pemetrexed.Vitamin B12 injection (hydroxocobalamin) 1000mcg given IM the week before chemo and every 3 cycles thereafter.



Investigations: Weight, Creatinine clearance, FBC, U&E’s, LFT’s before each cycle Where renal/hepatic function is abnormal, treatment is at consultant physician

discretion.

Dose Modifications:Myelosuppression: Delay treatment until neutrophils >1.5x109/L and platelets >150x109/LNon-haematological toxicity: delay treatment until symptoms recovered and modify subsequent doseRenal impairmentCreatinine clearance cisplatin dose> 50 mL / min 100%40 – 50 mL / min 75%< 40 mL / min no further Cisplatin

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Dose Modification Table for Non-Haematologic Toxicities



Any Grade 3 or 4 toxicities except mucositis


Any diarrhoea requiring hospitalisation (irrespective of grade) or Grade 3 or 4 diarrhoea


Grade 3 or 4 mucositis 50% of previous dose 100% of previous dose

1. Vogelzang NL, et al. J Clin Oncol. 2003; 21 (14): 2636-442. NICE Technology Appraisal 1353. SPC Pemetrexed

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HEAD AND NECK CANCER

Adjuvant

No proven role

LOCALLY ADVANCED DISEASE/RADICAL THERAPY

Neo-adjuvant

DOCETAXEL/CISPLATIN/5Fu (Followed by XRT)

Patient profile: Locally advanced, unresectable head and neck cancerXRT follows chemotherapy


Pre-medication: Dexamethasone 8mg p.o. twice daily for 3 days starting day before chemotherapy.

Chemotherapy: Docetaxel 75mg/m2 i.v. infusion over 1 hour Day 1Cisplatin 75mg/m2 i.v. infusion over 2 hours Day 15 Fluorouracil 750mg/m2/day cont. infusion Day 1-5

Urine should be maintained above 100mL/hr throughout treatment. If output falls below 400mL in any 4 hour period, then give furosemide 20mg i.v. repeated as necessary. Alternatively mannitol may be used.

Repeat every 21 days for 3-4 cycles


Investigations: Weight, FBC, U&E’s, LFT’s before each cycle

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Dose Modifications: GI toxicity : mucositis or diarrhoea >grade 3 or hand and foot

syndrome ≥2 reduce dose of 5FU to 2/3 dose Neurotoxicity or cutaneous reaction if severe : reduce dose of

Docetaxel to 60mg/m2

Hepatic Dysfunction:

AST/ALT Alk Phos Bilirubin DoseMild-moderate >1.5 ULN >2.5 x ULN Reduce dose of Docetaxel to

60mg/m2

Severe >3 ULN >6XULN >ULN Stop Docetaxel>4 x ULN Stop 5FU

Renal impairment Creatinine clearance cisplatin dose> 50 mL / min 100%40 – 50 mL / min 75%< 40 mL / min no further cisplatin

1. AWMSG Advice 1008-June 20082. Vermorken JB, Remenar E, Van Harpen C et al. Standard cisplatin/infusional 5-fluorouracil (PF) Vs docetaxel(T) plus PF (TPF) as

neoadjuvant chemotherapy for nonresectable locally advanced squamous cell carcinoma of the head and neck (LA_SCCHN): a phase III trial of the EORTC Head and neck cancer Group (EORTC#24971) J Clin Oncol 2004;22;14s

3. Posner M. Paradigm shift in the treatment of head and neck cancer: The role of Neo-adjuvant Chemotherapy. The ocologist 2005;10(suppl 3)11-19

4. Posner M. Scientific Special Session presentation: Docetaxel added to induction therapy in head and neck cancer. ASCO 2006 Annual meeting.

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DOCETAXEL/CISPLATIN/5Fu (Followed by ChemoXRT)

Patient profile: Locally advanced, unresectable head and neck cancer Induction chemotherapy followed by CXRT


Pre-medication: Dexamethasone 8mg po twice daily for 3 days starting day before chemotherapy.

Chemotherapy: Docetaxel 75mg/m2 i.v. infusion over 1 hour Day 1Cisplatin 100mg/m2 i.v. infusion over 2 hours Day 15 Fluorouracil 1000mg/m2/day cont. infusion Day 1-4






Dose Modifications: GI toxicity : mucositis or diarrhoea >grade 3 or hand and foot

syndrome ≥2 reduce dose of 5FU to 2/3 dose Neurotoxicity or cutaneous reaction if severe : reduce dose of

Docetaxel to 60mg/m2

Hepatic Dysfunction:

AST/ALT Alk Phos Bilirubin DoseMild-moderate >1.5 ULN >2.5 x ULN Reduce dose of Docetaxel to

60mg/m2

Severe >3 ULN >6XULN >ULN Stop Docetaxel

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>4 x ULN Stop 5FU


1. AWMSG Advice No.1008 June 2008

RADICAL CONCURRENT CHEMORADIATION (NASOPHARYNX)

CISPLATIN + XRT

Patient profile : Nasopharynx


Chemotherapy: Cisplatin 100 mg/m2 i.v. infusion Days 1,22 and 43concurrent with XRT


Consider 2 cycles neo-adjuvant


Investigations: Weight, creatinine clearance, U&E’s, FBC, LFT’s, before chemotherapy. Where renal/hepatic function is abnormal, treatment is at consultant physician

discretion.

Dose modifications:


1. Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefebvre JL, Greiner RH. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004 May 6;350(19):1945-52.

2. Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 2004 May 6;350(19):1937-44.

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CETUXIMAB + XRT

Patient profile : Patients with locally advanced squamous cell cancer of the head and neck .KPS 90% or greater and for whom all forms of platinum-based chemoradiotherapy treatment are contraindicated.

Pre-medication : Chlorphenamine10mg IV bolus over 3-5 mins

Chemotherapy: Cetuximab 400 mg/m2 iv infusion over 2 hours 1 week prior to XRT Cetuximab 250 mg/m2 iv infusion over 60 mins weekly

Cetuximab is continued throughout duration of radiotherapy (2-8 weeks).

Anti-emetics: Low emetic potential. Anti-emetics may not be required.

Investigations: Weight, U&E’s, FBC, LFT’s, before chemotherapy. Where renal/hepatic function is abnormal, treatment is at consultant physician

discretion.

Dose modifications:

Grade 3 or 4 Acneiform Rash

Action Outcome Dose Modification

1st occurrence Delay infusion 1 to 2 weeks

Improvement Continue at 250mg/m2

No improvement Discontinue2nd occurrence Delay infusion

1 to 2 weeksImprovement Continue at 200mg/m2

No improvement Discontinue3rd occurrence Delay infusion

1 to 2 weeksImprovement Continue at 150mg/m2

No improvement Discontinue4th occurrence Discontinue

1. NICE TA 145 Cetuximab for the treatment of head and neck cancer2. SPC Erbitux 20093. Bonner JA, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006 Feb

9;354(6):567-78

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http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Bonner%20JA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract

RADICAL CONCURRENT CHEMORADIATION (OROPHARYNX)

CARBO /5 FU INF

Patient profile: Stage III/IV Oropharynx (or nasopharynx if renal function inadequate for cisplatin)

Chemotherapy: Carboplatin 70mg/m2 iv infusion over 1 hour Days 1 – 45-FU 600mg/m2/24 hr continuous infusion Days 1 – 4 Weeks 1, 4 and 7 concurrent with XRT


Investigations: Weight, creatinine clearance, U&E’s, FBC, LFT’s before each cycle. Where renal/hepatic function is abnormal, treatment is at consultant physician

discretion.

Dose modifications:

Reduce dose of Carboplatin in renal impairment

1. Calais G et al. Proc Am Soc Clin Oncol 1998; Abstract 1484

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Palliative Chemotherapy

CISPLATIN + 5FU

Patient profile: First line chemotherapyHead and Neck cancerPS 0-2


Chemotherapy: Cisplatin 80mg/m2 i.v. infusion over 2 hours Day 15-fluorouracil 1000mg/m2 continuous infusion Days 1 – 4


Repeat at 21-day intervals until disease progression or limited by toxicity


Investigations: Weight, creatinine clearance, FBC, U&E’s, LFT’s before each cycle Where renal/hepatic function is abnormal, treatment is at consultant physician

discretion.

Dose modifications: Gastrointestinal Toxicities If Mucositis or Diarrhea > grade 3 in previous course REDUCE to 2/3 doseIf hand foot syndrome ≥ grade 2 REDUCE to 2/3 dose Renal impairment Creatinine clearance cisplatin dose> 50 mL / min 100%40 – 50 mL / min 75%< 40 mL / min no further cisplatin

1. Taylor SG et al. J Clin Oncol 1994; 12: 385-952. Martim M et al. Int J Radiat Oncol Biol Phys.1990; 19: 973-53. Jacobs C et al. J Clin Oncol; 1992; 10: 257-634 Forastiere AA et al. J Clin Oncol. 1992; 10: 1245-515 Al-Sarraf M et al. J Clin Oncol. 1998; 16: 1310-17

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VBMF

Patient profile: Second line chemotherapy

Chemotherapy: Vincristine 1.4 mg/m2 (max 2mg) i.v. bolus Day 1Bleomycin 30,000 units (fixed) i.v. bolus Day 1(maximum 10 doses or 300,000 units)5-FU 500 mg (fixed) i.v. bolus Day 1Methotrexate 100 mg/m2 i.v. bolus Day 1

Repeat at 14 day intervals for 6-12 cycles depending on responseAdditional Medication: Hydrocortisone 100mg intravenously given with the chemotherapy to

minimise the risk of bleomycin reactions.Folinic acid rescue 15-30mg po every four hours for 6 dosesStarting 24 hours after methotrexate dose.


Investigations: Chest x-ray day 1

Weight, FBC, U&E’s, LFT’s before each cycle

Dose Modifications: Haematological Toxicity: WBC < 3.0 x 109/L or Neutrophils < 1.5 x 109/L or

Platelets < 100 x 109/L Defer treatment for 1 week. Repeat FBC and if within normal parameters, continue with full dose.

Renal Impairment:

GFR (mL/min) Methotrexate Dose

> 80 Give 100%

60 Give 65%

45 Give 50%

< 30 Omit

GFR (mL/min) Bleomycin Dose

> 50 Give 100%

10-50 Give 75%

<10 Give 50%

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Hepatic Impairment : Methotrexate is contraindicated in severe hepatic impairment. Neuropathy: Vincristine should be reduced to 1mg/m2 in the presence of Grade 2

neuropathy (severe paraesthesia & mild weakness). Vincristine should be discontinued in the presence of Grade 3 -4 neuropathy.

Pulmonary Toxicity: Bleomycin must be discontinued permanently if symptoms of pulmonary toxicity occur, eg dyspnoea, abnormal CXR or decreased pulmonary function.

1. UKHAN trial (May 1990), UKCC Head & Neck Collaborative Group

BLADDER CANCER

GEMCITABINE + CISPLATIN

Patient group: Prior to radical surgery or radiotherapy in muscle invasive but non-metastatic disease.


Chemotherapy: Cisplatin 70mg/m2 i.v. infusion over 2 hours Day 1Gemcitabine 1200mg/m2 i.v.infusion over 30 minutes Day 1 & 8


Repeat for 2 – 3 cycles


Investigations: Weight, FBC, U&E’s, creatinine clearance, LFT’s before each cycle Where renal/hepatic function is abnormal, treatment is at consultant


Dose modifications:Give gemcitabine 1000mg/m2 if PS=2)Neutrophils<0.8x109/L omit dose and reduce subsequent doses by 25%Platelets <75x109/L omit dose and reduce subsequent doses by 25%AST or ALT >5 x upper limit reduce dose by 25%Gemcitabine can cause elevation of transaminases, which usually recovers after omitting treatment for 2-3 weeks. Resume at a lower dose.

1. R. Dienstmann et al Phase II trial of gemcitabine and cisplatin as neoadjuvant chemotherapy for invasive bladder cancer: Preliminary results. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 145902. Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Lancet, 2003;361(9373): 1927-343. Von der Maase H, Hansen SW, Roberts JT et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large randomized, multinational, multicenter phase III study. J Clin Oncol 2000; 18: 3068–3077.

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4. Luigi Dogliotti et al Gemcitabine plus Cisplatin versus Gemcitabine plus Carboplatin as First-Line Chemotherapy in Advanced Transitional Cell Carcinoma of the Urothelium: Results of a Randomized Phase 2 Trial European urology 52 ( 2 0 0 7 ) 134–141

GEMCITABINE + CARBOPLATIN

Patient group: Elderly and/or poor PS=2 and/or poor renal function (ClCr ≤40 mls/min)

Chemotherapy: Carboplatin AUC 5 i.v infusion over 1 hour Day 1Gemcitabine 1000mg/m2 i.v. infusion over 30 minutes Day 1 & 8

Additional Medication: Ciprofloxacin 500mg po BD for 7 days, starting day 8 of cycle.

Repeat every 21 days for 4-6 cycles

Anti-emetics: Moderate emetic potential (day 1)

Investigations: Weight, FBC, U&E’s, creatine clearance, LFT’s before each cycle. Where renal/hepatic function is abnormal, treatment is at consultant


Dose modifications: Gemcitabine: Neutrophils<0.8x109/l, omit dose and reduce

subsequent doses by 25% Platelets<75x109/l, omit dose & reduce subsequent doses by 25% AST or ALT > 5x upper limit reduce dose by 25%.Gemcitabine can

cause elevation of transaminases which usually recovers after omitting treatment for 2-3 weeks. Resume at a lower dose.

Carboplatin: reduce to AUC 4 in frail patients or according to calvert formula if poor renal function

1. Carles J, Nogue M, Domenech M, et. al. Carboplatin-gemcitabine treatment of patients with transitional cell carcinoma of the bladder and impaired renal function. Oncl 2000 Jun; 59(1): 24-7

2. J. Bellmunt J, de Wit R, Albanell J et al. A feasibility study of carboplatin with fixed dose ofgemcitabine in ‘unfit’ patients with advanced bladder cancer. E J Cancer; 37 (17): 2212-2215(2001).

3. Progress in the chemotherapy of metastatic cancer of the urinary tract. Raghaven D, Cancer 2003; 97 (8) Suppl: 2050 – 2055

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CMV

Patient profile: Standard treatment (transitional cell)


Chemotherapy: Methotrexate 30mg/m2 i.v. bolus Day 1 and 8Vinblastine 4mg/m2 (max 10mg) i.v. bolus Day 1 and 8Cisplatin 70mg/m2 i.v. infusion over 2 hours Day 1


Repeat every 21 days from day 1 for maximum of 6 cycles (Assess response after 2 cycles).

Additional Medication: Folinic acid 15mg p.o. x 6 hourly starting 24 hours post methotrexate.


Investigations: Weight, FBC, U&E’s, creatinine clearance, LFT’s before each cycle. Where renal/hepatic function is abnormal, treatment is at consultant


Dose modifications :FBC on day of treatment : Cisplatin Methotrexate VinblastineWBC > 3.5x109/L& Platelets >100x109/L

full dose full dose full dose

WBC 3-3.5x109/L &Platelets >100x109/L

full dose 75% 75%

WBC 2.5-2.9x109/L &Platelets >100x109/L

full dose 50% 50%

WBC<2.5 x 109/L &Platelets <100x109/L

Delay treatment for one week

1. Mead GM et al. Brit J Cancer, 1998; 78 (8): 1067-752. Jeffrey GM. Et al. Brit J Cancer, 1998; 66 (3): 542-

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CHOLANGIOCARCINOMAGEM/CIS

Patient group: 1st line chemotherapy for patients with unresectable or recurrent/metastatic cholangiocarcinoma, gall bladder, or billiary tract carcinoma (excluding pancreatic cancer).ECOG PS = 0-2 and Cr Cl= >45ml/min


Chemotherapy: Day 1 & 8Cisplatin 25mg/m2 i.v. infusion over 2 hours Followed by 500 ml 0.9% saline over 30 minsGemcitabine 1000 mg/m2 IV infusion in 250-500ml 0.9% saline over 30 mins Urine should be maintained above 100ml/l/hr throughout treatment. If output falls below 400ml in any 4 hour period, then give furosemide 20mg i.v. repeated as necessaryAlternatively mannitol may be used.



Investigations: Weight, FBC, U&E’s, creatinine clearance, LFT’s before each cycle Tumour markers (CEA, CA19-9) if raised prior to each cycle Tumour assessment prior to treatment and after 2 cycles to assess response Where renal/hepatic function is abnormal, treatment is at consultant


Dose modifications:Gemcitabine:Neutrophils<0.8x109/L omit dose and reduce subsequent doses by 25%Platelets <75x109/L omit dose and reduce subsequent doses by 25%AST or ALT >5 x upper limit reduce dose by 25%Gemcitabine can cause elevation of transaminases, which usually recovers after omitting treatment for 2-3 weeks. Resume at a lower dose.Cisplatin:Creatinine clearance Cisplatin dose> 50 mL / min 100%

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40 – 50 mL / min 75%< 40 mL / min no further cisplatin

1. J Bridgewater, J Valle et al. ABC-02 Trial. Gemcitabine, alone or in combination with cisplatin, in patients with advanced or metastatic cholangiocarcinomas and other biliary tract tumours: a multicentre, randomised phase III study. Abstract O- 0009 ESMO June 2009

RENAL CANCER

Adjuvant

No proven role/ trials only

Advanced disease

ALPHA INTERFERON

Patient profile: PS 0-1Relapse post nephrectomy >12 monthsLow volume diseasePatients should have 2 our of 3 criteria

Chemotherapy: α interferon 3-18mu s/c Mon, Wed, Fri.


Investigations: Weight, U&E’s, LFT’s, FBC before each cycle

Dose modifications: There are no specific recommendations for dose modifications in the presence of myelosuppression, renal or hepatic dysfunction.

1. MRC Renal Cancer Collaborators. Lancer 1999; 353: 14-72. Pyhonen S et al. J Clin Oncol, 1999; 17: 2859-673. Coppin C et al. Cochrane Database Syst Rev 2000; 3: CD0014254. Fossa S et al. Br J Oncol 1995; 76: 286-905. Negrier S et al. N Eng J Med 1998; 338: 1272-8

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SUNITINIB (Sutent®)

Patient profile: PS 0-11st line for patients with advanced and/or metastatic renal cell carcinoma who are suitable for immunotherapy.

Chemotherapy: Sunitinib 50 mg orally once daily for four consecutive weeks with a 2- week rest period (i.e.6 week cycle)

Treatment should be assessed after every two cycles, and if patients respond, continued until disease progression.


Additional Medication: Loperamide 2mg prn for diarrhoea (up to 8 in 24hrs)

Investigations: Baseline cardiac assessment. U&E, BP, renal function, LFT, FBC, thyroid function at start of each

course (every 6 weeks) CT scan as needed to assess disease before every two cycles (12

weeks)

Toxicities: Hypertension, fatigue, diarrhoea/constipation, headacheskin rash, nausea and vomiting (mild), hand and foot syndrome, poor appetite, altered hair/skin pigmentation, stomatitis, dyspepsia, altered taste, haemorrhage, abnormal LFT’s, increased creatinine, uric acid, amylase, lipase and hypo or hyperglycaemia.

Dose modification:Dose modifications in 12.5-mg steps may be applied based on individual safety and tolerability. Daily dose should not exceed 75 mg nor be decreased below 25 mg.Dose adjustments for renal & hepatic function – no specific recommendation- see current SmPC.

Additional information: Avoid grapefruit juice, take with food. Co-administration of potent CYP3A4 inducers such as dexamethasone,

phenytoin, carbamazepine, rifampin, phenobarbital or St. John's Wort, should be avoided. If this is not possible, the dose of sunitinib may need to be increased in 12.5 mg increments (up to 87.5 mg per day) based on careful monitoring of tolerability.

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Co-administration of sunitinib with potent CYP3A4 inhibitors, such as ketoconazole, ritonavir, itraconazole, erythromycin, clarithromycin should be avoided. If this is not possible the doses of sunitinib may need to be reduced to a minimum of 37.5 mg daily, based on careful monitoring of the tolerability.

1. Motzer, J et al. Sunitinib versus interferon alfa in metastatic renal –cell carcinoma. N Engl J Med 2007; 356: 115 – 124

2. NICE TA FDA Renal cell carcinoma - bevacizumab, sorafenib, sunitinib and temsirolimus3. SPC Sutent accessed via eMC on 19th March 2009, Revision date 10th Feb 2009

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PROSTATE CANCER

AdAd AdjuvantNo proven role

AdAd Advanced/metastatic disease

DOCETAXEL

Patient profile: Hormone refractory disease (NICE)PS 0 – 2Adequate hepatic and bone marrow function

Pre-medication: Dexamethasome 8mg po bd for 3 doses starting evening before treatment

Chemotherapy: Docetaxel 75mg/m2 i.v. infusion over 1 hour Day 1

Prednisolone 5mg p.o bd during treatment.

Repeat every 21 days for up to 10 cycles or until evidence of disease progression

Weekly Schedule

Patient profile: Patients with impaired bone marrow function could be considered for weekly rather than 3 weekly docetaxel

Pre-medication: Dexamethasome 8mg po bd for 3 doses starting evening before treatment

Chemotherapy: Docetaxel 30mg/m2 i.v. infusion over 1 hour Days 1,8,15,21+28

Prednisolone 5mg p.o bd continuous

Repeated every 42 days until evidence of stable disease or metastatic progression


Investigations:

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Weight, FBC, LFT’s U&E’s before each cycle

Dose modifications: Neutrophils < 1.0 x 109/L defer dosePlatelets < 100 x 109/L defer doseAST or ALT > 1.5 x upper limit normal reduce dose by 25%

> 3.5 x upper limit normal discontinue Non-haematological toxicities (excluding alopecia):if necessary delay

treatment by one or more weeks until recovery to grade 0 or 1; if recovery takes longer than one week or if toxicity of grade 3+ is documented during chemotherapy, the dose should be reduced by 20% in all subsequent cycles

1. National Institute for Health and Clinical Excellence. Technology Appraisal 101. Docetaxel for the treatment of hormone refactory prostate cancer. June 20062. Tannock IF, de Wit R, Berry W, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351(15): 1502-12.

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MITOXANTRONE/PREDNISOLONE

Patient profile: Hormone refractory diseasePS 0-1Normal FBC, renal, liver functionNo cardiac failure.

Chemotherapy: Mitoxantrone 12mg/m2 i.v. bolus over 3-5 minutes Day 1(Max cumulative dose of 160mg)

Prednisolone 5mg p.o bd continuous

Repeat at 21-day intervals for 6 cycles and may be continued if patient receiving symptomatic relief.




Dose modifications:

Hepatic dysfunction: Bilirubin > 2-3 x ULN REDUCE Mitoxantrone to 50% of dose

1. Tannock IF. Et al. J Clin Oncol 1996; 14: 1756-64

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TESTICULAR CANCER

Stage 1 Pure Seminoma

CARBOPLATIN

Patient profile: Fit, under 50. Not willing to undergo XRT

Chemotherapy: Carboplatin AUC 7 i.v. infusion over 1 hour

One dose only


Investigations: Creatinine clearance, Weight, U&E’s FBC, LFT’s

Dose modifications: N/A

1. Oliver RT et al Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomised trial Lancet. 2005 Jul 23-29;366(9482):293-3002. Patterson H. et al. Radiother Oncol 2001; 59: 5-113. M. Farisa, D. Moreya, A. Colea and M. Masona Evaluation of the role of a single cycle of carboplatin as an adjuvant treatment in stage I seminoma and as a neo-adjuvant prior to radiotherapy in stage II European Journal of Cancer, Volume 33, Supplement 8, September 1997 , pp. 43-43(1)

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http://www.ingentaconnect.com/content/els/09598049

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T68-3YK5Y4J-6F&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=561524957a00eaa08cd9350eb314f816#orfa%23orfa




EP (3 DAY)

Patient profile: Fit, under 50. Willing to have chemo/contra indication to RT


Chemotherapy: Day 1 Etoposide 165mg/m2 i.v. infusion over 1 hourCisplatin 50mg/m2 i.v. infusion over 2 hours

Day 2 Etoposide 165mg/m2 i.v. infusion over 1 hourCisplatin 50mg/m2 i.v. infusion over 2 hours

Day 3 Etoposide 165mg/m2 i.v. infusion over 1 hour

Urine should be maintained above 100ml/l/hr throughout treatment. If output falls below 400ml in any 4 hour period, then give furosemide 20mg i.v. repeated as necessary. Alternatively mannitol may be used

Repeat at 21 days for 2 cycles


Investigations: Weight, FBC, U&E’s, LFT’s, Creatinine clearance before each cycle Where renal/hepatic function is abnormal, treatment is at consultant


Dose modifications:

As dose modification of CISP/ETOP treatment may compromise its efficacy, it isrecommended that modification of this regimen be done only after discussion with a medical oncologist experienced in the treatment of testicular cancer.

1. COIN Guidelines – Testicular Germ Cell Tumours. Clinical Oncology 2000; 12: S178-2102. Bajorin DF. J Clin Oncol. 1993; 11:598-606

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Metastatic TeratomaBEP 5 Day

Patient profile: Germ cell tumours


Chemotherapy: Day 1: Hydrocortisone 100mg i.v. bolusBleomycin 30,000i.u i.v. infusion over 2 hoursEtoposide 100mg/m2 i.v. infusion over 1 hourCisplatin 20mg/m2 i.v. infusion over 2 hours


Days 2 to 5: Etoposide 100mg/m2 i.v. infusion over 1 hourCisplatin 20mg/m2 i.v. infusion over 2 hours


Day 8: Hydrocortisone 100mg i.v. bolusBleomycin 30,000i.u i.v. infusion over 2 hours

Day 15: Hydrocortisone 100mg i.v. bolusBleomycin 30,000i.u i.v. infusion over 2 hours

Repeat at 21 days for 4 cycles. Bleomycin given for the first 3 cycles only.

Anti-emetics: High emetic potential Day 1 to 5

Investigations: Chest x-ray Weight, Creatinine clearance, U&E’s. FBC, LFT,s before each cycle HCG, AFP,LDH weekly during treatment where appropriate

Dose modifications:As dose modification of BEP treatment may compromise its efficacy, it is recommended that modification of this regimen be done only after discussion with a medical oncologist experienced in the treatment of testicular cancer.

1. Journal of Clinical Oncology, Vol 19, Issue 6 (March) 2001: 1629 - 1640

119

BEP 500

Patient profile: Low risk metastatic (seminomatous and non-seminomatous) germ cell tumours




Day 2: Etoposide 165mg/m2 i.v. infusion over 1 hourCisplatin 50mg/m2 i.v. infusion over 2 hours

Day 3: Etoposide 165mg/m2 i.v. infusion over 1 hourDay 8: Hydrocortisone 100mg i.v. bolus

Bleomycin 30,000i.u i.v. infusion over 2 hoursDay 15: Hydrocortisone 100mg i.v. bolus

Bleomycin 30,000i.u i.v. infusion over 2 hours

Repeat at 21 days for 4 cycles. Bleomycin given for the first 3 cycles only (Max cumulative dose 270,000 IU)

Anti-emetics: High emetic potential Day 1 & 2



1. COIN Guidelines – Testicular Germ Cell Tumours. Clinical Oncology 2000; 12: S178-2102. Cullen MH. J Clin Oncol, 1996; 14: 1106-123. de Wit R, Roberts T, Wilkinson PM et al. Equivalence of three or four cycles of bleomycin,etoposide, and cisplatin chemotherapy and of a 3- or 5- day schedule in good-prognosis germcell cancer: a randomized study of the European Organization for research and treatment ofcancer genitourinary tract cancer cooperative group and the Medical Research Council. J ofClinical Oncology 2001, March 15; 19(6); 1629-40.4. Williams S, Birch R, Einhorn LH et al. Treatment of disseminated germ-cell tumors withcisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med, 1987; 316: 1435-144

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Adjuvant BEP 360

Patient profile: Stage 1 High Risk Teratoma and Mixed Seminoma / Teratoma




Day 2: Etoposide 120mg/m2 i.v. infusion over 1 hourCisplatin 50mg/m2 i.v. infusion over 2 hours

Day 3: Etoposide 120mg/m2 i.v. infusion over 1 hourDay 8: Hydrocortisone 100mg i.v. bolus

Bleomycin 30,000i.u i.v. infusion over 2 hoursDay 15: Hydrocortisone 100mg i.v. bolus

Bleomycin 30,000i.u i.v. infusion over 2 hours

Repeat after 21 days. Give 2 cycles.

Anti-emetics: High emetic potential Day 1 & 2



1. COIN Guidelines – Testicular Germ Cell Tumours. Clinical Oncology 2000; 12: S178-2102. Cullen MH. J Clin Oncol, 1996; 14: 1106-12

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MALIGNANT MELANOMA

Adjuvant

HIGH DOSE INTERFERON

Patient profile: High risk/selected patientsPS < 1CT brain, chest, abdomen, pelvis normalHistological regional node involvementAll macroscopic disease resected, margins clear.

Chemotherapy: Interferon alpha 20MU /m2 i.v infusion over 20 minutes daily on days 1-5

for 4 weeks followed by

Interferon alpha 10 MU/m2 s.c injection three times a weekfor 48 weeks


Investigations: Weight, U&E’s, FBC, LFT’s

1. ESMO report 1998. Is high dose interferon the standard adjuvant treatment in melanoma?

2. Kirkwood JM et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST1684. J Clin Oncol 1996;14:7-17

Metastatic/advanced disease

CARMUSTINE/DACARBAZINE/CISPLATIN(Dartmouth Regimen)

Patient profile: outside trial

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Chemotherapy: Carmustine 150mg/m2 i.v. infusion over 1 hour Day 1 for cycles 1,3 & 5 onlyDacarbazine 220mg/m2 infusion over 1 hour Days 1 – 3Cisplatin 25mg/m2 i.v. infusion over 2 hours Days 1 – 3

Urine should be maintained above 100mL/hr throughout treatment. If output falls below 400mL in any 4 hour period, then give furosemide 20mg i.v. repeated as necessary. Alternatively mannitol may be used

Repeat every 21 days until disease progression.Additional Medication: Tamoxifen 20mg daily (10mg twice daily or 20mg daily) throughout

treatment starting one week before first cycle.


Investigations: Weight, FBC, U&E’s, LFT’s before each cycle. Monitor serum creatinine

Dose modifications:


1. Chapman PB. Et al. Phase lll multicentre randomized trial of the Datmouth Rgimen verses dacarbazine in patients with metastatic melanoma.

DACARBAZINE

Patient profile: Standard therapy (outside trial)

Chemotherapy: Dacarbazine 800mg/m2 i.v. infusion over 30 minutes Day 1

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Repeat at 21-day intervals until evidence of disease progression


Investigations: Weight, FBC, U&E’s, LFT’s before each cycle.

Dose modifications:If there is mild to moderate renal or hepatic insufficiency alone, a dose reduction is not usually required. In patients with combined renal and hepatic impairment elimination of dacarbazine is prolonged. However, no validated recommendations on dose reductions can be given currently.1. Chapman PB. Et al. J Clin Oncol 1999; 17: 2745-512. Rusthoven JJ. Et al. J Clin Oncol, 1996; 14: 2083-903. Falkson CI, et al. J Clin Oncol,1998: 16: 1743-514. Hill GJ 2nd et al. Cancer 1984; 53(6): 1299-13055. Comis RL. Cancer Treatment Reports 1976; 60(2): 165–766. SPC Dacarbazine

VINDESINE

Patient profile: Outside trial

Chemotherapy Vindesine 3mg/m2 i.v bolus over 3-5 minutes Day 1

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Treatment is repeated every 7 days for 6-8 cycles and then every 14 days thereafter.


Investigations: Weight, U&E’s, LFT’s FBC before each cycle.

Dose modifications: N/A

1. JM Quagliana Vindesine in patients with metastatic malignant melanoma: a Southwest Oncology Group study Journal of Clinical Oncology, 1984 Vol 2, 316-319,

SARCOMAS

Adjuvant Soft Tissue Sarcoma

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IFOSFAMIDE

Patient profile: Adjuvant

Chemotherapy: Ifosfamide 5000mg/m2 i.v. infusion over 24 hours Day 1Mesna 5000mg/m2 i.v. infusion over 36 hours Day 1



Investigations Weight, FBC, LFT’s, U&E’s before each cycle

Special precautions: Ifosfamide therapy may cause encephalopathy characterised by confusion and repetitive speech and action. Methylene blue may be used as treatment.

Dose modifications:Dosage in renal failure: Serum creatinine (μmol/L) % usual dose >200 75% >300 67%

1. Bramwell VH, Mouridsen HT, Santoro A, et al. Cyclophosphamide versus ifosfamide: final report of a randomized phase II trial in adult soft tissue sarcomas. Eur J Cancer Clin Oncol 1987 Mar;23(3):311-21.

AdvancedDOXORUBICIN

Patient group: Advanced 1st linePS 0-1

Chemotherapy: Doxorubicin 75mg/m2 i.v bolus over 3-5 minutes Day 1

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(Maximum cumulative dose: 450-550mg/m2)



Investigations: Weight, FBC, U&E’s LFT’s before each cycle. LV ejection fraction prior to first cycle if patient has history of cardiac

problems.

Dose modifications: Doxorubicin dosage must be reduced if hepatic function is impairedBilirubin (μmol/L) Dose 20-50 75%51-85 50%>85 omit

1. Gottlieb JA et al, Cancer Chemother R, 1975; 6: 271-2822. Santoro A et al. J Clin Oncol 1995; 13: 1537-453. Keohan et al. Seminars in Oncology 1997; 24: 572-9

GASTRO-INTESTINAL STROMAL TUMOURSIMATINIB

Patient profile: Patients with metastatic GIST’s who have tested positive for c-Kit (NICE)

Chemotherapy: Starting dose: Imatinib 400mg orally daily (with a meal and a large glass of water) increasing to 600mg daily depending on toxicity

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Assess after 12 weeks and if responding continue until progression/unacceptable toxicity


Investigations: Weight, FBC, U&E’s, LFT’s

Dose modifications :If bilirubin > 3 x IULN or in liver transaminases > 5 x IULN Imatinib should be withheld until bilirubin levels have returned to < 1.5 x IULN and transaminase levels to < 2.5 x IULN. Treatment with Imatinib may then be continued at a reduced daily dose.

If ANC < 1.0 x 109 /L and/or platelets < 50 x 109 /L

1. Stop Imatinib until ANC 1.5 x 109 /L and platelets 75 x109/L.

2. Resume treatment with Imatinib at previous dose (i.e. before severe adverse reaction).

3. In the event of recurrence of ANC < 1.0 x 109 /L and/or platelets < 50 x 109 /L, repeat step 1 and resume Imatinib at reduced dose of 300 mg.

1. Rankin C et al, J Clin Oncol. 2004; 22(14 suppl): 90052. Verweij J et al. Lancet, 2005; 364(9440): 1127-343. Zalcberg JR et al. Eur J Cancer. 2005; 41(12): 1751-74. NICE Technology Appraisal No. 86

SUNITINIB

Patient profile: Patients with unresectable and/or metastatic malignant gastrointestinal stromal tumours if Imatinib treatment has failed because of resistance or intolerance and have (ECOG) performance status of 0 or 1.

Chemotherapy: Sunitinib 50 mg orally once daily for four consecutive weeks with a 2-week rest period (i.e.6 week cycle)

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Assess after 12 weeks (2 cycles) and if responding continue until progression/unacceptable toxicity


Additional Medication: Loperamide 2mg prn for diarrhoea (up to 8 in 24hrs)

Investigations: Baseline cardiac assessment. U&E, BP, renal function, LFT, FBC, thyroid function at start of each

course (every 6 weeks) CT scan as needed to assess disease before every two cycles (12

weeks)

Dose modifications :

Dose modifications in 12.5-mg steps may be applied based on individual safety and tolerability. Daily dose should not exceed 75 mg nor be decreased below 25 mg.

Dose adjustments for renal & hepatic function – no specific recommendation- see current SmPC.

1. NICE TA 179 Sunitinib for the treatment of gastrointestinal stromal tumours2. SPC Sutent [accessed via eMC on 19th July 2009]

APPENDIX I

PROCESS FOR APPROVING FORMULARY REGIMENSThe Network has now agreed the route through which changes to the formulary should be made. It is accepted that for a new drug or regimen to be introduced it should be effective, practical to introduce, fundable and applicable across the Network.

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In order to confirm that this is the case any proposed new drug/regimen needs to be assessed in a number of different contexts. The network needs to ensure that all these aspects are considered before granting approval.

Preparation of a clinical caseThe first step in introducing a new drug/regimen is to prepare a clinical case for the use of the drug. This may be done by one clinician but would carry more weight if discussed with and supported by other clinicians, other Trusts and the relevant DON. Preparation of a clinical case could be prompted by new clinical data, by a change in guidelines (local, regional or national) or by guidance from NICE or AWMSG.

The clinical case should be produced on a standard proforma (to be produced) and will include the following points:

Details of the drug/regimen including dose, route of administration, duration of treatment and any necessary adjunctive treatment (anti-emetics, CSFs, etc).

Intended patient population – disease, stage, age, PS, etc. Clinical rationale for use including relevant references Estimated number of patients/year Whether additional to the formulary or a replacement regimen Status of the drug regarding licensed indications and NICE approval Status of the drug in neighbouring Networks e.g. Christies, CCO, South Wales Names of clinicians supporting the application

Pharmacy AssessmentOnce the Clinical Case has been produced it needs to be assessed by the pharmacy departments at the three Trusts in North Wales. This assessment could be done by one lead department or coordinated by the Network Pharmacist. The assessment should include:

Confirmation that the pharmaceutical details of the case are correct (dose, route etc).

Confirmation that the regimen can be accommodated within the current workload taking account of numbers of patients, the complexity and duration of the regimen and of any regimens it would replace.

The amount of additional or saved pharmacy time/capacity. The cost of the regimen and the cost of any regimen it would replace.

Capacity Assessment (Day Treatment Unit)Once the Clinical Case has been produced it needs to be assessed by Day Treatment Unit or Ward (if an in-patient regimen) at the three Trusts in North Wales. This assessment could be done by one lead department or could be coordinated by the Network Lead Nurse. This assessment should include:

Confirmation that the regimen is practical to administer as a day case taking account of duration, toxicity, etc.

Confirmation that the regimen can be accommodated within the current workload taking account of numbers of patients, the complexity and duration of the regimen and of any regimens it would replace.

The amount of any additional or saved nursing time. Extent of additional resources that would be required in order to implement the

regimen.

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Presentation to the Network Formulary GroupFollowing Pharmacy and Capacity Assessment the Clinical Case should be submitted to the Network Formulary Group. Submissions should be accepted at any time and should be considered within 3 months i.e. quarterly meetings should take place if needed. Normally the NFG will ask the submitting clinician to attend the meeting to discuss the request in person.

Taking account of the information provided the Network Formulary Group will decide if it is appropriate to accept the regimen taking account the key issues of effectiveness, practicality, cost and equity of access.

If approved, the NFG will produce a brief statement outlining the reasons for approval e.g. more effective, more convenient, less toxicity, etc.

Alternatively, if the Clinical Case is rejected the NFG should explain the reasons why. It should also set out any additional information or changes that might allow the new drug/regimen to be implemented e.g. if approved by NICE, if more clinical results available.

The NFG may also consider conditional approval e.g. only for certain groups of patients, only for a limited number of patients each year or only for a limited period. It would also have the right to grant conditional approval on the basis that further information was provided after a defined period e.g. audit of local results after the first 6 months use.

Commissioning assessmentAssessment of the cost implications of any new regimen is essential and it is therefore essential that the commissioners of health care approve the use of any new drug/regimen.

Assessment/approval by the commissioners should take part through the work of the NFG i.e. as part of the same meeting but could also happen separately i.e. by submission of the relevant papers and the NFG recommendation to the lead oncology commissioners.

It is expected that the recommendation of the lead commissioners will be accepted by the LHBs across North Wales. When a high cost drug is being considered it is possible additional discussions will need to be held between the LHBs. However, for the majority of formulary changes the approval of the lead oncology commissioners should be accepted i.e. the change should be implemented automatically at all three Trusts.

Further workIf the drug/regimen is approved the submitting clinician would be asked to produce a full Clinical Practice Regimen. This would be an expansion of the clinical case but would include:

Required assessments before and during treatmentDetails of common toxicityStandard dose reductionsDetails of patient assessment points e.g. nursing assessment, medical review,

imaging.The aim of the Clinical Practice Regimen is to ensure the drug/regimen is safely implemented and to ensure good clinical governance. It is expected that the Clinical Practice Regimen would never be more than 2 A4 pages.

D+T committeesIf approved by the Network the new drug/regimen would be submitted to the D+T committee at each Trust by the Network Pharmacist and Network Lead Clinician (if appropriate).

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Submission should include the paperwork produced by the Network but should not require the production of additional forms. A covering letter from the Chair of the NFG should outline the reasons why the new drug/regimen has been approved.

While the D+T committees have the right (on behalf of their host Trust) to reject the recommendation of the Network it is expected that approval would be granted automatically and that rejection of the Network advice would be exceptional.

The Network’s aim would be to submit the new drug/regimen to the next D+T meeting of each Trust with the aim or it being approved for use across the Network within 2 months.

Other Trust CommitteesIf the new regimen has been approved following guidance from NICE then the network should also submit the information to the Trust and LHB committees overseeing implementation of NICE guidance to confirm that guidance has been accepted and is being implemented.

Appeal MechanismClinicians need a right of appeal. In the case of an appeal the Network will refer to clinical representatives from outside the network for further advice on the submission. The external referees will first be agreed by the submitting clinician

Table 1 Membership of Network Formulary Group

Position Representing Rationale

Director of Cancer Network Cancer Network and commissioners

Provide organisational support and direction

Link to commissioners

Network Pharmacist Cancer Network and pharmaceutical profession

Technical advice and information

Technical assessment

Process management

Network Lead Clinician Cancer Network clinical oncology perspective



Network Lead Oncology Nurse

Trust operational oncology nursing services

Operational interpretation



LHB Medical Director Commissioning/governance Link to commissioners

Governance advice

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NORTH WALES CANCER NETWORK

APPLICATION FOR A NEW DRUG/REGIMEN OR AMENDMENT TO CURRENT REGIMEN (Clinical Case)

No:

1. Details of Drug/Regimen including dose, route of administration and duration of

133

treatment.

2. Details of any necessary adjuvant treatment eg antiemetics, CSF’s, antibioticsetc.

3. Special Investigations (imaging, cardiac assessment etc)

investigation frequency

4. Intended patient population – disease, stage, age, PS etc.

5 License status:

Fully licensed Licensed drug – unlicensed indication

Unlicensed

6. Addition to formulary, replacement or amendment to current treatment

7. Regimen to be replaced/modified

8. Estimated number of patients per year

CTC Alaw Shooting Star

9. Treatment

daycase inpatient community

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10. Please indicate if this submission is the result of published guidance from NICE, AWMSG, SMC, Local Clinical Network or ‘Expert Body’ (if YES is the request in line with the guidance)

11. Please outline your reasons for requesting the new drug/regimen, making clear its advantages over existing therapy. The outline summary should be referenced and include the following information.

Summary of reasons for requesting new/alteration regimen:

Indicate place in management1st, 2nd 3rd line therapyWhat is the data to support the efficacy of the new treatment (response rates/ disease free and overall survival rates)?

What are the data comparing the treatment with current treatments?

Tolerability of regimen?(references)Further information if necessary:

References supporting the application, including the published guidance, as above where appropriate. (please state and attach to application).

Reference Title Author(s) Citation

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number1

2

3

4

5

Ia Meta-analysis of randomized controlled trialsIb At least one randomized controlled trialIIa At least one well-designed controlled study without randomizationIIb At least one other type of well-designed quasi experimental studyIII Well-designed non-experimental descriptive studies, such as comparative studies, correlation studies,

and case-control studies.IV Expert committee reports or opinions and/or clinical experience of respected authorities.

12 Name/s of clinicians supporting the application

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APPENDIX II

COCKCROFT-GAULT CREATININE CLEARANCE FORMULA

Men

((140 – age) x wt x 1.23) / creatinine

Women

((140 – age) x wt x 1.04) / creatinine

Age in years, weight in kilogrammes, and plasma creatinine in micromoles per litre

1. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976:16:31-41.

APPENDIX III

CALVERT FORMULA FOR CARBOPLATIN

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Carboplatin total dose in mg = AUC x ( creatinine clearance + 25 )

Desired area under the curve ( AUC ) normally 4 – 6 depending on protocol and clinical situation.

1. Calvert AH,Newell DR, Gumbrell LA, et l. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989:7:1748-56.

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APPENDIX IV

CISPLATIN DOSE GUIDELINES

Cisplatin is nephrotoxic and thus patients must have their renal function measured prior to each cycle.


> 50 mL / min 100%

40 – 50 mL / min 75%

< 40 mL / min no further cisplatin

Patients should only commence cisplatin chemotherapy if they have an adequate performance status ie 0 – 2. The only exception to this is patients with advanced germ cell tumours with poor PS who may commence treatment with low dose etoposide/platinum.

Patients should only receive second and subsequent cycles of cisplatin if they are well and have suffered no deterioration in performance status.

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APPENDIX IV

CISPLATIN HYDRATION POLICY

Cisplatin produces cumulative nephrotoxicity which may be potentiated by other nephrotoxic drugs such as aminoglycoside antibiotics. The serum creatinine, plasma urea or creatinine clearance and magnesium, sodium potassium, and calcium levels should be measured prior to initiating therapy, and prior to each subsequent course.

Addition of potassium and magnesium to pre and post hydration may prevent hypokalaemia and hypomagnesaemia that are common side effects of cisplatin.

Adequate pre-treatment and 'during treatment' hydration should be ensured and such agents as mannitol given to minimise hazards of renal toxicity. In addition, adequate post-treatment hydration and urinary output should be monitored. Urine output should be maintained above 100ml/hr throughout treatment. If output falls below 400mls in any 4 hour period despite adequate hydration, then give furosemide 20mg iv or 40mg po or further mannitol may be given.

All patients should be encouraged to drink at least 2 litres of fluid per day for 2 days after Cisplatin therapy.

Sample Hydration protocols:

Pre-hydration 1000ml sodium chloride 0.9% with 20mmol potassium and 8mmol magnesium over 1 hour.

Hydration Mannitol 20% 100ml over 15 minutes

Cisplatin In 1000ml Sodium Chloride 0.9%Administered over 2 hours.

Post-hydration 1000ml sodium chloride 0.9% with 40mmol potassium and 8mmol magnesium over 2 hours

500ml sodium chloride 0.9% with 10mmol potassium over 1 hour or ask patient to drink 500ml before discharge.

Remind patient to drink 2-3 litres per day for 48 hours.

1. Yao, Xin (2007) Cisplatin Nephrotoxicity: A Review. The American Journal of the Medical Sciences 334(2)2. SPC Cisplatin (Hospira UK Ltd) 20043. Fidlay et al Ann Oncol 1994; 5: 609-16

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APPENDIX VIHAEMATOLOGICAL PARAMETERS

Guidelines for the administration of chemotherapy

(1)

Platelets ≥ 100 x 109 / l administer +Total WBC ≥ 3 x 109 / l administer +Neutrophils ≥ 1.5 x 109 / l administer

(2)

Platelets 75 – 100 x 109 / l physician discretion orTotal WBC 2.0 – 2.9 x 109 / l physician discretion orNeutrophils < 0.5 – 1.5 x 109 / l physician discretion

(3)

Platelets < 75 x 109 / l defer orTotal WBC < 2.0 x 109/l defer orNeutrophils < 0.5 x 109 / l defer

These guidelines assume that patients are well and with good performance status, that other acute toxicities have resolved and the patient has not had a previous episode of neutropenic sepsis

In some situations, chemotherapy is given despite lower count values than those noted above. These include patients receiving adjuvant chemotherapy, those with curable metastatic malignancies such as germ cell tumours and lymphomas and also patients with bone marrow infiltration. These situations will be dealt with on a case by case basis.

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APPENDIX VII

ANTI-EMETIC POLICY FOR CYTOTOXIC CHEMOTHERAPYEach chemotherapy regimen should be accompanied by one of the standard initial anti-emetic regimens depending on the emetic potential of the regimen (high, moderate or low). Subsequent anti-emetic regimens will be tailored according to patient response. For further details, please refer to the North Wales Cancer Network Anti-emetic Policy.

Highly emetogenic regimensDexamethasone 8 mg i.v/oral on each day of chemotherapy followed by 8 mg OM

for 3 days (for regimens with cisplatin > 50 mg/m2 use 16 mg initially)

Ondansetron 8 mg BD i.v/p.o on each day of chemotherapy followed by 8 mg bd for 2 days

Domperidone 20 mg QDS orally for 5 days

Moderately emetogenic regimensDexamethasone 8 mg p.o. on each day of chemotherapy followed by 8 mg OM for 3

days

Ondansetron 8 mg p.o BD on each day of chemotherapy only

Domperidone 20 mg QDS orally for 5 days

Low emetogenic regimensDexamethasone 8 mg p.o. on each day of chemotherapy

Domperidone 10 – 20 mg QDS orally PRN for 5 days

Delayed Emesis If patient experiences vomiting more than 24 hours after chemotherapy consider:

Give dexamethasone 8 mg p o daily for three days if not previously given and consider a tapering dose beyond three days

Ensure domperidone taken at full dose of 20 mg QDS Add additional antiemetics e.g. levomepromazine 25 mg/day OR cyclizine 150 mg/day

OR haloperidol 5 mg/day by s.c. infusion

Emesis Leading to AdmissionIf patient experiences vomiting sufficiently severe to require admission consider adding:

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Aprepitant (Emend) 120 mg p.o. before chemotherapy followed by 80 mg o.d. for 2 days.

Anticipatory EmesisAnticipatory vomiting i.e. vomiting prior to chemotherapy is difficult to treat and does not respond to standard anti-emetics.

Give lorazepam 1 – 2 mg p.o. the night before and morning of chemotherapy. Non-pharmacological treatments such as behavioural therapy (relaxation techniques etc.) should also be considered.

CLASSIFICATION OF CHEMOTHERAPY BY EMETIC POTENTIAL

Table 1 Emetogenic potential of chemotherapy agents 1

Emetic Risk (incidence of emesis without anti-emetic)

Agent

High (>90%) CisplatinMechlorethamineStreptozotocinCyclophosphamide ≥1,500 mg/m2CarmustineDacarbazineDactinomycin

Moderate (30 to 90%) OxaliplatinCytarabine > 1000 mg/m2CarboplatinIfosfamideCyclophosphamide <1,500 mg/m2DoxorubicinDaunorubicinEpirubicinIdarubicinIrinotecan

Low (10% to 30%) PaclitaxelDocetaxelMitoxantroneTopotecanEtoposidePemetrexedMethotrexateMitomycinGemcitabineCytarabine <1,000 mg/m2FluorouracilBortezomibCetuximabTrastuzumab

Emetic potential of Chemotherapy regimens can also be classified using the Hesketh Classification2

1. Identify the most emetogenic agent in the combination.2. Determine the relative contribution of other agents to the emetogenicity of thecombination. When considering other agents, the following rules apply:

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(a) Level 1 agents do not contribute to the emetogenicity of a given regimen.(b) Adding one or more level 2 agents increases the emetogenicity of the combination by

one level greater than the most emetogenic agent in the combination.(c) Adding level 3 or 4 agents increases the emetogenicity of the combination by one level

per agent.

1. Kris et al American Society of Clinical Oncology Guideline for Antiemetics in Oncology: Update 2006..JCO 2006;24:19

2. P J Hesketh Oncologist 1999; 4;191-196

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APPENDIX VIII

INTRATHECAL CHEMOTHERAPY

Intrathecal chemotherapy may only be prepared and administered by specific named individuals.

Prescriptions must be written on the intrathecal prescription form Patients must receive any IV chemotherapy prior to IT treatment The doctor administering the IT drugs must collect them in person from the

pharmacy The drugs must be checked by the doctor and a qualified chemotherapy nurse prior

to administration All staff members involved (doctor, nurse, pharmacist) must be on the current IT

register.

The following may be given intrethecally:

Hydrocortisone Methotrexate Cytosine Thiotepa

All other drugs are potentially lethal when administered intrathecally.

Any diluent used to prepare an IT drug must be water based and preservative free.

Intrathecal chemotherapy must always be given under the direction of a consultant haematologist and be administered by one of the haematologists on the Trust’s register.

1. DoH Guidance on Intrathecal chemotherapy

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