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Cancer is the leading cause of death in women and men aged 60 to 79 years.1 More than 50% of all cancers and more than 70% of cancer-related deaths in the United States occur in patients aged 65 years or older.2 By 2030, an estimated 70% of all cancers will be diagnosed in adults aged 65 years or older.3 Older individuals are more prone to develop cancer than younger individuals. Furthermore, the aging of the U.S. population and increased life expectancy of the elderly mean that cancer in older adults is becoming an increasingly common problem.
Unique issues must be considered when caring for older adults with cancer. The biology of certain neoplasms and responsiveness to therapy changes with patient age.4 Furthermore, the patient’s physiologic status, comorbidities, and preferences may influence the selection and tolerance to certain therapies. Together, these age-related issues form the basis for the development of guidelines that address special considerations in older adults with cancer.
Older adults with cancer are underrepresented in clinical trials for new cancer therapies.5 Therefore fewer evidence-based data are available to guide the treatment of these patients. However, advanced age alone should not preclude the use of effective cancer treatment that could improve quality of life or extend meaningful survival.6,7 Treatment that diminishes quality of life with no significant survival benefit should be avoided. The available data suggest that older patients with good performance status are able to tolerate commonly used chemotherapy regimens as well as younger patients, particularly when adequate supportive care is provided.8-10 However, few studies have addressed patients at the extremes of age or those with poor performance status. The physiological changes associated with aging may impact an older adult’s ability to tolerate cancer therapy and should be considered in the treatment decision-making process.
These guidelines address specific issues related to the management of cancer in older individuals, including screening and comprehensive geriatric assessment, assessment of the risks and benefits of treatment, prevention of or decreasing complications from therapy, disease-specific issues, and management of patients unfit for standard treatment.
*To view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org.
Socioeconomic issues: see page 165
Psychosocial distress: see NCCN Guidelines for Distress Management*
Nutritiona l Status
*To view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org.
iSee Procedure for Functional Assessment Screening in Elderly Persons (page 178).
jMortality can be predicted using weight, body mass index, nutrition, fatigue, and existing medical conditions.
|Target Area||Assessment Procedure||Abnormal Result||Suggested Intervention|
|Vision||Test each eye with Jaeger card while|
patient wears corrective lenses (if
|Inability to read|
|Refer to ophthalmologist.|
|Hearing||Whisper a short, easily answered|
question, such as “What is your name?” in
each ear while the examiner’s face is out
of direct view.
|Inability to answer|
|Examine auditory canals for cerumen and clean if necessary.|
Repeat test; if still abnormal in either ear, refer for audiometry and
|Arm||Proximal: “Touch the back of your head|
with both hands.”
Distal: “Pick up the spoon.”
|Inability to do|
|Examine the arm fully (muscle, joint, and nerve) paying attention|
to pain, weakness, limited range of motion.
Consider referral for physical therapy and occupational therapy.
|Leg||Observe the patient after asking “Rise|
from your chair, walk 10 ft, return, and sit
|Inability to walk or|
transfer out of chair
|Do full neurologic and musculoskeletal evaluation, paying|
attention to strength, pain, range of motion, balance, and
traditional assessment of gait. Consider referral for physical
therapy and occupational therapy.
|Ask patient: “Do you ever lose your urine|
and get wet?”
|Yes||Ascertain frequency and amount. Search for remediable causes|
including local irritations, polyuric states, and medications.
Consider urologic referral.
|Nutrition||Weigh the patient. Measure height.||Weight is below|
|Do appropriate medical evaluation.|
Consider dietician referral.
|Tell the patient: “I am going to name three|
objects (pencil, truck, book). I will ask you
to repeat their names now and then again
a few minutes from now.”†
|Inability to recall all|
3 objects after 1
|Administer Folstein mini-mental status examination. If score is|
< 24, search for causes of cognitive impairment. Ascertain onset,
duration, and fluctuation of overt symptoms. Review medications.
Assess consciousness and affect. Do appropriate laboratory tests.
|Depression||Ask patient: “Do you often feel sad or|
|Yes||Administer Geriatric Depression Scale. If positive (normal score, 0|
to 10), check for antihypertensive, psychotropic, or other pertinent
medications. Consider appropriate pharmaceutical or psychiatric
|ADL-IADL||Ask patient: “Can you get out of bed|
yourself?”; “Can you dress yourself?”;
“Can you make your own meals?”; “Can
you do your own shopping?”
|No to any question||Corroborate responses with patient’s appearance; question family|
members if accuracy is uncertain. Determine reasons for the
inability (motivation compared with physical limitation). Institute
appropriate medical, social, or environmental interventions.
|Ask patient: “Do you have trouble with|
stairs inside or outside of your home?”;
ask about potential hazards inside the
home with bathtubs, rugs, or lighting.
|Yes||Evaluate home safety and institute appropriate|
|Ask patient: “Who would be able to help|
you in case of illness or emergency?”
|…||List identified persons in the medical record. Become familiar with|
available resources for the elderly in the community. Consider
social worker referral.
ADL, activities of daily living; IADL, instrumental activities of daily living.
Adapted with permission from Lachs MS, Feinstein AR, Cooney LM Jr, et al. A simple procedure for general screening for functional disability in elderly patients. Ann Intern Med 1990;112:699-706.
Older patients can be classified into 3 categories: 1) young old patients are aged 65 to 75 years; 2) old patients are aged 76 to 85 years; and 3) oldest old patients are older than 85 years.11 Proper selection of patients is the key to administering effective and safe cancer treatment. The challenge of managing the older cancer patient is to assess whether the expected benefits of treatment are superior to the risk in a population with decreased life expectancy and decreased tolerance to stress.
Chronologic age alone is not reliable in estimating life expectancy, functional reserve, or the risk of treatment complications.12 Although a physician cannot predict the exact life expectancy of an individual patient, they can provide an estimate of whether a patient is likely to live longer or shorter than an average person of similar age. Life expectancy at a given age can be estimated using life table data as suggested by Walter and Covinsky.13 For example, approximately 25% of the healthiest 75-year-old women will live more than 17 years, 50% will live at least 12 years, and 25% will live less than 7 years. Lee et al.14 developed and validated a potentially useful tool for clinicians to estimate the 4-year mortality risk. Patients can be stratified into 3 groups of varying risk of mortality (high, intermediate, or low) based on the prognostic index, which incorporates demographic variables (age and sex), self-reported comorbid conditions, and functional measures.14 Carey et al.15 also developed a similar functional morbidity index based on self-reported functional status, age, and gender to stratify elders into varying risk groups for 2-year mortality. In a pooled analysis of individual data from 9 selected cohorts, Studenski et al.16 reported that gait speed was associated with survival in older adults.
Comprehensive geriatric assessment (CGA) is a multidisciplinary in-depth evaluation to assess life expectancy and risk of morbidity from cancer in elderly patients.17-19 CGA includes assessment tools to predict the functional age of elderly patients with cancer based on functional status, comorbidities that may interfere with cancer treatment, polypharmacy, nutritional status, cognitive function, psychological status, socioeconomic issues, and geriatric syndromes. The feasibility of CGA has been shown in elderly patients with cancer.20-22 Balducci and Extermann20 studied CGA in the older cancer patient, including an evaluation of functional status, comorbidity, socioeconomic conditions, cognitive and emotional function, nutritional status, polypharmacy, and geriatric syndromes. Ingram et al.21 used a self-administered CGA, including demographics, comorbid conditions, functional status, pain, financial well-being, social support, emotional state, spiritual well-being, and quality of life, to characterize older cancer patients. Repetto et al.22 showed that CGA adds substantial information on the functional assessment of elderly cancer patients (aged ≥ 65 years). Among patients with a good performance status, 13% had 2 or more comorbidities; 9.3% and 37.7% had limitations in activities of daily living (ADLs) or instrumental activities of daily living (IADLs), respectively.
CGA components (comorbid conditions, functional status, geriatric syndromes, and nutritional status) have been associated with the type of cancer treatment and survival in elderly patients with cancer.23-27 For example, in women aged 65 years or older diagnosed with stage I through III primary breast cancer, the all-cause and breast cancer-specific death rate at 5 and 10 years was consistently approximately 2 times higher in women with 3 or more cancer-specific CGA deficits, regardless of age and stage of disease.26 In another prospective study of 375 consecutive elderly patients with cancer (ELCAPA study), a multivariate analysis showed that a lower ADL score and malnutrition were independently associated with cancer treatment changes.27
Although CGA is helpful for physicians to develop a coordinated plan for cancer treatment and to guide appropriate interventions to the patient’s problems, it can be time-consuming and may not be practical for all patients. Hurria et al.28,29 developed a brief but comprehensive geriatric assessment of older patients with cancer. A multicenter study involving 500 older patients (median age, 73 years) with cancer showed that this brief geriatric assessment (including functional status, comorbidity, cognition, psychological status, social functioning and support, and nutritional status) is largely self-administered and can be completed by most older patients without assistance.28 The geriatric assessment also identified deficits and problems that may impact morbidity and mortality.29 Recent results from the CALGB 360401 study showed the feasibility of including this brief, primarily self-administered geriatric assessment tool in future cooperative group clinical trials.30 Overcash et al.31,32 developed an abbreviated CGA that could be helpful in screening for elderly patients who would benefit from an entire CGA.
Functional status in older patients with cancer can be evaluated based on their ability to complete ADLs and IADLs.33,34 IADLs encompass complex skills that are necessary for maintaining independence in the community, and ADLs encompass more basic functions required to maintain independence in the home. In older patients with cancer, independence in IADLs has been associated with improved treatment tolerance and improved survival.23-25,35 In addition to ADL and IADL scales, other screening tests (discussed later) have also been used to determine the functional status in elderly cancer patients.
A quick screening test to assess mobility is the “timed up and go” (TUG) test. Older individuals are asked to get up from an armchair without using their arms, walk 10 feet forward at their usual pace, turn around, walk back to the chair, and then sit down again. This tool can be use to assess overall motor function, and the score has been predictive of the risk of falls in older adults.
Lachs et al.36 developed a screening tool to assess vision, hearing, arm and leg mobility, urinary incontinence, nutrition, mental status, depression, disabilities in the ADLs and IADLs, home environment, and social support. This screening test is performed by a physician (or office staff), and may be very useful for assessing whether a CGA is necessary.
Saliba et al.37,38 developed a useful questionnaire called the Vulnerable Elders Survey (VES-13) that can predict the probability of death and functional decline in older patients. A score of 3 or more on the VES-13 indicates that patients are vulnerable. Patients can quickly fill out this survey at home or in the office. Saliba et al.37 tested the questionnaire in 6205 Medicare beneficiaries aged 65 years and older. The VES-13 assesses whether elderly patients are at risk for functional decline or death. The advantage of this questionnaire is that it minimizes the amount of time required to examine patients in the office. The survey assesses age, self-rated health, limitation in physical function, and functional disabilities. Recently, Luciani et al.39 reported that the VES-13 is highly predictive of impaired functional status and can be considered a useful preliminary means of assessing older patients with cancer before undertaking a full CGA.
In the future, laboratory tests may be used to assess which elderly patients are at increased risk for functional decline or mortality. Cohen et al.40 showed that high levels of interleukin-6 and D-dimer were associated with mortality and functional dependence in home-dwelling individuals aged 71 years and older. Higher levels of interleukin-6 and C-reactive protein have been associated with slower walking speed and poor grip strength in adults older than 70 years.41 In addition, cognitive decline has been found to be associated with elevated levels of D-dimer.42 Thus, assessment of markers of inflammation and coagulation (e.g., interleukin-6, D-dimer) may be used to predict the physiologic age of elderly patients.
Older adults have an increased prevalence of comorbidities, which can impact cancer prognosis and treatment tolerance.43,44 Cardiovascular problems, including congestive heart failure (CHF), diabetes, renal insufficiency, dementia, depression, anemia, and osteoporosis, are some frequently encountered comorbid conditions in elderly cancer patients.
Specific comorbidities have been shown to have an impact on prognosis and treatment outcome in patients with cancer.45-47 For example, in a series of 5077 men (median age, 69.5 years) with localized or locally advanced prostate cancer, neoadjuvant hormonal therapy was significantly associated with an increased risk of all-cause mortality (26.3% vs. 11.2%) among men with a history of coronary artery disease, CHF, or myocardial infarction after a median follow-up of 5.1 years.45 In a randomized adjuvant chemotherapy trial of 3759 patients with high-risk stage II and III colon cancer, those with diabetes mellitus experienced a significantly higher rate of overall mortality and cancer recurrence. At 5 years, the disease-free (48% vs. 59%), overall (57% vs. 66%), and recurrence-free survival rates (56% vs. 64%) were significantly worse for patients with diabetes than for those without.46 In the SEER database analysis of elderly patients (aged ≥ 66 years) diagnosed with stages I through III breast cancer, those with diabetes had increased rate of hospitalizations for any chemotherapy toxicity and higher all-cause mortality.47 In elderly cancer patients with comorbidities, the interaction of cancer treatment with comorbidity may impact functional status or worsen the comorbidity. Cancer treatment may be too risky because of the type and severity of comorbidity, and, finally, cancer or cancer treatment may not have any impact on life expectancy because of the risk of morbidity or mortality associated with the comorbid condition. The effect of comorbidity on life expectancy should be evaluated before initiation of treatment.
The guidelines recommend that the number and severity of comorbidities should be assessed. The adult comorbidity evaluation-27 (ACE-27) index,48 Charlson Comorbidity Index (CCI),49 Cumulative Illness Rating Scale (CIRS),50 and OARS Multidimensional Functional Assessment Questionnaire51 are commonly used indices to determine the risk of mortality associated with comorbidity in elderly patients. ACE-27,52,53 CCI,54-56 and CIRS57,58 have also been used to determine treatment tolerance in elderly cancer patients. In a study of 310 elderly patients (aged ≥ 70 years) with head and neck cancer, comorbidity measured using the ACE-27 index was an indicator of overall survival.59 In a randomized trial that compared vinorelbine alone or in combination with gemcitabine in elderly patients with locally advanced non-small cell lung cancer (NSCLC), a CCI of greater than 2 was associated with a higher risk of early treatment suspension (82% vs. 30%, respectively).53 In a phase III trial comparing platinum-doublet therapy as first-line treatment in patients with stage IIIB or IV NSCLC, those with severe comorbidities (as measured with CIRS) benefited from and tolerated platinum-doublet chemotherapy as well as those with no comorbidities.56 However, the former group had a higher risk of neutropenic fever and death from neutropenic infections.
Polypharmacy can be defined in various ways, including the use of an increased number of medications (≥ 5), more than is clinically indicated; the use of potentially inappropriate medications; medication underuse; and medication duplication.60,61 Although polypharmacy can be an issue across all age groups, it can be a more serious problem in elderly patients because of the presence of increased comorbid conditions treated with one or more drugs. In this patient population, the use of drugs for the management of cancer-related symptoms or side effects can result in polypharmacy.62-64
The use of multiple medications can lead to increased incidences of adverse drug reactions (which can lead to functional decline and geriatric syndromes), drug-drug interactions, and nonadherence.60,65,66 Among patients receiving systemic anticancer therapy for solid tumors, one or more drug-drug interactions were observed in 27% of patients, which increased to 31% among patients receiving palliative care only.66,67 Older patients, those with comorbid conditions, those with brain tumors, and those taking many medications are at greater risk for drug interactions.67
Alterations in pharmacokinetics and pharmacodynamics of drug metabolism in elderly patients can also contribute to adverse drug interactions.60 Most of the commonly prescribed medications, such as opioids, antidepressants, antibiotics, and antipsychotics, and anticancer drugs induce or inhibit cytochrome P450 enzymes. In a retrospective analysis, Popa et al.68 assessed the impact of polypharmacy on toxicity from chemotherapy in 290 elderly patients (aged ≥ 70 years). Results showed that cytochrome P450 inhibition may contribute to nonhematologic toxicities, whereas hematologic toxicities may be associated with protein binding interactions. The role of protein binding and cytochrome P450 inhibition should be further explored.
The use of one or more potentially inappropriate medications among elderly patients has also been documented in several studies.69-71 In one study, the use of inappropriate medications increased from 29% to 48% among cancer patients in the palliative care setting.70 In a more recent study of 500 elderly cancer patients (aged ≥ 65 years) starting a new chemotherapy regimen, polypharmacy (≥ 5 drugs) was observed in 48% of patients, and the use of potentially inappropriate medications was seen in 11% to 18%.71 Although polypharmacy did not increase the risk of chemotherapy-related toxicity in this cohort, it was associated with a higher frequency of hospitalization and early discontinuation of chemotherapy.71
The guidelines recommend that medication review for duplication and appropriate use be performed at every visit. Beers criteria and the Medication Appropriateness Index (MAI) are 2 of the most common approaches used to evaluate potentially inappropriate medication use in older patients. The screening tool of older persons’ prescriptions (STOPP) and the screening tool to alert doctors to right treatment (START) criteria were recently developed to evaluate drug interactions, medication duplication, and medication underuse.
The Beers criteria identify inappropriate medications that have potential risks that outweigh potential benefits based on the risk of toxicity and the presence of potential drug-disease interaction in elderly cancer patients.72,73 The criteria are appropriate for persons older than 65 years, and provide a rating of severity for adverse outcomes and a descriptive summary of the prescribing information associated with the medication. The updated 2003 Beers criteria have been used to evaluate polypharmacy in older patients with cancer both in an oncology-specific acute care unit (oncology-acute care for elders [OACE]; n = 47, with a median age of 73.5 years) and in the outpatient setting (n = 154, with a median age of 74 years).74,75 The Beers criteria-based polypharmacy was observed in 21% and 11% of patients, respectively. Both of these studies included medication review and pharmacist-based interventions to improve the appropriateness of prescribing. In the OACE study, 53% had a subsequent alteration in their medication regimen, and 28% had a potentially inappropriate medication discontinued.74 In the outpatient study, 50% of patients required specific interventions after geriatric management evaluation.75
The MAI was developed to measure appropriate prescribing based on a 10-item list and a 3-point rating scale.76 Samsa et al.77 subsequently modified the MAI to include a single summated MAI score per medication, which showed acceptable reliability in assessing medication appropriateness among 1644 medications prescribed to 208 elderly veterans from the same clinic. This modified MAI seems to be a valid and relatively reliable measure to detect medication appropriateness and inappropriateness in the community pharmacy setting, and in ambulatory elderly patients on multiple medications.78,79 MAI scores were significantly lower for medications with a high potential for adverse effects than for those with a low potential (1.8 vs. 2.9).78 Higher MAI scores were also associated with lower self-related health scores in older adults.80 MAI has not been evaluated extensively in elderly cancer patients.
The STOPP/START criteria were established by a Delphi consensus process involving 18 experts in geriatric pharmacotherapy from Ireland and the United Kingdom.81 The STOPP criteria is composed of 65 indicators for potentially inappropriate prescribing, including drug-drug and drug-disease interactions, therapeutic duplication, and drugs that increase the risks of geriatric syndromes, whereas the START criteria incorporate 22 evidence-based indicators to identify prescribing omissions in older people.82,83 In a randomized trial of 400 hospitalized patients (aged ≥ 65 years), unnecessary polypharmacy, the use of drugs at incorrect doses, and potential drug-drug and drug-disease interactions were significantly lower in the group assigned to screening using STOPP/START criteria with recommendations provided to their attending physicians, compared with a control group assigned to routine pharmaceutical care.84 Significant improvements in prescribing appropriateness were sustained for 6 months after discharge.
Nutritional deficiency or malnutrition is a common and serious condition in older patients. Although some of the malnutrition is attributed to the underlying illness, in most patients it is from inadequate intake of calories. The Mini-Nutritional Assessment (MNA) was designed and validated to provide a single, rapid assessment of nutritional status of elderly patients in outpatient settings.85,86 The MNA is composed of simple measurements and brief questions that help identify people at risk for malnutrition before severe changes in weight or albumin levels occur. Rubenstein et al.87 developed a shortened version of the MNA, which also has good diagnostic accuracy. Special attention should also be given to vitamin D deficiency, because it may be related to osteoporosis and fractures.88
Geriatric patients with cancer who are cognitively impaired have an increased risk of functional dependence and a higher incidence of depression, and are at greater risk for death. Cognitive function was also predictive of medication adherence across diagnoses, regardless of the complexity of regimen.89 In addition, the association between cognitive impairment and the ability to weigh the risks and benefits of cancer treatment decisions must be considered. Cognitively impaired patients should be cared for by an experienced multidisciplinary geriatric oncology team and receive good supportive care throughout the treatment.90 Anticholinergics, antipsychotics, benzodiazepines, corticosteroids, and opioids can be associated with cognitive impairment in older adults.91 Special considerations for overuse or underuse, duration of therapy, and dosage should be in place with the use of these classes of medications. Hilmer et al.92 developed a drug burden index that is a useful evidence-based tool for assessing the effect of medications on the physical and cognitive performance in elderly people.
Dementia and delirium are among the most common causes of cognitive impairment.93 See Geriatric Syndromes on this page for the assessment of dementia and delirium in older cancer patients.
Social ties have been identified as significant predictors of mortality in older adults.94,95 In a study of 2835 women diagnosed with breast cancer, socially isolated women had an elevated risk of mortality after a breast cancer diagnosis.96 An evaluation of social support is an integral part of geriatric assessment. The patient’s treatment goals should be discussed with them. In addition, the patient’s living conditions, presence and adequacy of caregiver, and financial status should also be taken into consideration. Consultation with a social worker should be encouraged. Consultation with a financial expert to discuss the cost and coverage options of treatment would also be beneficial.
Dementia, delirium, depression, distress, osteoporosis, falls, fatigue, and frailty are some of the most common syndromes in elderly cancer patients.97 Elderly patients with cancer experience a higher prevalence of geriatric syndromes compared with those without cancer. In analysis of a national sample of 12,480 community-based elders, 60.3% of patients with cancer reported one or more geriatric syndromes compared with 53.2% of those without cancer.98 In this cohort, the prevalence of hearing trouble, urinary incontinence, falls, depression, and osteoporosis were significantly higher in patients with cancer than in those without.
Dementia is a permanent cognitive impairment and is often present in elderly patients as a comorbid condition. In a SEER database analysis, elderly patients (aged ≥ 67 years) with colon cancer and dementia were less likely to receive invasive diagnostic methods or therapies with curative intent.99 Preexisting dementia was also associated with high mortality, mostly from noncancer causes in patients aged 68 years or older diagnosed with breast, colon, or prostate cancer.100
The Blessed Orientation-Memory-Concentration test (BOMC), Mini-Mental State Examination (MMSE), or Montreal Cognitive Assessment (MoCA) can be used to screen for cognitive impairment in older adults.101-104 The BOMC is a 6-item derivative of the Blessed Information-Memory-Concentration test.103 The MMSE is an 11-item screening test that quantitatively assesses the severity of cognitive impairment and documents cognitive changes occurring over a period of time.101,102 However, the MMSE is not adequate for mild cognitive impairment and does not predict future decline. The MoCA is a brief screening tool with high sensitivity and specificity for detecting mild cognitive impairment in patients performing in the normal range on the MMSE.104 The MoCA has been shown to be superior as a prognostic indicator over the MMSE in patients with brain metastases.105,106 In a feasibility study of the MoCA in patients with brain metastases, cognitive impairment was detected in 80% of the patients using this test compared with 30% using the MMSE.105 Among the 28 patients with a normal MMSE, 71% had cognitive impairment according to the MoCA.
The use of antipsychotic medications in patients with dementia is associated with higher mortality rates.107-109 Antipsychotic drugs should be used with caution even when short-term therapy is being considered.109
Delirium is an acute decline in attention and cognition. It is the most common and underrecognized problem in older adults and can pose serious complications in patients with advanced cancer.110 Dementia is the leading factor for delirium, and approximately two-thirds of cases of delirium occur in older patients with dementia.111 It can contribute to poorer clinical outcome and affects communication between patients and physicians.
Several screening tools are available to identify patients with delirium. The Confusion Assessment Method (CAM) is a screening and diagnostic tool based on 4 important features of delirium: acute onset and fluctuating course, inattention, disorganized thinking, and altered level of consciousness.112,113 The Memorial Delirium Assessment Scale (MDAS) is a 10-item validated instrument developed for repeated use to quantify the severity of delirium symptoms in patients with advanced cancer.114 The Nursing Delirium Screening Scale (Nu-DESC) is an observational 5-item scale that has been validated in the oncology inpatient setting and is associated with high sensitivity and specificity.115 Medications that can contribute to delirium should be used with caution in elderly patients with cancer.116,117 See the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Distress Management for the management of dementia and delirium (to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org).
The Geriatric Depression Scale (GDS) is a reliable and valid tool for screening for depression in older patients with no cognitive impairment and in patients with mild to moderate cognitive impairment.118 The GDS was originally developed by Yesavage et al.118 as 30-item scale. Recently, shortened versions of the GDS have been found be equally accurate and less time-consuming in screening for depression in older adults.119,120 Cancer-related fatigue and depression frequently occur together; therefore, patients reporting fatigue should probably be assessed for depression.121-123
Psychological distress is common among patients with cancer. Hurria et al.124 reported that significant distress was identified in 41% of patients aged 65 years or older with cancer, and that poorer physical function was the best predictor of distress. Screening tools have been found to be effective and feasible in reliably identifying distress and the psychosocial needs of patients.125-127 The Distress Thermometer (DT) and the accompanying 36-item problem list is a well-known screening tool, specifically developed for cancer patients by the NCCN Distress Management Panel (see the NCCN Guidelines for Distress Management, available online at www.NCCN.org).128,129 The NCCN DT has been validated by several studies in patients with different types of cancer and has revealed good correlation with the more comprehensive Hospital Anxiety and Depression Scale (HADS).127 Patients can quickly complete this distress assessment tool in the waiting room, and the results can alert the physician to potential problems. This tool identifies whether cancer patients have problems in 5 different categories: practical, family, emotional, spiritual/religious, and physical.
Frailty is a biologic syndrome of decreased reserve and resistance to stressors, causing vulnerability to adverse outcomes.130 Frail patients are at risk for falling, disability, hospitalization, and death. The Cardiovascular Health Study (CHS) developed a screening tool to identify frail patients.131 Frail patients have 3 or more of the following criteria: unintentional weight loss (≥ 10 lb in past year), self-reported exhaustion, weakness (grip strength), slow walking speed, and/or low physical activity.131 Fit, frail, and pre-frail patients had different 5-year mortality rates and different risks of developing functional dependence at 3 and 7 years. The CHS screening tool was tested in 5317 men and women aged 65 years and older.
Cancer-related fatigue is a persistent, subjective sense of tiredness related to cancer or cancer treatment that interferes with usual functioning. In advanced cancer, the prevalence of fatigue is greater than 50% to 70%.132 In a study that evaluated the prevalence of common symptoms in patients with advanced cancer, fatigue was independently associated with chemotherapy, hemoglobin level, and other symptoms, such as pain and depression.133 Patients perceive fatigue to be one of the most distressing symptoms associated with cancer and its treatment; fatigue is more distressing than pain or nausea and vomiting.134,135 In contrast to normal fatigue, cancerrelated fatigue is refractory to sleep and rest, perhaps because cancer patients have aberrant sleep patterns. It is reasonable to expect that fatigue may precipitate functional dependence, especially in patients who are already dependent in IADLs.136-138
Multiple factors can contribute to fatigue, including pain, emotional distress, anemia, comorbidities, and/or sleep disturbance, and many of these conditions are treatable. Certainly, the best strategy is avoidance of any fatigue that may precipitate functional dependence in older individuals. Energy conservation, exercise programs, stress management, sleep therapy, and psychostimulants are some of the interventions that have proved valuable. Screening for fatigue can be performed using a brief screening questionnaire: “Since your last visit, how would you rate your worst fatigue on a scale of 0 to 10 (0 = no fatigue and 10 = worst fatigue)?” (See the NCCN Guidelines for Cancer-Related Fatigue; to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org).
Falls are one of the most common geriatric syndromes. Risk factors include older age, muscle weakness, and impairments in gait, balance, vision, cognition, and ADLs.139 In a prospective study of incidences of falls in patients with advanced cancer, 52% of patients fell during a follow-up of up to 6 months, regardless of age. The median time to fall was 85 and 80 days for those younger than 65 years and those aged 65 years or older, respectively.140 Evidence from a meta-analysis of randomized trials and a systematic review identified interventions, such as multifactorial falls risk assessment and management, exercise, environmental modifications, and education, that are very effective in preventing falls in older adults, and also in reducing both risk and rate of falling.141 Multifactorial risk assessment and management was the most effective intervention for both the risk of falling and the monthly rate of falls. Exercise programs were effective in reducing the risk of falling but did not have a beneficial effect in reducing the monthly fall rate.141
The American Geriatrics Society/British Geriatrics Society Clinical Practice Guideline for Prevention of Falls in Older Persons recommend a multifactorial risk assessment followed by multicomponent interventions to address the identified risks and to prevent falls in elderly patients aged 75 years or older with 2 or more falls in the past 12 months, or difficulty with walking or with balance or gait.142 Recommended interventions include minimizing the number of medications; providing a tailored exercise program to improve strength, balance, gait, and coordination; treating vision impairment (including cataracts); managing postural hypotension, heart rate, and rhythm abnormalities, and addressing foot and footwear problems; providing vitamin D supplementation; modifying the home environment; and providing education and necessary information.142
Osteoporosis and its associated increase in fracture is a major risk factor in cancer patients, especially in women undergoing chemotherapy or hormonal therapy for breast cancer and in men undergoing hormonal therapy for prostate cancer. Osteoporosis can be prevented with appropriate screening, lifestyle interventions, and therapy. The diagnosis of osteoporosis is based on assessment of bone density using dual energy x-ray absorptiometry (DEXA) scan. Management of bone health has become an integral part of comprehensive cancer care. Elderly patients should be made aware of the impact of cancer therapies on bone health and should adhere to treatment recommendations for maintaining bone health.143 The NCCN task force report on bone health in cancer care discusses effective screening and therapeutic options for the management of treatment-related bone loss.144
The risk of morbidity from cancer is generally established according to the stage at diagnosis, aggressiveness of the tumor, and risk of recurrence and progression. After initial screening and CGA, patients with a low risk of dying or suffering from cancer during their lifetime can receive symptom management and supportive care as detailed in the appropriate NCCN Guidelines for Supportive Care (see list of NCCN Guidelines, available online, at www.NCCN.org). Patients in the moderate- or high-risk group can be further evaluated to assess their functional dependency, decision-making capacity, overall goals, and desire for proposed treatment.145,146
Irrespective of age, a person who is functionally independent and without serious comorbidities should be a good candidate for most forms of cancer treatment. Functionally independent patients with contraindications to treatment and patients with major functional impairment with or without complex comorbidity should be managed according to the appropriate NCCN Guidelines for Supportive Care (see list of NCCN Guidelines, available online, at www.NCCN. org). Patients who are dependent in some IADLs, with or without severe comorbidities, are at increased risk of treatment complications. For these patients with intermediate functional impairment who have milder problems (e.g., dependence in one or more IADL, milder comorbidity, depression, minor memory disorder, mild dementia, inadequate caregiver), treatment may still be administered with special individualized precautions, including attempts to reverse the problem and cautious dosing of treatment.147,148 In patients without decision-making capacity, the guidelines recommend considering consultation with an ethics committee.
The benefits of cancer treatment include prolonged survival, maintenance and improvement of quality of life and function, and palliation of symptoms. For patients who are able to tolerate curative treatment, options include surgery, radiation therapy (RT), chemotherapy, and targeted therapies. Symptom management and supportive care as detailed in the appropriate NCCN Guidelines for Supportive Care are recommended for all patients (see list of NCCN Guidelines, available online, at www. NCCN.org).
In general, age is not a primary consideration for surgical risk, although the physiologic status of the patient must be assessed. Performance status and comorbidities of the older patient are more important factors than age when considering surgical treatment options.149 Special efforts should be made to prevent or avoid emergency surgery, because it carries increased risk of complications. After surgery, physical and/or occupational therapy should be considered to expedite the patient’s return to their preoperative functional level.
The surgical task force report from the International Society of Geriatric Oncology (SIOG) reported that in many malignancies (breast, gastric, and liver), the surgical outcomes in older patients with cancer were not significantly different from those of their younger counterparts.150 The Preoperative Assessment of Cancer in Elderly (PACE) was developed to determine the suitability of older patients for surgical intervention.151 PACE incorporates CGA, the brief fatigue inventory (BFI), performance status, and American Society Anesthesiologists (ASA) grade. In an international prospective study, 460 consecutive older patients completed PACE before surgery.152,153 In a multivariate analysis, moderate to severe fatigue, a dependent IADL, and an abnormal performance status were identified as the most important independent predictors of postsurgical complications. Disability determined based on ADL, IADL, and performance status was associated with an extended hospital stay. This study showed that PACE is a useful tool that will enable physicians to evaluate older cancer patients’ fitness for surgery. The reliability of this tool must be confirmed in large prospective trials as applied to specific cancer types in elderly patients.
RT (external beam RT or brachytherapy) can be offered either in the curative or palliative setting.154 Hypofractionated RT may be an alternative treatment option in patients who are unable to tolerate conventional-dose RT.155 Available data from the literature indicate that RT is highly effective and well tolerated, and that age is not a limiting factor in elderly cancer patients.156-158 Concurrent chemoradiation, however, should be used with extreme caution; dose modification of chemotherapy may be necessary to reduce toxic side effects. Nutritional support and pain control for RT-included mucositis are recommended for patients receiving RT.
Several retrospective studies have reported that the toxicity of chemotherapy is not more severe or prolonged in persons older than 70 years.159-163 However, the results of these studies cannot be generalized for the following reasons:
Nevertheless, these studies are important, because they show that age alone is not a contraindication to cancer chemotherapy. Therefore, patient selection is extremely important to maximize the benefits of adjuvant chemotherapy in older patients with breast cancer, NSCLC, and colon cancer.
Age has been associated with pharmacokinetic and pharmacodynamic changes and with increased susceptibility of normal tissues to toxic complications. In general, all of these changes increase the risks of chemotherapy.164,165 Pharmacodynamic changes of interest include reduced repair of DNA damage and increased risk of toxicity. Pharmacokinetic changes of major concern include decrease in the glomerular filtration rate (GFR) and volume of distribution of hydrosoluble drugs. Although the hepatic uptake of drugs and the activity of cytochrome P450 enzymes also decrease with age, the influence of these changes on cancer chemotherapy is not clear. Intestinal absorption may decrease with age, but it does not appear to affect the bioavailability of anticancer agents. The pharmacokinetics of antineoplastic drugs is unpredictable to some extent; thus, drug doses should be adjusted according to the degree of toxicity that develops. However, adequate dosing is necessary to ensure the effectiveness of therapy.
Extermann et al.166 devised the MAX2 index for estimating the average per-patient risk for toxicity from chemotherapy. In a retrospective analysis, Shayne et al.167 identified advanced age (≥ 65 years), greater body surface area, comorbidities, anthracycline-based regimens, a 28-day schedule, and febrile neutropenia as independent predictors of reduced dose-intensity among patients with early-stage breast cancer undergoing adjuvant chemotherapy.167 In another retrospective analysis of elderly patients (aged ≥ 65 years) with invasive breast cancer, the type of adjuvant chemotherapy regimen was a better predictor of toxicity than increased age or comorbidity score.55 An anthracycline-based regimen resulted in greater grade 3 or 4 toxicity, hospitalization, and/or febrile neutropenia, whereas treatment delays because of myelosuppression were more frequent with a cyclophosphamide-containing regimen. Among elderly patients with ovarian cancer, those receiving standard-dose chemotherapy were more likely to experience cumulative toxicity and delays in therapy.56
Other investigators have developed tools incorporating components of CGA to assess the individual risk of severe toxicity from chemotherapy in older patients.35,168,169 Extermann et al.168 developed the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score, which could be useful in predicting significant differences in the risk of severe toxicity in older cancer patients starting a new chemotherapy. With this model, diastolic blood pressure, IADLs, lactate dehydrogenase, and the type of therapy are the best predictors of hematologic toxicity, whereas performance status, cognitive function, nutritional status, and the type of therapy are the best predictors of nonhematologic toxicity. Hurria et al.169 developed a scoring algorithm for predicting chemotherapy toxicity in older adults with cancer. The following factors were predictive of grade 3 to 5 chemotherapy toxicity: 1) age of 72 years or older, 2) cancer type (gastrointestinal or genitourinary), 3) standard dosing of chemotherapy, 4) polychemotherapy, 5) hemoglobin (male: < 11 g/dL; female: < 10 g/dL), 6) creatinine clearance less than 34 mL/min (Jelliffe formula using ideal weight),170 7) hearing impairment described as fair or worse, 8) one or more falls in past 6 months, 9) limited in walking one block, 10) the need for assistance with taking medications, and 11) decreased social activities because of physical or emotional health.169
Adherence to the prescribed regimen, especially oral therapy, is essential to derive maximal clinical benefit. Older adults are at increased risk for poor adherence to oral therapy for a variety of reasons, including cognitive impairment, comorbid conditions, polypharmacy, higher risk of side effects from drug interactions, limited insurance coverage, social isolation, and inadequate social support.171 Several studies have evaluated the adherence to adjuvant therapy in older patients with estrogen receptor-positive breast cancer.172-175 In one study, the discontinuation rate was 49% before the completion of 5 years, with women aged 75 years or older showing an increase in the number of cardiopulmonary comorbidities at 3 years, and those who had received breast-conserving surgery without RT being at higher risk of discontinuation.174 In a cohort of 161 elderly women receiving oral adjuvant chemotherapy with capecitabine for breast cancer (CALGB 49907 study), 25% of the patients took fewer than 80% of the planned doses.175 Nonadherence was more likely among women with node-negative disease and mastectomy. Although nonadherence was not associated with shorter relapse-free survival in this study (maybe because of limited sample size), Hershman et al.176 recently reported that early discontinuation and nonadherence to adjuvant hormonal therapy are associated with increased mortality in women with breast cancer. Therefore, interventions designed to educate older patients about the benefits and risks of oral therapy may help reduce nonadherence.
In older patients undergoing chemotherapy, the most common complications include myelosuppression resulting in neutropenia, anemia, or thrombocytopenia; mucositis; renal toxicity; cardiac toxicity; and neurotoxicity. Older patients seem to be at special risk for severe and prolonged myelosuppression and mucositis; increased risk of cardiomyopathy; and increased risk of central and peripheral neuropathy. In addition, they are also at risk for infection (with or without neutropenia), dehydration, electrolyte disorders, and malnutrition, either as a side effect of the chemotherapy or directly from the tumor. Chemotherapy can also affect cognition, function, balance, vision, hearing, continence, and mood.93 The combination of these complications enhances the risk of delirium and functional dependence. These complications (that may interfere with treatment) must be detected and corrected to achieve maximum benefit from chemotherapy. Prevention and/or amelioration of some of the common chemotherapy-related complications are discussed.
Anthracyclines are associated with increased cardiac toxicity resulting in CHF. Other antineoplastic drugs may have additional effect on anthracycline-induced cardiac toxicity.177 Risk factors for anthracycline-induced cardiotoxicity include an existing or history of heart failure or cardiac dysfunction, hypertension, diabetes, and coronary artery disease; older age (independent of comorbidities and performance status); prior treatment with anthracyclines; higher cumulative doses; and short infusion duration.178,179
Trastuzumab has also been associated with cardiac dysfunction and CHF in patients with metastatic breast cancer.180 Other trials, including the NSABP B-31181 and NCCTG N9831 studies,182 which evaluated trastuzumab in combination with doxorubicin and cyclophosphamide followed by paclitaxel in patients with HER2-positive breast cancer, identified older age (≥ 50 years), lower left ventricular ejection fraction, and the use antihypertensive medications as risk factors for cardiac dysfunction in patients receiving trastuzumab. However, in the long-term follow-up of the Herceptin Adjuvant (HERA) trial, the incidence of severe CHF, left ventricular dysfunction, and discontinuation of trastuzumab as a result of cardiac disorders remained low (0.8%, 9.8%, and 5.1%, respectively) in patients who received trastuzumab.183 A combined review of cardiac data from the NSABP B-31 and NCCTG N9831 trials also showed that the incidence of symptomatic heart failure events was 2.0% in patients treated with adjuvant trastuzumab, and most of these patients recovered with appropriate treatment.184
In a recently published single-center retrospective analysis of elderly patients (aged ≥ 70 years; n = 45) with breast cancer, Serrano et al.185 reported an increased incidence of cardiotoxicity among those with a history of cardiac disease and/or diabetes treated with trastuzumab. Asymptomatic cardiotoxicity was observed in 12.5% of patients with early-stage breast cancer and 24% of those with advanced breast cancer, and 8.9% of all patients with advanced breast cancer developed symptomatic CHF.
Emerging data from clinical studies (BCIRG 006 and BCIRG 007) suggest that trastuzumab, when used in combination with non-anthracycline-based chemotherapy, has similar efficacy with lower rates of cardiac events in patients with early-stage and metastatic HER2-positive breast cancer.186,187 However, the median age of all patients in both trials was 50 to 52 years. Additional data regarding the tolerability of these regimens in older adults are needed.
In patients aged 65 years or older with both HER2-positive and HER2-negative early-stage breast cancer, the US Oncology Research Trial 9735 showed that non-anthracycline-based adjuvant chemotherapy with docetaxel and cyclophosphamide was associated with a disease-free and overall survival benefit compared with doxorubicin plus cyclophosphamide.188 In this study, 160 of the 1016 enrolled patients (16%) were aged 65 years or older.
The GFR decreases with age, which in turn delays elimination of many drugs. Delayed renal excretion may enhance the toxicity of drugs whose parent compounds are excreted by the kidneys (carboplatin, oxaliplatin, methotrexate, bleomycin) and drugs that are converted to active (idarubicin, daunorubicin) or toxic metabolites (high-dose cytarabine).11 Dose adjustment to the measured GFR should be considered for these drugs to decrease systemic toxicity.
Renal insufficiency is common in elderly cancer patients, particularly in those receiving nephrotoxic drugs and those with genitourinary cancers or multiple myeloma. In patients with preexisting renal problems who are at a greater risk of renal impairment, the use of nephrotoxic drugs should be limited or avoided. A SIOG task force provides several recommendations for the clinical management of older cancer patients with renal insufficiency.192 Dose adjustments and calculation of creatinine clearance to assess renal function are recommended for all patients.
Neurotoxicity is also a dose-limiting toxicity associated with chemotherapy.193 Vinca alkaloids, cisplatin, and taxanes induce peripheral neurotoxicity. Methotrexate, cytarabine, and ifosfamide are associated with central neurotoxic side effects. Purine analogs (e.g., fludarabine, cladribine, pentostatin) are associated with life-threatening neurotoxicity at significantly higher doses than the recommended clinical dose.194 High-dose cytarabine can cause an acute cerebellar syndrome. Patient age (> 60 years); drug dose and schedule; and renal and hepatic dysfunction are the most important risk factors for cytarabine-induced cerebellar toxicity.195,196
Management of neurotoxicity mainly consists of dose reductions or lower dose-intensities. Older patients are particularly susceptible to the toxicity of cytarabine-based regimens because of decreased renal excretion of the toxic metabolite ara-uridine and increased vulnerability of the cerebellum. Particular attention should be paid to the use of cytarabine in high doses, especially in patients with renal insufficiency. Dose reductions are necessary in patients with reduced GFR. The guidelines recommend monitoring for cerebellum function, hearing loss, and peripheral neuropathy. Alternative regimens with nonneurotoxic drugs should be considered, particularly in patients with significant hearing loss.
Available data from various studies have shown that the risk of myelosuppression increases substantially by age 65 years.197-202 The risk of myelosuppression is decreased by 50% when using growth factors.203-205 Dose reductions may compromise the effectiveness of treatment. The use of growth factors in these circumstances does not appear to be associated with increased cost, and may even be cost-saving if it prevents lengthy hospitalizations from neutropenic infections in older persons.
Neutropenia is the major dose-limiting toxicity associated with chemotherapy, especially in older patients. Several prospective studies of older patients with large cell lymphoma have shown that older age is a risk factor for neutropenic infections in patients treated with regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone).205-211 In patients aged 60 years or older undergoing induction or consolidation chemotherapy for acute myeloid leukemia (AML), the prophylactic use of hematopoietic growth factors results in faster recovery of neutrophil and shorter hospitalization but does not impact overall survival.212,213
Meta-analysis of controlled clinical trials on the prophylactic use of recombinant granulocyte colony-stimulating factors (G-CSF) has confirmed their effectiveness in reducing the risk of febrile neutropenia.214 Some concerns have been expressed that the combination of growth factors and topoisomerase II inhibitors may be associated with increased risk of acute leukemia; however, these data are contoversial.215,216 Despite these caveats, the use of growth factors seems to be the best established strategy to improve treatment in this group of patients.217 The EORTC issued similar recommendations for the prophylactic use of G-CSF in older patients with cancer.218 The NCCN Guidelines for Myeloid Growth Factors address the use of G-CSFs in patients with solid tumors and nonmyeloid malignancies (to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org).
Anemia has been shown to be a risk factor for chemotherapy-related toxicity, and is one of the factors responsible for reduction in volume of distribution, which may result in increased peak concentration and increased toxicity of drugs.219 Anemia is also associated with cardiovascular disease, CHF, coronary death, and dementia.220-223
In patients with severe anemia, blood transfusions are necessary to prevent serious clinical consequences. There is increasing controversy regarding the use of erythropoietic stimulating agents (ESAs). ESAs have been shown to decrease the need for transfusion in patients receiving chemotherapy.224 It also seems beneficial to complement the administration of erythropoietin with oral or parenteral iron, although this is not specific for elderly patients. However, recent randomized studies have reported decreased survival and poorer tumor control among cancer patients receiving erythropoietic drugs for correcting anemia and targeting hemoglobin levels at 12 g/dL or greater.225 The use of ESAs in patients with cancer is also associated with increased risks of venous thromboembolism (VTE) and mortality.226 The risks of shortened survival and of disease progression have not been excluded when ESAs are dosed to achieve hemoglobin levels of less than 12 g/dL.
Based on the results of these trials, in July 2008 the FDA strengthened its warnings to alert physicians of increased risk of tumor progression and shortened survival in patients with advanced breast, cervical, head and neck, lymphoid, and non-small cell lung cancers. Physicians were advised to use the lowest dose necessary to avoid transfusion. In addition, the use of ESAs is restricted to the treatment of anemia specifically related to myelosuppressive chemotherapy without curative intent. ESAs should be discontinued once the course of chemotherapy has been completed and the anemia has resolved. The panel recommends that anemia in elderly cancer patients should be managed as outlined in the NCCN Guidelines for Cancer- and Chemotherapy-Induced Anemia (to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org).
Chemotherapy-induced thrombocytopenia (CIT) is a common hematologic toxicity associated with cytotoxic and myeloablative chemotherapy. Dose reductions and/or interruptions of chemotherapy regimens are necessary in patients with severe thrombocytopenia. Although chemotherapy-induced anemia and neutropenia can be managed with hematopoietic growth factors, safe and effective treatment of CIT is still a significant problem. Recombinant interleukin-11 is the only currently approved for the treatment of CIT in patients with nonmyeloid malignancies.227 However, it is toxic and of minimal clinical benefit. Ongoing clinical trials are also evaluating the efficacy of thrombopoietin-like agents, such as romiplostim and eltrombopag, for the treatment of CIT.228
Diarrhea is a well-recognized side effect associated with several chemotherapeutic agents, and is particularly associated with regimens containing 5-fluorouracil (5-FU) and irinotecan. Chemotherapy-induced diarrhea can lead to discontinuation of chemotherapy and poorer clinical outcomes. Loss of fluid associated with persistent and severe diarrhea can lead to dehydration, renal insufficiency, and electrolyte imbalance. Older adults with chemotherapy-induced diarrhea should be treated with early rehydration. ASCO guidelines for the treatment of chemotherapy-induced diarrhea229 recommend comprehensive evaluation at the onset of diarrhea to determine the severity. Based on the results from various clinical trials, the ASCO guidelines recommend loperamide therapy for mild to moderate diarrhea and octreotide (subcutaneous or intravenous if the patient is severely dehydrated) treatment for severe diarrhea or for chemotherapy-induced diarrhea that is refractory to loperamide therapy.
Oral and gastrointestinal mucositis are significant complications of radiotherapy and chemotherapy. The risk of mucositis increases with age. The Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology developed guidelines for preventing, evaluating, and treating oral and gastrointestinal mucositis.230 An NCCN task force also published a comprehensive approach to the management of mucositis in patients with cancer.231 Once mucositis has occurred, patients should be kept well hydrated with intravenous fluids and hospitalization, if necessary. Until recently, no pharmacologic agents have been shown to effectively treat mucositis. In 2004, the FDA approved palifermin (human keratinocyte growth factor) for the treatment of oral mucositis in patients with hematologic malignancies undergoing myelotoxic therapy requiring hematopoietic stem cell support.232 Rosen et al.233 reported that palifermin was well tolerated and resulted in significant reduction of oral mucositis in patients with metastatic colorectal cancer treated with 5-FU-based chemotherapy. However, the safety and efficacy of palifermin is yet to be firmly established in nonhematologic malignancies. A new time-released preparation of glutamine has shown promising results in the management of oral mucositis in patients with breast cancer undergoing anthracycline-based chemotherapy.234
Recently, the emergence of targeted therapies such as monoclonal antibodies and tyrosine kinase inhibitors has revolutionized the treatment and improved outcomes of a variety of malignancies. Limited but increasing data are available on the toxicity of these targeted therapies in older adults with cancer, and their use should be individualized.235 In patients who are not able to tolerate cytotoxic chemotherapy, the risk/benefit ratio should be considered before targeted therapy is initiated. Prospective clinical trials that include a sufficiently large number of older patients are needed to accurately determine the efficacy and tolerability of targeted therapies in this cohort of patients. See the next section on Disease-Specific Issues for the efficacy and tolerability of specific targeted therapies in elderly cancer patients.
Because the biologic characteristics of certain cancers are different in older patients compared with their younger counterparts, and partly because of the decreased tolerance of treatment by older patients, chemotherapy should be individualized based on the nature of the disease and the performance status of the patient. Disease-specific issues related to age in some cancer types are discussed.
Older patients with AML may have decreased sensitivity to chemotherapy because of increased prevalence of multidrug resistance and unfavorable cytogenetic profiles.236 In view of the seriousness of the complications of AML treatment, the panel recommends that older patients with AML be treated according to the NCCN Guidelines for AML in centers skilled in the management and supportive care of AML (to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org).
Intravesical immunotherapy with Bacillus Calmette-Guérin (BCG) has decreased efficacy, particularly in patients older than 80 years.237,238 In one study, at a median follow-up of 24 months, the cancer-free survival rates were 39% and 61%, respectively, for patients older than 80 years and patients aged 61 to 70 years treated with BCG (P = .0002).237 Age was an independent risk factor for response after taking into account the disease stage and grade and the patient’s sex and prior treatment.237 In the second study, the percent free from disease at 5 years after BCG therapy was 27% and 37% (P = .005) for patients aged 70 years or older and those younger than 70 years, respectively.238
Age alone should not be a criterion for making decisions regarding cystectomy, RT, and chemotherapy in elderly patients. Radical cystectomy with pelvic lymph node dissection (PLND) is the standard treatment for patients with muscle-invasive bladder cancer. In a SEER database analysis of 10,807 patients diagnosed with muscle-invasive bladder cancer, radical cystectomy resulted in a longer overall survival than treatment with RT in all age groups.239 Although the overall survival benefit was significantly higher in the radical cystectomy arm for patients aged 70 to 79 years (33 vs. 19 months), the survival benefit was smaller in patients aged 80 years or older (18 vs.15 months). In patients aged 80 years or older, radical cystectomy with PLND showed a small overall survival benefit compared with bladder preservation with RT (21 vs.15 months, respectively).239 In a randomized study that compared neoadjuvant chemotherapy plus cystectomy with cystectomy alone, the addition of neoadjuvant chemotherapy resulted in improved survival among patients with locally advanced cancer.240 Median survival was 46 and 77 months, respectively (P = .06), for patients assigned to cystectomy and cystectomy plus neoadjuvant chemotherapy, and the survival benefit was preserved with age.240
Breast cancer in older women is associated with a more favorable tumor biology because of the high prevalence of hormone receptor-positive, HER2-negative, slowly proliferating tumors.241,242 However, women older than 75 years receive less-aggressive treatment and have higher mortality rates from early-stage breast cancer than younger women.243-245
Axillary lymph node dissection (ALND) in patients with early breast cancer improves locoregional control and provides staging information but is also associated with undesirable morbidity. Data from a randomized clinical trial suggest that ALND did not result in improved disease-free or overall survival compared with sentinel lymph node dissection alone in patients with invasive breast cancer (T1/T2) with limited sentinel lymph node involvement who were treated with breast conservation and systemic therapy.246 Elderly patients with early-stage and clinically node-negative breast cancer also did not benefit from ALND in terms of breast cancer mortality or survival.247,248 In the absence of definitive evidence showing superior survival associated with ALND, this procedure can be considered optional for elderly patients with particularly favorable tumors, those with serious comorbid conditions, and those for whom the selection of adjuvant systemic therapy is unlikely to be affected.
RT as a component of breast conserving-therapy is not always necessary in selected women aged 70 years or older with stage I breast cancer. In a study that randomized women (aged ≥ 70 years) with clinical stage I estrogen receptor-positive breast cancer to receive lumpectomy and tamoxifen with whole-breast RT or lumpectomy and tamoxifen for 5 years, no differences were seen in overall survival or breast cancer-specific survival.249,250 However, locoregional recurrence was higher among women who did not receive RT (4% vs. 1% for those who received RT).
Older women with stage I through III breast cancer derive similar clinical benefits from adjuvant chemotherapy compared with younger patients. However, older patients have an increased risk of treatment-related side effects and mortality.251 Adjuvant chemotherapy with CMF (cyclophosphamide, methotrexate, and 5-FU) or doxorubicin plus cyclophosphamide was superior to capecitabine alone.252 The 3-year relapse-free survival rates were 68% and 85%, respectively, for the capecitabine group and the standard chemotherapy group (P < .001).The corresponding overall survival rates were 86% and 91%, respectively (P = .02).252 The benefit was pronounced in women with hormone receptor-negative tumors (P < .001).
Trastuzumab is approved for the treatment of patients with HER2-positive early-stage and metastatic breast cancer. However, few elderly patients (aged ≥ 70 years) have been included in the pivotal trastuzumab trials.253,254 Cardiac toxicity has been a concern in patients receiving trastuzumab-based therapy,181 and age is a risk factor for CHF in patients receiving trastuzumab-based regimens. In elderly patients (aged ≥ 70 years), trastuzumab-related cardiotoxicity was associated with a history of cardiac disease and diabetes185 (see Cardiac Toxicity on page 188).
Surgery is the primary treatment option for patients with newly diagnosed glioblastoma multiforme. Available evidence suggests that gross total resection is associated with greater overall survival in patients aged 70 years or older.255,256 In a small, randomized study involving patients aged 65 years or older (n = 30), the estimated median survival time was longer after open craniotomy and resection of the tumor (171 days compared with 85 days after the stereotactic biopsy; P = .035).255 For patients aged 65 years or older, gross total resection was associated with a longer survival compared with biopsy and subtotal resection in a retrospective analysis.256 Given the small size of the randomized trials studies and the retrospective nature of other studies, whether the improved survival is a direct effect of the degree of surgery or related to selection bias is unclear. Furthermore, the median survival after resection alone is less than 12 months, indicating that additional treatment options are needed. In a retrospective review, aggressive treatment with all 3 components (RT, chemotherapy, and surgery) was associated with best overall survival.257
Postoperative RT alone or in combination with temozolomide has been effective in improving clinical outcomes in elderly patients.258-260 At a median follow-up of 21 weeks in a small randomized study of patients aged 70 years or older (n = 85), median survival was longer for those who received postoperative RT plus supportive care than for those who received supportive care alone (29 and 17 weeks, respectively).259 RT was not associated with severe adverse events, and the results of quality-of-life and cognitive evaluations over time also did not differ significantly between the treatment groups. In another randomized trial, overall survival times were similar for postoperative standard RT (5.1 months) and shorter-course RT (5.6 months) for elderly patients (aged ≥ 60 years; n = 100).258 However, among those who completed RT as planned, more patients who received standard RT required a posttreatment increase in corticosteroid dosage (49% compared with only 23% of those who received shorter-course RT). These results suggest that postoperative shorter-course RT is a reasonable treatment option for patients aged 70 years or older.
In a phase III randomized trial, the addition of temozolomide concurrently with RT followed by 6 months of adjuvant temozolomide improved survival rates in patients between ages 60 and 70 years with newly diagnosed glioblastoma multiforme.260 At 5-year follow-up, overall survival rates were 27%, 16%, 12%, and 9.8% at 2, 3, 4, and 5 years, respectively, for those who received RT with concurrent temozolomide. The corresponding survival rates were 11%, 4%, 3%, and 2% for those treated with RT alone. However, the benefit of concurrent chemoradiation therapy is unclear in patients older than 70 years, but it is likely to be helpful in selected “fit” patients.261
Bevacizumab, an anti-vascular endothelial growth factor receptor (VEGFR) antibody, resulted in a significant improvement in progression-free and overall survival in patients aged 55 years or older and with poor performance status, in a single-institution retrospective analysis.262 VEGFR expression was also significantly higher in patients aged 55 years or older, implying that bevacizumab could be beneficial for this group of patients with recurrent glioblastoma multiforme.262
Methotrexate-based chemotherapy is associated with superior outcome in elderly patients with primary central nervous system (CNS) lymphoma. In patients older than 60 years, high-dose methotrexate-based chemotherapy with or without whole-brain RT resulted in a median overall survival of 29 months.263 However, a striking increase in neurotoxicity was seen in patients older than 60 years compared with younger patients (75% vs. 26%). In a more recent retrospective analysis, Ney et al.264 also reported similar median overall survival (25 months) in elderly patients treated with chemotherapy alone. In another retrospective review of 31 elderly patients (aged ≥ 70 years), high-dose methotrexate induced an overall radiographic response rate of 97%; the progression-free and overall survival rates were 7 and 37 months, respectively.265 These results indicate that patients aged 60 years or older with primary CNS lymphoma should be treated initially with chemotherapy, with whole-brain RT reserved for those with recurrent or refractory disease, given the increase in neurotoxicity.
Age alone should not be a contraindication for curative surgery in elderly patients with early-stage and resectable colorectal cancer.266-268 Results of a retrospective study that evaluated age-related surgical risk and outcome in patients with colorectal cancer showed that the long-term results after surgery were more dependent on the stage of disease and type of adjuvant or palliative treatment than on age.266 In the metastatic setting, Adam et al.269 compared the outcome of liver resection for colorectal metastases between elderly and younger patients, and reported 3-year overall survival rates of 57% and 60%, respectively (P < .001). The overall survival was similar among patients aged 70 to 75, 75 to 80, or at least 80 years (58%, 55%, and 54%, respectively; P = .160). Careful preoperative planning and nonemergent surgery are more likely to result in optimal outcomes.269
In the adjuvant setting, older patients derive similar benefit from 5-FU-based chemotherapy to that of younger patients.10,270 However, older patients may be at an increased risk for hematologic toxicities. In a pooled analysis of adjuvant chemotherapy trials, the relative benefit of overall survival from adjuvant chemotherapy was similar across all age groups, with no increased incidence of toxicities among patients aged 70 years or older, except for leukopenia in one study.10 The 5-year overall survival rate was 71% for those who received adjuvant chemotherapy compared with 64% for those who were untreated. However, after 5 years, the absolute benefit of chemotherapy was smaller in patients aged 70 years or older because of competing causes of deaths. Pooled analyses of data from adjuvant trials using newer regimens containing oxaliplatin did not show significant benefit in disease-free or overall survival compared with 5-FU and leucovorin in patients aged 70 years or older.271 Scant data are available among patients older than 80 years. Because of the lack of data from prospective randomized studies, adjuvant chemotherapy with newer regimens should be considered on an individual basis for patients aged 70 years or older.
For patients with metastatic disease, 5-FU-0based palliative chemotherapy resulted in equal overall survival (10.8 and 11.3 months, respectively; P = .31) and progression-free survival (5.5 and 5.3 months, respectively; P = .01) in elderly (aged ≥ 70 years) and younger patients with metastatic colorectal cancer.272 Infusional 5-FU was more effective than bolus 5-FU in both age groups. A recent prospective randomized trial (MRC FOCUS2) reported some improvement in median progression-free survival with the addition of reduced-dose oxaliplatin to 5-FU-based chemotherapy in elderly and frail patients with metastatic colorectal cancer, but the difference was not significant (5.8 vs. 4.5 months; P = .07).273 The replacement of 5-FU with capecitabine resulted in higher risk of grade 3 or higher toxicity and no improvement in quality of life. In the OPTIMOX-1 study, oxaliplatin-based chemotherapy stop-and-go (FOLFOX7 for 6 cycles, maintenance without oxaliplatin for 12 cycles, and reintroduction of FOLFOX7) had similar efficacy and tolerability as the standard oxaliplatin-based regimen (FOLFOX4) regimen in patients aged between 76 and 80 years with metastatic colorectal cancer,274 implying that stop-and-go strategies or maintenance 5-FU-based chemotherapy may be desirable for elderly patients with metastatic disease to minimize toxicities.
Bevacizumab275,276 and the anti-epidermal growth factor receptor (EGFR) antibodies cetuximab277-279 and panitumumab280,281 have also been evaluated for the treatment of elderly patients with metastatic colorectal cancer. Data from retrospective studies have shown that cetuximab as a single agent or in combination with irinotecan has a favorable safety profile in heavily pretreated elderly patients (aged ≥ 70 years) with metastatic colorectal cancer, and the efficacy was similar to that observed in younger patients with acceptable tolerability.277,278 Response rates and progression-free survival were significantly higher for elderly patients (aged ≥ 70 years) with wild-type KRAS mutations than for those with KRAS mutations.278 In a phase II clinical trial, cetuximab was safe and moderately active when used as a first-line single agent in fit elderly patients with metastatic colorectal cancer.279
In the phase III trial that evaluated the activity of panitumumab plus best supportive care versus best supportive care alone in patients with metastatic colorectal cancer, panitumumab had a favorable effect on progression-free survival regardless of age (hazard ratio, 0.51 and 0.60, respectively, for patients younger than 65 years and older than 65 years).280 Progression-free survival, overall survival, and overall response rates were similar in elderly and younger patients. In this study, the efficacy of panitumumab is confined to patients with wild-type KRAS mutations.281 The safety and efficacy of bevacizumab in elderly patients (aged ≥ 65 years) were comparable to those of younger patients.275,276 In the BRiTE (Bevacizumab Regimens: Investigation of Treatment Effects and Safety) study, the median progression-free survival was similar across all age cohorts. However, median overall survival and survival beyond progression declined with age.276 In a retrospective analysis, the addition of bevacizumab to chemotherapy significantly improved progression-free and overall survival in patients aged 65 years or older with metastatic colorectal cancer.275 However, it is associated with higher rate of arterial thromboembolic events in elderly patients.
Surgery is associated with good clinical outcomes and acceptable complication rates in elderly patients; however, complication rates increase with comorbidities.53,282 In a retrospective analysis of elderly patients (aged ≥ 70 years), 63% and 54% experienced clinically important surgical and/or medical complications.282 Bilateral neck dissection, male sex, presence of 2 or more comorbidities, and advanced stage of disease were associated with postoperative complications.53
Elderly patients (aged ≥ 70 years) with squamous cell carcinoma of the head and neck (SCCHN) who are treated with RT experience similar overall survival to younger patients.283 Although no significant differences in late toxicities were seen between older patients and those younger than 70 years (median follow-up of 3 years), severe grade 3 and 4 functional acute toxicity was significantly more frequent in older patients (67% for patients aged 65 years or older compared with 49% in younger patients).283 Few patients older than 70 years have been included in trials evaluating induction chemotherapy, and limited data exist on the efficacy and toxicity of this approach in this subset of patients.284,285 Randomized trials and meta-analyses have reported that concurrent chemoradiation offers greater benefit than RT or induction chemotherapy alone.286,287 In a prospective randomized study that included 255 patients aged 60 years or older, concurrent chemoradiation was superior to RT alone or induction chemotherapy followed by RT for laryngeal preservation and locoregional control in patients (both older and younger than 60 years) with localized laryngeal cancer.286 In the meta-analysis of chemotherapy in head and neck cancer (MACH-NC), concurrent chemoradiation offered a significant overall survival benefit of 4.5% at 5 years compared with RT alone in patients with nonmetastatic SCCHN. However, this survival benefit decreased with increased age (≥ 71 years). In another retrospective analysis, older age was identified as the most significant factor associated with severe late toxicities (feeding tube dependence 2 years after RT, pharyngeal and laryngeal dysfunction) after concurrent chemoradiation.288 Data in patients older than 70 years are insufficient to draw firm conclusions regarding a survival advantage of adding concurrent chemotherapy to RT. Similarly, too few patients older than 70 years with resected SCCHN have been evaluated in the adjuvant therapy trials, and data are limited on the benefit of adding cisplatin to RT.
Cisplatin-based chemotherapy is associated with increased toxicity in elderly patients with recurrent head and neck cancer.289 In a review of 2 phase III randomized trials conducted by ECOG that evaluated cisplatin with paclitaxel or 5-FU, objective response rates (28% vs. 33%; P = .58) and median time to progression (5.25 vs. 4.8 months; P = .69) were similar for older and younger patients, respectively.289 However, the incidences of severe nephrotoxicity, diarrhea, and thrombocytopenia were higher among elderly patients.
Cetuximab has been evaluated in only few patients with head and neck cancer. For patients with locally advanced SCCHN, limited evidence exists regarding the benefit of adding cetuximab to RT in patients older than 64 years.290 Available evidence for this group of patients does not allow firm conclusions to be drawn regarding a survival advantage of concurrent cetuximab plus RT. Limited evidence is also available regarding the benefit of adding cetuximab to chemotherapy in the treatment of patients older than 64 years with recurrent or metastatic SCCHN.291
Surgical resection remains an effective treatment for patients with localized renal cell carcinoma (RCC). However, in a recent study, Lane et al.292 reported that surgical management of clinically localized renal cortical tumors was not associated with increased survival in patients aged 75 years or older. Radical nephrectomy resulted in renal dysfunction in 86% of patients and was a significant predictor of cardiovascular mortality. The authors concluded that the surgical management of elderly patients with localized RCC should be individualized based on predicted life expectancy.
Recently, several targeted therapies, including bevacizumab,293 tyrosine kinase inhibitors (sorafenib294,295 and sunitinib296,297), and mammalian target of rapamycin (mTOR) inhibitors (everolimus298 and temsirolimus299) have been evaluated in elderly patients with metastatic RCC. Sorafenib, sunitinib, and everolimus have similar efficacy in younger and older patients with advanced RCC.
In the retrospective analysis of the Advanced Renal Cell Carcinoma Sorafenib (ARCCS) program in North America, the median overall (46 vs. 50 weeks; P = .4) and progression-free survivals (42 vs. 35 weeks; P = .8) were similar for patients aged 70 years or older and patients younger than 70 years with advanced RCC.295 Incidences of the most common adverse events (grade 3 or higher; rash or desquamation [5% in both groups], hand-foot skin reaction [8% and 10%, respectively], hypertension [5% vs. 4%, respectively], and fatigue [7% vs. 4%, respectively]) were also similar in both age groups.295 In a pooled analysis of 6 clinical trials that evaluated the efficacy and safety of sunitinib in patients with metastatic RCC, the median progression-free (9 and 11 months, respectively; P = .0830) and overall survivals (23.3 and 23.7 months, respectively; P = .5441) were similar in patients younger than 70 years and those aged 70 years or older.297 The incidences of adverse events were also similar, although some (fatigue, decreased appetite/weight, cough, peripheral edema, thrombocytopenia, and anemia) were more common in elderly patients.
Temsirolimus was associated with improved overall (P = .008) and progression-free survivals (P < .001) compared with interferon among patients with metastatic RCC and poor prognosis.299 In a multicenter, randomized phase III trial, the median overall survival was 10.9 months for temsirolimus group compared with 7.3 and 8.4 months, respectively, in the groups treated with interferon-α alone or in combination with temsirolimus. Temsirolimus alone was associated with fewer incidences of grade 3 or 4 adverse events than interferon. Interferon is not recommended for elderly patients because of its increased toxicity. In a subgroup analysis of a phase III trial evaluating the safety and efficacy of everolimus in patients with metastatic RCC, median progression-free survivals were 5.36 and 5.13 months, respectively (P < .001), for patients aged 65 years or older and 70 years or older.298 Older patients were at increased risk of adverse events, including stomatitis, anemia, and infection.
In elderly patients with newly diagnosed multiple myeloma, induction chemotherapy with the combination of melphalan, prednisone, and thalidomide (MPT) was associated with significantly superior response rates, progression-free survival, time-to-treatment progression, and event-free survival compared with melphalan and prednisone (MP) in randomized studies.300-307 However, overall survival benefit for MPT was reported only in 2 of these studies. In the IFM 99-06 trial, which compared MPT, MP, and reduced-intensity autologous stem cell transplant, median overall survival times were 51.6, 33.2, and 38.3 months, respectively; the MPT regimen was associated with a significantly better overall survival than the MP regimen (P = .0006) or reduced-intensity autologous stem cell transplant (P = .027).302 In the IFM 01/01 trial, median overall survival times were 44 and 29 months, respectively (P = .028), for elderly patients (aged ≥ 75 years) treated with MPT and MP.303 However, MPT was associated with significant toxicity (constipation, fatigue, VTE, neuropathy, cytopenias, and infection).307 Deep vein thrombosis (DVT) prophylaxis with low-molecular-weight heparin (LMWH) is recommended for elderly patients receiving thalidomide-based regimens. In a phase III randomized trial, aspirin and fixed low-dose warfarin showed similar safety and efficacy in reducing thromboembolic complications compared with LMWH in patients with myeloma treated with a thalidomide-based regimen, except in elderly patients, in whom LMWH was more effective than warfarin.308
Bortezomib, melphalan, and prednisone (VMP) was superior to MP alone in patients (median age, 71 years) with newly diagnosed multiple myeloma who were ineligible for high-dose therapy and the survival benefit was seen across all age groups.309,310 However, the rates of adverse events (peripheral neuropathy, cytopenias, and fatigue) were higher among patients in the VMP group than those in the MP group. The subgroup analyses of the VISTA trial showed that VMP resulted in longer overall survival among patients younger than 75 years than in those aged 75 years or older (3-year overall survival rates were 74.1% and 55.5%, respectively; P = .011).310 In another randomized trial, in the induction phase, bortezomib, thalidomide, and prednisone (VTP) and VMP resulted in similar response rates (partial response rates were 81% and 80%, respectively) and overall survival, with different side-effect profiles.311 Incidences of infection were higher in the VMP group, and VTP was associated with higher incidences of cardiac events. In the maintenance setting, complete response rates were higher with bortezomib and thalidomide (44%) than with bortezomib and prednisone (39%); however, peripheral neuropathy was higher with bortezomib and thalidomide.311 In a phase III study, the 4-drug combination of bortezomib, melphalan, prednisone, and thalidomide (VMPT) followed by maintenance with bortezomib and thalidomide (VT) was associated with higher response rates and progression-free survival compared with VMP alone but did not result in an improvement in overall survival.312 The 3-year overall survival rates were 89% and 87%, respectively, for VMPT followed by VT and for VMP (P = .77). VMPT followed by VT was also associated with higher-grade 3 or 4 toxicities (neutropenia, cardiologic, and thromboembolic events).
Dexamethasone-based regimens are associated with increased mortality and severe hematologic toxicities compared with MP in elderly patients with newly diagnosed multiple myeloma not eligible for high-dose therapy.313,314 In a large randomized trial (IFM 95-01) comparing MP with dexamethasone-based regimens (dexamethasone, alone or in combination with melphalan or interferon), although no difference was seen in overall survival among the 4 treatment groups, the response rate was significantly higher in patients receiving dexamethasone and melphalan, and progression-free-survival was significantly better for patients receiving MP and melphalan and dexamethasone. However, the toxicities associated with dexamethasone-based regimens (severe pyogenic infections in the melphalan-dexamethasone arm, and hemorrhage, severe diabetes, and gastrointestinal and psychiatric complications in the dexamethasone arms) were significantly higher than with MP.313 The results of a recent randomized trial suggest that the low-dose dexamethasone used in combination with lenalidomide is associated with better short-term overall survival and lower toxicity than high-dose dexamethasone and lenalidomide in patients with newly diagnosed myeloma.314
In randomized clinical trials, the outcome in older patients who received full-dose anthracycline-based therapy was comparable to that of younger patients. However, the complete response rates drop to 45% in patients aged 70 years or older.315 Age and serum interleukin-6 levels have been identified as independent prognostic factors for complete response and failure-free survival in patients with diffuse large B-cell lymphoma (DLBCL).316-320 Rituximab (an anti-CD20 monoclonal antibody) has been well tolerated and effective in the treatment of elderly patients with DLBCL, with no apparent increase in toxicity. Several randomized trials involving older adults exclusively have shown that the addition of rituximab to CHOP improves survival in patients with advanced-stage DLBCL.211,321-323
Hepatitis B virus (HBV) reactivation has been reported to occur in patients treated with chemotherapy with or without rituximab; treatment with rituximab alone is also a risk for HBV reactivation.324 Antiviral prophylaxis has been shown to prevent chemoimmunotherapy-associated HBV reactivation.325-327 Because of the significant of risk of HBV reactivation associated with rituximab, the panel recommends that elderly patients receiving rituximab should be monitored for HBV reactivation as outlined in the NCCN Guidelines for Non-Hodgkin’s Lymphoma (to view the most recent version of these guidelines, visit the NCCN Web site at www. NCCN.org).
Surgery is the standard treatment for patients with localized NSCLC. Retrospective studies have shown that age alone is not a contraindication for surgery, and that surgery is well tolerated in carefully selected patients.328-332 Long-term follow-up of elderly patients (aged ≥ 70 years) showed that the mortality and prognosis were similar to those of younger patients.328 The postoperative mortality and 5-year survival rates were 3% and 48%, respectively, for elderly patients. However, pneumonectomy was associated with a higher mortality rate in patients aged 70 or older compared with younger patients (22% and 3.2%, respectively; P < .005).333 Therefore, pneumonectomy should be performed with caution in elderly patients.
Older patients with completely resected NSCLC treated with adjuvant chemotherapy derive similar survival benefits to younger patients.334-336 A pooled analysis of 4584 patients from 5 trials of adjuvant cisplatin-based chemotherapy showed that elderly patients had a survival benefit similar to that of their younger counterparts, without significant toxicity.336 Another retrospective analysis of the Intergroup study (JBR.10) also showed that adjuvant vinorelbine and cisplatin improved survival in patients older than 65 years, with acceptable toxicity.335
Combined modality therapy is feasible and effective in elderly patients with locally advanced disease; however, it is associated with more toxicities (esophagitis, pneumonitis, and myelosuppression), especially in patients with poor performance status (Karnofsky performance status < 90).337,338 Langer et al.337 reported that concurrent chemotherapy with once-daily RT was beneficial to elderly patients with locally advanced NSCLC. Median survival time was 22.4 months for patients treated with concurrent chemotherapy with daily RT compared with 16.4 months for patients treated with concurrent chemotherapy with twice-daily RT, and 10.8 months for those treated with sequential chemotherapy and daily RT. Short-term toxicities were more pronounced in the elderly patients. Schild et al.338 also reported that elderly and younger patients derived similar survival benefit from concurrent chemoradiation therapy. The 2- and 5-year survival rates were 36% and 13%, respectively, in elderly patients with locally advanced disease compared with 39% and 18%, respectively, in patients younger than 70 years (P = .4). Pneumonitis and myelosuppression were more pronounced in the elderly patients. In some studies, combined modality treatment was associated with excess toxicity and no survival benefit for the elderly.339,340
Chemotherapy is associated with improved quality of care compared with best supportive care in elderly patients with advanced disease.341,342 In the ELVIS study, vinorelbine plus best supportive care was superior to best supportive care alone in terms of both survival and quality of life.341 Median and 1-year survivals were significantly better in the vinorelbine arm. The results of the subgroup analyses of phase III trials evaluating chemotherapy for patients with advanced NSCLC have shown that elderly patients with good performance status derive similar clinical benefit from combination chemotherapy to younger patients; however, the incidences of toxicities are higher among elderly patients.337,343,344 The 2 trials that have compared the combination of vinorelbine and gemcitabine with single-agent vinorelbine or gemcitabine in elderly patients with advanced NSCLC have shown conflicting results.345,346 The results of the Southern Italy Cooperative Oncology Group (SICOG) phase III trial showed that the combination of gemcitabine and vinorelbine was associated with a significantly better survival than vinorelbine alone in elderly patients with NSCLC,345 whereas in the MILES study, the combination of gemcitabine and vinorelbine was more toxic and failed to show any survival advantage over single-agent therapy with vinorelbine or gemcitabine alone.346 Emerging data are confirming the survival benefit of 2-drug regimens compared with single-agent therapy for patients with advanced disease. In the recent multicenter randomized phase III trial (IFCT-0501), the combination of paclitaxel and carboplatin was associated with significantly longer survival in patients aged 70 years or older (performance status 0-2) with advanced NSCLC than single-agent therapy with vinorelbine or gemcitabine, despite an increased risk of side effects (e.g., febrile neutropenia, asthenia, toxic death rate) with combination therapy.347 Median overall survivals were 10.3 and 6.2 months, respectively, and the 1-year survival rates were 44.5% and 25.4%, respectively.
Bevacizumab348 and erlotinib, an EGFR inhibitor,349,350 have been evaluated in elderly patients with advanced NSCLC. In a subset analysis of a phase III study (ECOG 4599), elderly patients with NSCLC who were randomized to paclitaxel and carboplatin with bevacizumab experienced a higher degree of toxicity and no improvement in overall survival compared with those who received paclitaxel and carboplatin.348 Bevacizumab should be used with caution in older patients. Erlotinib, although active and relatively well tolerated in chemotherapy-näive elderly patients (aged ≥ 70 years) with advanced NSCLC, is associated with higher incidences of interstitial lung disease and toxicity-related discontinuation (5% and 12%, respectively),348 compared with only 1% and 5%, respectively, observed in the erlotinib arm of the BR.21 trial, in which the median age was only 62 years. A recent subgroup analysis of the BR.21 trial also confirmed that elderly patients experienced greater toxicity and prolonged dose interruptions compared with younger patients, even though survival and quality-of-life benefits were similar for both groups.350
Management of elderly patients with prostate cancer is similar to that of younger patients.351 Treatment options are based on anticipated life expectancy of individual patients and whether they are symptomatic. See the NCCN Guidelines for Prostate Cancer for the management of patients with localized or locally advanced disease (to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org).
Docetaxel-based chemotherapy has been effective in elderly patients with metastatic castration-resistant prostate cancer.352,353 In the subgroup analysis of the TAX 327 trial, the survival benefit of 3-weekly docetaxel with prednisone compared with mitoxantrone with prednisone was seen across all age groups; median overall survival was 18.1 months for patients aged 69 years or older compared with 17.6 months for patients aged 68 years or younger.354 The hazard ratios for younger and older patients were 0.81 and 0.77, respectively. The hazard ratio was 0.80 with the age cutoff of 75 years.
Recently, cabazitaxel has shown activity in patients with metastatic castration-resistant prostate cancer that has progressed on docetaxel-based chemotherapy.355 In a randomized phase III trial, cabazitaxel with prednisone improved overall survival compared with mitoxantrone plus prednisone. The survival benefit was seen across all age groups.356 The hazard ratios for overall survival were 0.62 and 0.81, respectively, for older (age ≥ 65 years) and younger patients. Growth factor support is strongly recommended for patients aged 65 years or older receiving cabazitaxel because of the increased risk of neutropenia in these patients.
Cancer is the leading cause of death in women and men aged 60 to 79 years. The biologic characteristics of certain cancers are different in older patients compared with their younger counterparts, and older patients also have decreased tolerance to chemotherapy. Nevertheless, advanced age alone should not be the only criteria to preclude effective cancer treatment that could improve quality of life or lead to a survival benefit in older patients. Treatment should be individualized based the nature of the disease, the physiologic status of the patient, and patient preferences.
Chronologic age is not reliable in estimating life expectancy, functional reserve, or the risk of treatment complications. Whether cancer treatment is appropriate may be best determined through careful assessment of the older patient. CGA can be used to assess life expectancy and risk of morbidity from cancer in elderly patients, in turn enabling physicians to develop a coordinated plan for cancer treatment and guide interventions tailored to the patient’s problems.
*Arti Hurria, MD/Chair†ρα
City of Hope Comprehensive Cancer Center
gIlene S. Browner, MD†α
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
eHarvey Jay Cohen, MD†α
Duke Cancer Institute
gCrystal S. Denlinger, MD†
Fox Chase Cancer Center
*bMollie deShazo, MD†
University of Alabama at Birmingham Comprehensive Cancer Center
eMartine Extermann, MD, PhD†
H. Lee Moffitt Cancer Center & Research Institute
*cApar Kishor P. Ganti, MD†
UNMC Eppley Cancer Center at The Nebraska Medical Center
hJimmie C. Holland, MDθ
Memorial Sloan-Kettering Cancer Center
eHolly M. Holmes, MDραΣ
The University of Texas MD Anderson Cancer Center
hMohana B. Karlekar, MDρ
Vanderbilt-Ingram Cancer Center
eNancy L. Keating, MD, MPHρ
Dana-Farber/Brigham and Women’s Cancer Center
eJune M. McKoy, MD, JD, MBAρα£
Robert H. Lurie Comprehensive Cancer Center of Northwestern University
*fBruno C. Medeiros, MD‡
Stanford Cancer Institute
*aEwa Mrozek, MD†‡
The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute
aTracey O’Connor, MD†
Roswell Park Cancer Institute
fStephen H. Petersdorf, MD†‡ζ
University of Washington Medical Center/Seattle Cancer Care Alliance
aHope S. Rugo, MD†‡
UCSF Helen Diller Family Comprehensive Cancer Center
eRebecca A. Silliman, MD, PhD, MPHα
*aWilliam P. Tew, MD†ρ
Memorial Sloan-Kettering Cancer Center
eLouise C. Walter, MDα
UCSF Helen Diller Family Comprehensive Cancer Center
*dAlva B. Weir, III, MD†‡
St. Jude Children’s Research Hospital/University of Tennessee Cancer Institute
*fTanya Wildes, MD†
Siteman Cancer Center at Barnes-Jewish Hospital and Washington University
NCCN gratefully acknowledges the review of the Senior Adult Oncology Guidelines by *Efrat Dotan, MD†
NCCN Staff: Mary Anne Bergman, and Hema Sundar, PhD
*Writing Committee Member
Subcommittees: aBreast/Gynecological Cancers; bBladder, Kidney, and Prostate Cancers; cNon–Small Cell Lung Cancers; dHead and Neck/Central Nervous System Cancers; eGeriatric Assessment; fHematologic Malignancies; gGastrointestinal Cancers; hPsychological/Palliative Care
Specialties: †Medical Oncology; ρInternal Medicine, including Family Practice, Preventive Management; αGeriatric Medicine; θPsychiatry, Psychology, including Health Behavior; ΣPharmacology/Pharmacy; £Supportive Care including Palliative and Pain Management; ‡Hematology Oncology; ζBone Marrow Transplantation
NCCN Categories of Evidence and Consensus
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representation or warranties of any kind regarding their content, use, or application and disclaims any responsibility for their applications or use in any way.
Disclosures for the NCCN Guidelines Panel for Senior Adult Oncology
At the beginning of each NCCN Guidelines panel meeting, panel members disclosed any financial support they have received from industry. Through 2008, this information was published in an aggregate statement in JNCCN and online. Furthering NCCN’s commitment to public transparency, this disclosure process has now been expanded by listing all potential conflicts of interest respective to each individual expert panel member.
Individual disclosures for the NCCN Guidelines for Senior Adult Oncology panel members can be found on page 209. (The most recent version of these guidelines and accompanying disclosures, including levels of compensation, are available on the NCCN Web site at www.NCCN.org.)
These guidelines are also available on the Internet. For the latest update, visit www.NCCN.org.
|Panel Member||Clinical Research Support||Advisory Boards, Speakers Bureau,|
Expert Witness, or Consultant
|Ilene S. Browner, MD||None||None||None||None||7/22/11|
|Harvey Jay Cohen, MD||None||None||None||None||7/6/11|
|Crystal S. Denlinger, MD||AstraZeneca|
Genentech, Inc.; Chugai
Pharmaceutical Co. Ltd.;
Inc.; Roche Laboratories,
|Mollie deShazo, MD||None||None||None||None||7/21/11|
|Efrat Dotan, MD||Biocompoatibles UK Ltd.||None||None||None||11/2/11|
|Martine Extermann, MD,|
|Apar Kishor P. Ganti, MD||Pfizer Inc.||None||None||None||4/25/11|
|Jimmie C. Holland, MD||None||None||None||None||10/5/11|
|Holly M. Holmes, MD||None||None||None||None||5/16/11|
|Arti Hurria, MD||Abraxis Oncology;|
Celgene Corporation; and
|Mohana B. Karlekar, MD||None||None||None||None||6/22/11|
|Nancy L. Keating, MD, MPH||None||None||None||None||7/21/11|
|June M. McKoy, MD, JD,|
|Bruno C. Medeiros, MD||Celgene Corporation;|
Millennium Pharmaceuticals, Inc.;
and Novartis AG
|Ewa Mrozek, MD||None||None||None||None||6/23/11|
|Tracey O’Connor, MD||None||None||None||None||10/28/11|
|Stephen H. Petersdorf, MD||Genzyme Corporation||None||None||None||2/25/11|
|Hope S. Rugo, MD||None||None||None||None||7/5/11|
|Rebecca A. Silliman, MD,|
|William P. Tew, MD||None||None||None||None||5/25/11|
|Louise C. Walter, MD||None||None||None||None||7/21/11|
|Alva B. Weir, III, MD||None||None||None||None||4/6/11|
|Tanya Wildes, MD||None||None||None||None||5/16/11|
The NCCN guidelines staff have no conflicts to disclose.