ctpdcmuoaib

Age and Comorbidity Considerations Relatedto Radiotherapy and Chemotherapy AdministrationGeorge Rodrigues, MD, FRCPC, MSc,*,† and Michael Sanatani, MD, FRCPC‡,§

Oncological treatment decision-making is a highly complex enterprise integrating multiplepatient, tumor, treatment, and professional factors with the available medical evidence.This management complexity can be exacerbated by the interplay of patient age andcomorbid non-cancer conditions that can affect patient quality of life, treatment tolerance,and survival outcomes. Given the expected increase in median age (and associatedcomorbidity burden) of Western populations over the next few decades, the use of evi-dence-based therapies that appropriately balance treatment intensity and tolerability toachieve the desired goal of treatment (radical, adjuvant, salvage, or palliative) will beincreasingly important to health care systems, providers, and patients. In this review, wehighlight the evidence related to age and comorbidity, as it relates to radiotherapy andchemotherapy decision making. We will address evidence as it relates to age and comor-bidity considerations separately and also the interplay between the factors. Clinical con-siderations to adapt radiation and/or chemotherapy treatment to deal with comorbiditychallenges will be discussed. Knowledge gaps, future research, and clinical recommenda-tion in this increasingly important field are highlighted as well.

Semin Radiat Oncol 22:277-283 © 2012 Elsevier Inc. All rights reserved.

sthcl

mmsams

apne

In 2011, an estimated 1.6 million people will be diagnosedwith cancer and approximately 570,000 people will die

from various forms of this disease.1 Sixty percent of incidentancer cases and 70% of mortality occurs in individuals overhe age of 65 years.1 Given the demographic changes ex-ected in Western countries, the absolute number of peopleiagnosed with cancer will increase over the next few de-ades. In parallel to this trend, an increase in observed co-orbid illness burden with increasing age has been well doc-mented in the medical literature,2 which is consistent withur collective medical experience. These trends of increasingge in the general population with the respective associatedncreases in cancer incidence and mortality as well as comor-idity burden can manifest in complex interplay relation-

*Department of Radiation Oncology, London Health Sciences Centre, Lon-don, ON, Canada.

†Department of Epidemiology and Biostatistics, University of Western On-tario, London, ON, Canada.

‡Department of Medical Oncology, London Health Sciences Centre, Lon-don, ON, Canada.

§University of Western Ontario, London, ON, Canada.Address reprint requests to George Rodrigues, MD, FRCPC, MSc, Depart-

ment of Radiation Oncology, London Health Sciences Centre and De-partment of Epidemiology and Biostatistics, and University of WesternOntario, A3-808, 790 Commissioners Road East, London, ON, Canada

N5C 4E4. E-mail: george.rodrigues@lhsc.on.ca

1053-4296/12/$-see front matter © 2012 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.semradonc.2012.05.004

hips affecting issues, such as multimodality treatment selec-ion, cancer- and treatment-related symptomatology andealth-related quality of life, and competing-risk survivalonsiderations between cancer-related and non–cancer-re-ated mortality.

Chronologic age is a known risk factor for the develop-ent of cancer, cancer biology, tolerability/response to treat-ent, and survival outcomes in a variety of cancer tumor

ites. Although the epidemiologic relationship between agend cancer incidence is well described, the exact biologicalechanisms underlying this association are not well under-

tood.3 Examples of age-related differential cancer biology(breast cancer, acute myelocytic leukemia) and outcomes(glioblastoma multiforme, brain metastases, prostate cancer)directly impacting on treatment selection do exist in the med-ical literature and published guidelines.4-11 Research into thescertainment of physiological age of the individual as op-osed to the patients’ chronologic age has produced someon-cancer literature defining a frail phenotype.12 Other rel-vant health-related quality of life instruments13 exist that

should be further validated in cancer populations to deter-mine their utility in this regard.

Comorbidity in cancer patients refers to other concurrentpatient illnesses that occur contemporaneously with themanagement of the primary cancer situation. Comorbidities

can be either unrelated to the cancer itself or a relationship

277

tiai

csytmtpanspceaat

rbptmatdor

fc1mvpayCswcmvvm

tpvmafitOi

278 G. Rodrigues and M. Sanatani

can exist between the comorbidity and the cancer (eg,chronic obstructive pulmonary disease and lung cancer withunderlying relationship to cigarette smoking). Additionally,both negative and positive relationships between cancertreatment and underlying comorbidity may exist in prostatecancer in terms of cardiac disease and hormonal therapy14

and breast cancer with diabetes and metformin,15 respec-ively. Irrespective of whether the relationship between anyndividual comorbidity is direct or indirect or independent,dditional comorbidity burden can affect treatment tolerabil-ty and important clinical outcomes, such as survival.16-18

Elderly patients and/or patients with significant comorbid-ity burden are routinely excluded from randomized con-trolled trials because of a general focus on explanatory clini-cal trials to optimally demonstrate anticancer treatmenteffects.19 This, in part, is likely related to concerns regardingompeting risks of death that will increase the clinical trialample size required to have sufficient cancer deaths for anal-sis. Equally important, individuals with comorbid condi-ions frequently require treatment modality and intensityodulation/scheduling that are difficult to implement within

he context of an explanatory clinical trial. When elderlyatients are included in clinical trials, they may only make upminority of patients on the trial and are likely to have few oro associated comorbid illnesses. Therefore, clinical trial re-ults may still have limited external validity for many elderlyatients. If this knowledge gap is not addressed, this lack oflinical trial information on patients with comorbidities andlderly patients will make decision making and delivery ofnticancer therapies, such as radiotherapy and chemother-py increasingly problematic given current populationrends.

This review will summarize the existing informationegarding the individual impact of age and comorbidityurden (and their interplay effects) on important endoints, such as survival, health-related quality of life, andreatment selection on general cancer populations. Theain focus of this article will be on the evidence base and

daptation strategies related to radiotherapy and chemo-herapy administration. This review will conclude with aiscussion regarding knowledge gaps in the literature, rec-mmended lines of research, and a summary with clinicalecommendations for the practitioner.

Age, Comorbidity,and Clinical OutcomesGiven the relative paucity of randomized controlled trial datainforming the treatment outcomes of cancer patients, muchof the available literature on clinical outcomes is based onvarious population-based studies.2,20-23 Population-basedstudies can help to inform clinicians and investigators regard-ing treatment selection and clinical outcomes for cohorts ofreal patients to assess relationships between explanatory vari-ables (such as age and comorbidity burden as well as othertraditional cancer-related factors) and outcome variables,

such as treatment selection and outcome. By interpreting

these analyses, hypotheses regarding treatment improve-ments both at a population and cancer site-specific level canbe the subject of future research inquiries.

Kendal20 published an analysis to study the interplay ef-ects of age, comorbidity in the 22 most common types ofancer in �784,000 patients diagnosed between 1984 and993, which were contained within the Surveillance, Epide-iology, and End Results American database. Several pro-

ocative and important findings were demonstrated from theroportional hazard (overall survival, cancer-related death,nd comorbidity-related death) and competing hazard anal-ses (cumulative incidence of competing risks of failure).ancer site was associated with overall survival and cancer-

pecific survival more than age, whereas age was associatedith comorbid mortality more than cancer site. Kendal con-

luded from his interpretation of the data that attention andanagement of comorbidities in elderly and/or other indi-

iduals with comorbidities might provide substantial sur-ival benefits on the order of those provided by cancer treat-ent.Other investigators have explored the relationship be-

ween age, comorbidity, and outcome using other canceratient registries.2,21-23 Janssen-Heijnen et al22 observed sur-ival decrements related to age and comorbidities, with co-orbidity having a minimal role in patients with highly

ggressive tumors. Similarly, Piccirillo et al2 have also con-rmed the impact of comorbidity, age, and tumor stage inerms of survival in a 19,269 patient hospital-based registry.ther important relevant relationships have been described

n the medical literature:

1. Age, comorbidity, functional impairment, and cancersite are all independent contributors to survival time.24

2. Comorbidity burden can have a differential impact onsurvival in cancer populations with different baselinesurvival rates.25

3. Comorbidity and functional status are separate entitieswithin the context of elderly patients and need to bemeasured individually.26

4. Type/intensity of cancer treatment and their relatedcomplication patterns can be impacted by both age andcomorbidity status.22

5. Observed population-based treatment adaptations ow-ing to age and/or comorbidity considerations dependon the cancer site involved.22

6. Frequently observed adaptive therapies include less useof surgery when alternative approaches are available(chemoradiation, radiation alone, chemotherapy alone,hormonal therapy), less use of adjuvant radiationand/or chemotherapy after surgery, and increased useof observation strategies where available.22

7. Age and comorbidity burden have impacts on bothhealth-related quality of life13 and symptom burden.27

In a population of cancer survivors, younger age wasassociated with higher symptom burden than older

patients.27

ZaTotp

Age and comorbidity in RT and CT 279

RadiotherapeuticConsiderationsRadiotherapy can be an attractive alternative to other modal-ities of treatment, including surgery and chemotherapy. Thisis likely owing to the noninvasive nature of treatment, whichbalances the therapeutic ratio between treatment effective-ness with low treatment morbidity and mortality, organ dys-function, and performance status/health-related quality oflife considerations. In the setting of possible multimodalitytherapy, these radiotherapy treatment advantages have led topotential under treatment of patients who could have bene-fitted from more intensive treatment protocols, includingsurgery or chemoradiation protocols. Even in treatment sce-narios where radiation (or chemoradiation) is the primarytreatment modality of choice, the long duration of radicalradiation therapy (�5 weeks) and geographic considerations(patient travel time away from home) can play a critical rolein patient selection of palliative or best supportive care treat-ment where a more radical course would be generally indi-cated.

Treatment decision making involving both the use andintensity of radiotherapy can be highly complex and involvemultiple factors, including chronologic age, physiologicalage, performance/functional status, comorbidities, relativecontraindications to radiotherapy, treatment toxicities/toler-ance, radiotherapy outcomes, patient preferences, and pa-tient longevity. Despite the various curative, adjuvant, andpalliative roles that radiotherapy can play in the managementof various cancers, relatively limited information regardingtreatment selection, tolerability, and outcomes related to ageand comorbidity considerations are available in the literature.

Impact of Age and ComorbidityTyldesley et al28 performed a population registry analysis in2000, assessing the impact of patient chronologic age and func-tional status on radiotherapy utilization in the Province of On-tario. Their group found that radiotherapy utilization was im-pacted negatively by patient age particularly in the palliative andadjuvant treatment scenarios. In the context of radical treat-ment, decrease in expected radiotherapy utilization was seenacross all cancer sites except nasopharyngeal tumors. Most ofthe observed decline in radiotherapy utilization was due to re-ductions in referral to a cancer center as opposed to decreases inradiation oncologist utilization of radiotherapy as a modality oftreatment. The observed drops in utilization (and referral) weregreater than one would expect using available functional statusinformation from the general Canadian population. This wouldlead to the hypothesis that chronologic age directly (apart fromfunctional status and disease comorbidity expected with an ag-ing patient cohort) would explain some of the utilization reduc-tions. These data confirm that education regarding patients’ re-ferral and management needs to extend outside the walls of thecancer center to ensure optimal consideration of treatment op-tions.

Several case cohorts of elderly patients assessing treatment

effectiveness and tolerability of patients aged 80 or older29-30

and 90 or older31 have been published in the literature.achariah et al29 studied 203 radical and palliative radiother-py patients aged 80 or older in a report published in 1997.reatment response was documented in approximately 80%f patients. Observed treatment tolerance issues were relatedo diarrhea/enteritis, dysphagia/mucositis, weight loss, androgressive disease. Wasil et al30 reported similar findings in

a group of 183 patients. Seventy-seven percent of courseswere completed with 36% of all treatment courses requiringa treatment break mainly because of skin desquamation andmucositis. Oguchi et al31 published on a series of 23 patients�90 years of age demonstrating some durable responses totreatment and, not unexpectedly, also many cases of deathfrom intercurrent illness. Typical toxicities related to radio-therapy volume, such as dermatitis, mucositis, esophagitis,and cystitis, were observed in this patient cohort. All 3 seriesconclude that either radical or palliative radiotherapy can bea tolerable treatment for elderly patients when comorbiditiesfunctional status is assessed and integrated into the treatmentplan. Also attention to radiation treatment details to mini-mize toxicity should be performed to balance treatment effectversus side effects.

Disease entities that are relative/absolute contraindicationsto radiotherapy or diseases that impact treatment toleranceare another important consideration regarding comorbid ill-ness and radiation therapy tolerance. Collagen vascular dis-eases (eg, lupus, scleroderma, Sjogren syndrome), hypersen-sitivity syndromes (eg, Ataxia-telangiectasia and Nevoid[Gorlin] basal cell carcinoma syndrome), and inflammatorydisorders (eg, Crohn disease, Ulcerative Colitis, multiplesclerosis) are well-known examples of disorders that are as-sociated with poor radiotherapy tolerability.32 Other com-mon disease entities of elderly people (and the general pop-ulation) that can impact radiation tolerability includediabetes mellitus and hypertension.

Adaptive Treatment ApproachesAs oncologists, we are often faced with challenging clinicalscenarios that require an adjustment in evidence-based clin-ical management to consider patient-related treatment toler-ability. This adjustment can relate to the use and sequencingof multimodality treatments, such as surgery and chemother-apy. For example, surgery can be used for primary treatmentinstead of radiotherapy in scenarios where relative or abso-lute contraindications to radiotherapy exist owing to preex-isting comorbidities, such as systemic lupus, inflammatorybowel disease, or multiple sclerosis. Similarly, in the contextof chemoradiotherapy, the selection of chemotherapy drugsused, their sequencing (neoadjuvant or adjuvant to radio-therapy), and delivered drug intensities can be altered toimprove treatment tolerability in patients who have signifi-cant comorbidity burden or frailty issues.

Similarly, within the practice of radiation oncology, vari-ous technical parameters such as patient immobilization,simulation, planning, and delivery can be altered to solvechallenging radiotherapy treatment scenarios. These com-

plex treatment scenarios can include issues well known to

cqso

gs

wm

db

u1pturliVui

ion on

280 G. Rodrigues and M. Sanatani

practicing radiation oncologists’, such as large treatment vol-umes and/or significant overlap volumes with radiosensitivecritical structures. However, technical considerations of radio-therapy simulation, planning, and delivery can also assist in thedelivery of treatment to frail patients and those with significantcomorbidity burdens. The various “tools” at the disposal of theradiation oncologist (in concert with other cancer specialists) toadapt treatment are depicted in Figure 1.

Palliative Radiotherapy ConsiderationsAge, comorbidity, and functional status considerations areroutinely integrated into treatment decision making revolv-ing around palliative radiotherapy. A prime example of this iswithin the decision making around radiotherapy for brainmetastases. Clinical trials assessing treatment with postoper-ative radiotherapy after surgical resection33 and radiosur-gery34 have demonstrated improvements in clinical out-omes, such as survival, local control, and health-relateduality of life. However, not all patients benefit from aggres-ive therapy as evidenced by the Radiation Therapy Oncol-gy Group Recursive Partitioning Analysis 8 and the more

current Graded Prognostic Assessment.6-7 Both these systemsuse a scoring strategy based on tumor extent (and type forGraded Prognostic Assessment), patient’s chronologic age,and patient’s performance status. Similarly, various recursivepartitioning analyses from the Radiation Therapy OncologyGroup9 and the European Organization for Research andTreatment of Cancer and National Cancer Institute of Can-ada10 have stratified patients with primary gliomas into sub-roups based primarily on age and performance status. These

Radia�on On• Treatment Intent (Radical, Adap�ve Radica

• Alterna�ve Therapies (Surgery, Chemother

• Frac�ona�on (Total Dose, Dose/frac�on, O

• Cri�cal structure volume in radiotherapy fi

• Pa�ent immobiliza�on (tradi�onal vs. stere

• Radiotherapy simula�on (CT simula�on, M

• Radiotherapy planning– Beam type (photons, electrons, protons, brachyther

– Beam energy

– Beam arrangement/weigh�ng

– Field matching

– Beam modifica�on (wedges, mutlileaf collima�on, c

– Isodose and dose volume histogram assessment

– Intensity Modulated Radia�on Therapy (IMRT) and S

– Adap�ve planning strategies

• Radiotherapy delivery– Image guided radia�on therapy (2D/3D kilovoltage o

– Treatment ga�ng

– Tumor tracking

• Modifica�on of chemoradia�on– Chemotherapy dose reduc�on

– Chemotherapy agent selec�on

– Decoupling of chemotherapy and radia�on (non-con

• Medical management of comorbidi�es and

Figure 1 The radiat

coring systems can be used to triage patients into groups that

ill benefit from aggressive versus palliative radiation treat-ent based on outcome data.Treatment guidelines now exist for the evidence-based ra-

iation treatment of several palliative scenarios, includingone,35 lung,36 and brain metastases radiosurgery.37 In pa-

tients for whom functional impairment and/or significant co-morbidities exist, the use of short palliative fractionationsmay be warranted. In the context of uncomplicated bonemetastases (not spinal cord compression or impending frac-ture), a single dose of 8 Gy can be highly effective at achievinga palliative pain response with minimal toxicity and retreat-ment rates.35 In thoracic palliation, short fractionation sched-

les such 20 Gy in 5 fractions, 16-17 Gy in 2 fractions withinweek, or a single dose of 10 Gy (for patients with very poorerformance status) are highly effective regimens to palliatehoracic symptoms.36 More intense dose fractionation sched-les of 30 Gy in 10 fractions or higher equivalent should beeserved for patients with good performance status, moreimited stage IV disease, and more physiological reserve (ow-ng to the increased treatment toxicity, such as esophagitis).arious effective palliative whole-brain fractionation sched-les exist in the literature, such as 20 Gy in 5 fractions, 30 Gy

n 10 fractions, and 37.5 Gy in 15 fractions.37

ChemotherapeuticConsiderationsSimilar to the considerations between radiotherapy, aging, andcomorbidity burden, important patient selection and treatment

gists’ Toolboxant, Salvage, and Pallia�ve)

rmonal Therapy, Targeted Therapy)

ime, Altered Frac�ona�on, Hypofrac�ona�on)

ered margins/volumes)

)

n, PET fusion)

ors)

c Abla�ve Radiotherapy (SABR)

ltage) to reduce margins

pproach)

ent related toxici�es

cologists’ toolbox.

colol, Adjuv

apy, Ho

verall T

eld (alt

otac�c

RI fusio

apy)

ompensat

tereotac�

r megavo

current a

treatm

delivery issues require consideration for the safe and effective

tnknbbs

wbArccl

eblcc

ridbibtntsanam

Age and comorbidity in RT and CT 281

delivery of chemotherapy and other agents (hormonal and tar-geted therapies) to at-risk patient populations. Also similar toradiotherapy decision making, intentions of chemotherapytreatment can include curative, adjuvant, salvage, and palliative.The different intents of chemotherapy usage (curative or pallia-tive) are especially important to consider in the context of el-derly patient populations. This is due not only to the inherentinteraction of the side effects of therapy on organ and patientfunctioning but also on the competing risks of cancer recur-rence, and intercurrent mortality from so-called natural causes.Given the movement to personalize treatment on a biologicaland psychosocial level, further adaptation of drug therapy basedon patient factors, such as chronologic age, physiological age,functional status, patient preference congruent with life phase,and comorbidity burden is appropriate to optimize importantpatient outcomes.

Impact of Age and ComorbidityImportant physiological and pharmacokinetic changes areknown to occur related to the aging process. Changes related toaging that have important effects on chemotherapy dosing andtolerance include decreased renal function, decreased volume ofdistribution, decreased liver cytochrome P450 function, de-creased gastrointestinal absorption, and decreased bone marrowreserve.38 Additionally, important chemotherapy-related toxici-ies can also be related to aging and include cardiomyopathy,europathies, mucositis, and myelodysplasia/acute myeloid leu-emia. Special attention must be paid to the relationship ofewer targeted agents’ toxicities and possibly age-related comor-idities, such as those related to trastuzumab (cardiotoxicity),evacizumab (hypertension and thromboembolism), andunitinib (congestive heart failure and hypertension).

From the standpoint of patient comorbidities, publishedork has demonstrated that the presence of patient comor-idity can have a direct impact on chemotherapy utilization.dditionally, evidence exists that increased chemotherapy-elated morbidity is related to the underlying presence ofomorbidities. However, this relationship between baselineomorbidity and drug therapy is complex and is highly re-ated to the cancer site and drug class being used. Clinical

Medical Oncologists’ • Consider treatment intent (Cura�ve vs Pallia�v

• Consider alterna�ve therapies (Surgery, Radia�

• Medical management/op�miza�on of comorb

• Chemotherapy agent selec�on (consider altern

• Chemotherapy dose reduc�on

• Chemotherapy regimen altera�on (e.g. omissio

• Modifica�on of Chemoradia�on regimens e.g.

• Special Organ-Specific Considera�ons [39]– Neurotoxicity (Consider alterna�ve drugs, monitor hearin

– Cardiac (Cau�on with anthracyclines as well as with trast

– Renal (Dose adjustment for glomerular filtra�on rate for

– Bone Marrow (Anemia, Thrombocytopenia, Neutropenia

– Gastrointes�nal (Mucosi�s, Diarrhea, Cons�pa�on, Naus

Figure 2 The medical onc

xamples demonstrating this relationship between comor-idities and patient outcomes are available in the medical

iterature and include specific examples, such as prostateancer/hormonal therapy, gastrointestinal cancer/5-fluroura-il, and breast cancer/metformin.3

Adaptive Treatment ApproachesThe consensus-based National Comprehensive Cancer Net-work (NCCN) Senior Adult Oncology guideline is an excel-lent online resource for the management of “at risk” patientpopulations.39 Although the guideline covers surgical andadiotherapy issues as well, the main focus of this documents to assist the clinician to adapt chemotherapy and otherrug therapies for elderly patients with or without comor-idities. Specific guidance is given to the practitioner regard-

ng the neurotoxicity, cardiac toxicity, renal toxicity, andone marrow suppression effects of treatment. Specifically,he NCCN guidelines recommend dose adjustment for re-ally excreted drugs by calculation of the glomerular filtra-ion rate, hemoglobin maintenance at or above 12 g/dL, withpecial consideration of the use of myeloid growth factors, suchs filgrastim/pegfilgrastim, in patients 65 years or older. Alter-ative drug regimens with improved toxicity profiles shouldlso be considered where clinically indicated, as should doseodifications.38 Chemotherapy administration form can be

changed to adapt expected toxicities to the patients’ comorbidi-ties, for example, using infusional 5-fluorouracil instead of bolus5-fluorouracil in a patient with poor oral intake where mucositiswould be a serious threat to health. Naturally, such changesmust always be made acknowledging that a possible compro-mise is being made in regards to antitumor efficacy. Adaptivechemotherapy “tools” for the medical oncologist are summa-rized in Figure 2.

Knowledge Gapsand Future ResearchAlthough information regarding radiotherapy and chemo-therapy administration in elderly people and in patient pop-

motherapy Toolbox

rmonal Therapy, Targeted Therapy)

and treatment related toxici�es

for pa�ents with baseline comorbidi�es)

ne or more agents in polychemotherapy)

single agent radiosensi�zer (carbopla�n, 5FU)

ebellar func�on and peripheral neuropathy)

ly/par�ally renally excreted drugs)

sion, colony s�mula�ng factors)

mi�ng – hydra�on, medical management/prophylaxis, hospitaliza�on)

Chee)

on, Ho

idi�es

a�ves

n of o

use of

g and cer

uzumab)

complete

– Transfu

ea and Vo

ologists’ toolbox.

282 G. Rodrigues and M. Sanatani

ulations with significant comorbidities is increasingly avail-able in the medical literature, several important knowledgegaps relevant to the discussion of integrating age and comor-bidity burden into treatment decision making still exist.

1. An increased focus on prospective clinical trial designand information collected on relevant cancer patientpopulations to guide treatment decision making toadapt for age, functional status, and comorbidities.These trials can be integrated into existing clinical trialsor stand-alone studies assessing adaptive treatments(eg, dose fractionation, altered volume, planning tech-nique—intensity modulated radiotherapy (IMRT) ver-sus Three-dimensional Conformal Radiation (3DCRT),and image-guidance procedures) can be considered.

2. Continued “mining” of existing population and coop-erative group databases to assess effectiveness and tol-erability outcomes for various “at risk” populationscompared with controls.

3. Research to delineate and enhance patient and physi-cian decision-making processes when selecting stan-dard of care treatments versus adaptive (more tolerableand less intensive) alternatives, considering both phys-ical and psychosocial/life cycle factors.

4. The introduction of robust nomograms/models intoclinical practice to understand at an individual patientlevel expected cancer versus intercurrent death outcomesstratified on treatment intensity (radical, adapted radical,and palliative).

5. Evidence-based (and consensus) guidelines on the in-teraction of comorbidities, functional status, physio-logical, and chronologic age into decision making in avariety of cancer scenarios. The NCCN guideline onsenior oncological management can serve as a templatefor further work in this area.39

6. Research and validation of physician and patient-re-ported tools to better assess comorbidity burden, pa-tient frailty, and functional status in the clinic to assistin treatment decision making. There exists evidencesupporting the inclusion of geriatric assessment in can-cer decision making.40

7. Further radiotherapy utilization research could be con-ducted to identify and remove barriers to patient’s re-ferral and treatment.

8. Educational programs at the residency training andspecialty-wide level should be considered to improvefuture delivered care to patients based on evidence andtreatment guidelines.

Summary and ClinicalRecommendationsBased on this review of the literature, the following clinicalrecommendations should be considered in the evaluation ofpatients of advanced age or patients with any comorbidityburden that may impact treatment tolerability. Multidisci-plinary oncological consultation (radiation oncology and/or

medical and surgical oncology) to discuss indications, logis-

tics, and outcomes of standard of care (and adaptive) treat-ments is critical to optimize patient care, maximize survival,and health-related quality of life outcomes and to ensureappropriate treatment utilization rates. A complete patientassessment should include documentation of the patients’chronologic age, estimated physiological age, presence andseverity of comorbidities, contraindications to radiotherapy(and chemotherapy), and performance/functional status.Chronologic age should not routinely be used as a surrogatefor other entities, such as lower performance/functional sta-tus or comorbidity burden. There are notable exceptions tothis rule, as evidenced by data related to primary and meta-static Central Nervous System (CNS) malignancies. A clearlystated intention and rationale of treatment (radical, adjuvant,salvage, or palliative) should be documented in the medicalrecord. Cases should be discussed in multidisciplinaryrounds, ideally, including geriatrician input, to optimize pa-tient care for the individual and to improve group decisionmaking in this patient population.

Both radiotherapy and chemotherapy have a documentedtrack record with regards to treatment tolerability and effi-cacy in elderly populations. However, chemoradiation pro-grams should be used with some caution balancing the out-come benefits with treatment risks.39 Treatments can beadapted by cancer site-specific considerations (eg, observa-tion in low-risk prostate cancer) or using radiation technol-ogies (dose fractionation, treatment volume, IMRT, Image-Guided Radiation Therapy, Stereotactic Body RadiationTherapy, etc.) to optimize the therapeutic ratio. Advantagesand disadvantages of any proposed adaptive treatments totake into account patient factors, such as comorbidities,treatment tolerability, competing risks, and patient prefer-ences, should be discussed with the patient. Medical optimi-zation of baseline comorbidities before treatment should beconsidered to optimize patient treatment tolerability and toreduce comorbidity impact and mortality.

References1. American Cancer Society: Cancer Facts and Figures 2011. Atlanta, GA,

American Cancer Society, 20112. Piccirillo JF, Tierney RM, Costas I, et al: Prognostic importance of

comorbidity in a hospital-based cancer registry. jama 291:2441-2447,2004

3. Pal SK, Hurria A: Impact of age, sex, and comorbidity on cancer therapyand disease progression. J Clin Oncol 28:4086-4093, 2010

4. Appelbaum FR, Gundacker H, Head DR, et al: Age and acute myeloidleukemia. Blood 107:3481-3485, 2006

5. Diab SG, Elledge RM, Clark GM: Tumor characteristics and clinicaloutcome of elderly women with breast cancer. J Natl Cancer Inst 92:550-556, 2000

6. Sperduto PW, Chao ST, Sneed PK, et al: Diagnosis-specific prognosticfactors, indexes, and treatment outcomes for patients with newly diag-nosed brain metastases: A multi-institutional analysis of 4,259 patients.Int J Radiat Oncol Biol Phys 77:655-661, 2010

7. Sperduto PW, Berkey B, Gaspar LE, et al: A new prognostic index andcomparison to three other indices for patients with brain metastases: Ananalysis of 1,960 patients in the RTOG database. Int J Radiat Oncol BiolPhys 70:510-514, 2008

8. Gaspar L, Scott C, Rotman M, et al: Recursive partitioning analysis

(RPA) of prognostic factors in three radiation therapy Oncology Group

1

1

1

1

1

1

1

1

1

1

2

2

2

2

2

2

2

2

2

2

3

3

3

3

3

3

3

3

3

3

4

Age and comorbidity in RT and CT 283

(RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys37:745-751, 1997

9. Curran WJ Jr, Scott CB, Horton J, et al: Recursive partitioning analysisof prognostic factors in three radiation therapy Oncology Group ma-lignant glioma trials. J Natl Cancer Inst 85:704-710, 1993

0. Mirimanoff RO, Gorlia T, Mason W, et al: Radiotherapy and temozo-lomide for newly diagnosed glioblastoma: Recursive partitioning anal-ysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial.J Clin Oncol 24:2563-2569, 2006

1. Mohler JL: The 2010 NCCN clinical practice guidelines in oncology onprostate cancer. J Natl Compr Cancer Netw 8:145, 2010

2. Fried LP, Tangen CM, Walston J, et al; Cardiovascular Health StudyCollaborative Research Group. Frailty in older adults: Evidence for aphenotype. J Gerontol A Biol Sci Med Sci 56:M146-M156, 2001

3. Yun YH, Kim SH, Lee KM, et al: Age, sex, and comorbidities wereconsidered in comparing reference data for health-related quality of lifein the general and cancer populations. J Clin Epidemiol 60:1164-1175,2007

4. Nanda A, Chen MH, Braccioforte MH, et al: Hormonal therapy use forprostate cancer and mortality in men with coronary artery disease-induced congestive heart failure or myocardial infarction. jama 302:866-873, 2009

5. Jiralerspong S, Palla SL, Giordano SH, et al: Metformin and pathologiccomplete responses to neoadjuvant chemotherapy in diabetic patientswith breast cancer. J Clin Oncol 27:3297-3302, 2009

6. Frasci G, Lorusso V, Panza N, et al: Gemcitabine plus vinorelbineversus vinorelbine alone in elderly patients with advanced non-small-cell lung cancer. J Clin Oncol 18:2529-2536, 2000

7. Zauderer M, Patil S, Hurria A: Feasibility and toxicity of dose-denseadjuvant chemotherapy in older women with breast cancer. BreastCancer Res Treat 117:205-210, 2009

8. Meyerhardt JA, Catalano PJ, Haller DG, et al: Impact of diabetes melli-tus on outcomes in patients with colon cancer. J Clin Oncol 21:433-440, 2003

9. Yancik R, Yates JW, Cumberlin R: Research recommendations for ra-diation therapy in older cancer patients. Report from the NationalInstitute on Aging, National Cancer Institute, and American College ofRadiology Workshop: Radiation therapy and cancer in older persons.Int J Radiat Oncol Biol Phys 43:3-5, 1999

0. Kendal WS: Dying with cancer: The influence of age, comorbidity, andcancer site. Cancer 112:1354-1362, 2008

1. Vulto AJ, Lemmens VE, Louwman MW, et al: The influence of age andcomorbidity on receiving radiotherapy as part of primary treatment forcancer in South Netherlands, 1995 to 2002. Cancer 106:2734-2742, 2006

2. Janssen-Heijnen ML, Houterman S, Lemmens VE, et al: Prognosticimpact of increasing age and co-morbidity in cancer patients: A popu-lation-based approach. Crit Rev Oncol Hematol 55:231-240, 2005

3. Coebergh JW, Janssen-Heijnen ML, Post PN, et al: Serious co-morbid-

ity among unselected cancer patients newly diagnosed in the southeast-

ern part of The Netherlands in 1993-1996. J Clin Epidemiol52:1131-1136, 1999

4. Wedding U, Röhrig B, Klippstein A, et al: Age, severe comorbidity andfunctional impairment independently contribute to poor survival incancer patients. J Cancer Res Clin Oncol 133:945-950, 2007

5. Read WL, Tierney RM, Page NC, et al: Differential prognostic impact ofcomorbidity. J Clin Oncol 22:3099-3103, 2004

6. Extermann M, Overcash J, Lyman GH, et al: Comorbidity and func-tional status are independent in older cancer patients. J Clin Oncol16:1582-1587, 1998

7. Mao JJ, Armstrong K, Bowman MA, et al: Symptom burden amongcancer survivors: Impact of age and comorbidity. J Am Board Fam Med20:434-443, 2007

8. Tyldesley S, Zhang-Salomons J, Groome PA, et al: Association betweenage and the utilization of radiotherapy in Ontario. Int J Radiat OncolBiol Phys 47:469-480, 2000

9. Zachariah B, Balducci L, Venkattaramanabalaji GV, et al: Radiotherapyfor cancer patients aged 80 and older: A study of effectiveness and sideeffects. Int J Radiat Oncol Biol Phys 39:1125-1129, 1997

0. Wasil T, Lichtman SM, Gupta V, et al: Radiation therapy in cancerpatients 80 years of age and older. Am J Clin Oncol 23:526-530, 2000

1. Oguchi M, Ikeda H, Watanabe T, et al: Experiences of 23 patients �or � 90 years of age treated with radiation therapy. Int J Radiat OncolBiol Phys 41:407-413, 1998

2. Chon BH, Loeffler JS: The effect of nonmalignant systemic disease ontolerance to radiation therapy. Oncologist 7:136-143, 2002

3. Patchell RA, Tibbs PA, Regine WF, et al: Postoperative radiotherapy inthe treatment of single metastases to the brain: A randomized trial. jama280:1485-1489, 1998

4. Andrews DW, Scott CB, Sperduto PW, et al: Whole brain radiationtherapy with or without stereotactic radiosurgery boost for patientswith one to three brain metastases: Phase III results of the RTOG 9508randomised trial. Lancet 363:1665-1672, 2004

5. Lutz S, Berk L, Chang E, et al; American Society for Radiation Oncology(ASTRO). Palliative radiotherapy for bone metastases: An ASTRO evi-dence-based guideline. Int J Radiat Oncol Biol Phys 79:965-976, 2011

6. Rodrigues G, Videtic GMM, Sur R: Palliative thoracic radiotherapy inlung cancer: An American Society for Radiation Oncology evidence-based clinical practice guideline. Pract Radiol Oncol 1:60-71, 2011

7. Gaspar LE, Mehta MP, Patchell RA, et al: The role of whole brainradiation therapy in the management of newly diagnosed brain metas-tases: A systematic review and evidence-based clinical practice guide-line. J Neurooncol 96:17-32, 2010

8. Carreca I, Balducci L: Cancer chemotherapy in the older cancer patient.Urol Oncol 27:633-642, 2009

9. Balducci L, Cohen HJ, Engstrom PF: National Comprehensive CancerNetwork. Senior adult oncology clinical practice guidelines in oncol-ogy. J Natl Compr Cancer Netw 3:572-590, 2005

0. Aliamus V, Adam C, Druet-Cabanac M, et al: Geriatric assessmentcontribution to treatment decision-making in thoracic oncology [in

French]. Rev Mal Respir 28:1124-1130, 2011.