Clinical Trials in Older Adults With Cancer: Past and Future

The risk of cancer increases with age, and as the US population rapidly ages, the number of older adults seeking treatment for cancer is also increasing dramatically. However, this growing population of older adults has been underrepresented in clinical trials that set the standards for oncology care. In addition, most clinical trials conducted to date have not addressed the problems that accompany aging, including reduced physiologic reserve, changes in drug pharmacokinetics, and the impact of comorbid medical conditions and polypharmacy on treatment tolerance. As a result, there are variations in treatment patterns between older and younger adults and few evidence-based guidelines accounting for the changes in physiology or pharmacokinetics that occur with aging. This article examines the demographics of cancer and aging, the barriers to enrollment of older adults on clinical trials, and approaches for future trials to address the needs of the older patient.

Although older adults account for the majority of cancer incidence and mortality, few clinical trials have focused on this patient population (Figure 1).[1] At the same time, the US population is aging, and the average life expectancy is increasing. (Over the 20th century, US life expectancy increased from 47.3 years in 1900 to 76.9 years in 2000.)[2] Projections show that the US population age 65 and older will double by 2030, when 1 in 5 adults will be over the age of 65.[2] The population age 85 and older (known as the "oldest old") will also double from 2000 to 2030, then double again from 2030 to 2050.[2] Since approximately 60% of cancer incidence and 70% of cancer mortality occur in adults age 65 and older, it is projected that the number of older cancer patients and cancer survivors seeking treatment will also go up exponentially in the near future.

Representation of Older Adults in Clinical Trials

The growing worldwide population of older adults has been underrepresented in clinical trials that set the standards for oncology care.[3-7] From 1993 to 1996, only 25% of patients enrolled in Southwest Oncology Group (SWOG) trials were age 65 or older, but approximately 63% of cancers were diagnosed in this age group.[3] During this same period, a similar underrepresentation of older patients was reported in Canadian trials, where only 22% of patients enrolled in clinical trials performed by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) were age 65 and older.[4] However, more recent data from SWOG and the Cancer and Leukemia Group B (CALGB) demonstrate some improvement in accrual of older adults to clinical trials. From 2001 to 2003, 38% of patients enrolled in SWOG trials and 36% of patients in CALGB trials were age 65 or older.[8,9] This accrual increase may result in part from a policy change in the year 2000 that required Medicare to reimburse providers for routine costs of patient care in clinical trials.[8]

While improvement in the enrollment of older adults in clinical trials is encouraging, the representation of older adults on trials is still far from ideal, and the enrollment fraction of patients 75 and older in clinical trials (ie, the number enrolled divided by estimated cancer cases) worsens with increasing age. For example, in the National Cancer Institute (NCI) trials for breast, colorectal, lung, and prostate cancer from 2000 to 2002, the enrollment fraction was 3% for patients aged 30 to 64, 1.3% for patients aged 65 to 74, and 0.5% for patients aged 75 and older.[5] Perhaps the most concerning statistics are that older adults are underrepresented in registration trials of new drugs approved by the US Food and Drug Administration (FDA), despite the FDA's recommendation to include older adults in clinical trials (Table 1).[10] As a result, the standard drug dosing and expected side-effect profile is primarily derived from a younger cohort of patients.

In this article, we discuss the barriers to enrollment of older adults in clinical cancer trials, and propose research priorities to address these barriers and to overcome this knowledge gap in the treatment of older adults with cancer. We review age-related changes in physiology and pharmacokinetics that can affect treatment tolerance and efficacy in older adults, and discuss the role of a geriatric assessment in pinpointing factors other than chronologic age that are independent predictors of morbidity and mortality.

Barriers to Clinical Trial Enrollment of Older Patients

In a retrospective case-controlled study of patients with breast cancer, Kemeny et al sought to determine whether older patients (age ≥ 65 years) were as likely as younger patients (age < 65 years) to be offered and to accept treatment on a clinical trial.[11] The pairs of older and younger patients were matched by disease stage and treating physician. The study results demonstrated that older patients were significantly less likely to be offered a clinical trial (35% vs 51%; P=.006); however, if offered, they were as likely to accept enrollment (50% ≥ age 65 vs 56% < age 65; P = .67). In a multivariate analysis, age and stage were significant predictors for whether a clinical trial was offered.

Older and younger patients declined to participate in a clinical trial for similar reasons: They wanted to choose their own treatment, wanted a treatment that was not offered, and they did not want to be an "experiment."[11] The most common reason physicians did not offer a clinical trial to older and younger patients differed. For an older patient, the most common physician concern was that the treatment was too toxic, which was cited in 33% of the cases. Additional reasons for not offering a clinical trial included the doctor's perception that the trial did not offer the best treatment option, the doctor was unaware that a trial was available, the doctor thought the patient was not eligible, or the doctor was concerned about comorbid conditions affecting tolerance to therapy.

At the Canadian NCIC CTG meeting in 2000, 40 physicians were surveyed regarding the enrollment of older adults in clinical trials.[4] Only 10% of the physicians reported that they enrolled more than 15% of their older patients on clinical trials. Concern regarding increased toxicity was the barrier cited in 50% of cases. Other reasons included comorbid medical conditions, patient or family members' preference, the older patient's lack of social support, time required for patient enrollment and follow-up, and physician preference for conventional treatment.[4]

A total of 156 physicians from 10 CALGB institutions were surveyed regarding their perception of the most important barriers to accrual of older adults.[12] The most commonly cited barriers included concern regarding the effect of comorbid conditions on the ability to tolerate treatment, concern regarding the patient's ability to comprehend a complicated treatment trial resulting in poor compliance, concern regarding treatment toxicity in the older patient, and the older patient not meeting the specified eligibility criteria. The most frequent suggestions for interventions to improve the accrual of older adults to clinical trials included making personnel available in clinic to explain the trial and providing educational materials to the physician concerning treatment toxicity in older patients.

Based on these suggestions, investigators from the CALGB Cancer in the Elderly Committee tested the impact of an educational intervention to improve the accrual of older adults to clinical trials. In this study by Kimmick et al,[9] CALGB main member institutions were randomized to receive either standard information or an educational intervention. The standard information consisted of access to the CALGB website and periodic notification about protocols. The educational intervention consisted of a geriatric oncology educational seminar, educational materials, a list of protocols available to older patients placed in the patient's chart, and monthly e-mail and mail reminders. Despite this intervention, study results demonstrated that accrual of older patients to clinical trials decreased in comparison to baseline, and there was no accrual improvement in the intervention arm compared to the control arm in the first year (36% vs 32%; P = .35) or second year (31% vs 31%; P = .83). The authors postulated that a more intense, multifaceted intervention was needed to improve the accrual of older adults in clinical trials.

While older patients are underrepresented in clinical cancer trials for multifaceted and complex reasons, among the most commonly cited reasons by physicians for not enrolling older adults on clinical trial is a concern about treatment toxicity.[4,11] Previous studies disagree on whether older patients are truly at increased risk; however, these studies likely enrolled a select group of older patients who were deemed fit for participation in a clinical trial, making it difficult to extrapolate study results to the population as a whole.[13-17]

Future studies are needed to address ways for improving clinical trial accrual of older patients. A significant barrier to enrollment is the physician's concern regarding the age-related risk of inordinate toxicity. In order to address this concern, further trials are needed to evaluate the toxicity and efficacy of cancer therapies in older adults (taking into account age-related changes in physiology and pharmacokinetics that may affect treatment tolerance), to evaluate the role of supportive care measures that can improve treatment tolerance, and to pinpoint factors other than chronologic age that may be independent predictors of morbidity and mortality.

Designing Clinical Trials for Older Patients

Accounting for Age-Related Changes in Pharmacokinetics and Physiologic Reserve

Studies of the pharmacokinetics and pharmacodynamics of new cancer therapies in older patients can help guide drug dosing and inform health-care providers regarding age-related changes in the toxicity profile. Cancer and cancer treatment can be considered physiologic stressors, and age-related declines in organ function and/or changes in pharmacokinetics can play an important role in the tolerance of cancer therapy among older adults. With age comes a decrease in physiologic reserve.[18,19] This decrease may not be apparent at rest but becomes more apparent at times of stress.

Age-related differences in pharmacokinetics may increase the risk of treatment toxicity in older adults. For example, changes occur in the volume of drug distribution, primarily attributable to changes in body composition with age, including an increase in body fat, decrease in lean body mass, and decrease in total body water.[20] In addition, anemia or hypo-albuminemia may affect the volume of distribution of drugs bound to hemoglobin or albumin. Age-related changes in the gastrointestinal system may impact the absorption of oral drugs. For example, gastric motility decreases with age, splanchnic blood flow and digestive enzymes decrease, along with mucosal atrophy.[21-25] As the use of oral cancer therapies is increasing in frequency, further studies evaluating the bioavailability of oral cancer drugs in older patients are needed.

• Impact of Age on Renal Function-Age-related changes in renal function can have an impact on both the pharmacokinetics and tolerance of cancer therapy in older adults. Over a lifespan, renal mass decreases by approximately 25% to 30%, leading to a decrease in functional nephrons and a decreased ability to concentrate and dilute urine.[20] Moreover, renal blood flow decreases by approximately 1% per year after age 50, and the glomerular filtration rate decreases by 0.75 to 1 mL/min per year after age 40.[20,26] Because of the decline in muscle mass with age, these changes in renal function may not be reflected in the serum creatinine level, making it an inadequate reflection of renal function in the older patient.[27]

The importance of adjusting chemotherapy dose based on renal function, and the utility of performing trials in older patients whose age-related declines in organ function should dictate appropriate drug dosing were demonstrated in a study evaluating capecitabine (Xeloda) in patients aged 65 and older with metastatic breast cancer.[28] The study entry criteria required that participants have a serum creatinine of < 1.6 mg/dL. Patients were given the standard FDA-approved dose of capecitabine (2,500 mg/m²/d). In the first cohort of patients, two toxic deaths occurred due to diarrhea and dehydration, in an 80-year-old and a 75-year-old patient.

When the authors calculated the creatinine clearance of the patients enrolled in the study, they found that all showed a decrease in creatinine clearance, reinforcing the principle that serum creatinine alone is an inadequate measure of renal function in the older patient.[28] The authors reported that at the time the study began-and was amended-there were no reports available on the impact of renal function on capecitabine's safety. The importance of capecitabine dosing based on renal function only became evident when the drug was studied in older patients, because a high proportion of participants had an age-related decrease in renal function.

• Impact of Age on Hepatic Function-Hepatic blood flow and hepatic mass decrease with increasing age. The impact of this decrease on hepatic enzyme activity, however, remains controversial.[19,29-31] Liver biopsies of patients over age 70 contained a 30% decrease in cytochrome p450 content compared to younger patients less than age 70, but the reported impact of age-related changes in the pharmacokinetics of hepatically metabolized drugs varies between studies, with only some studies demonstrating age-related changes in pharmacokinetics.[32-39]

For example, a study of the pharmacokinetics of paclitaxel delivered at 175 mg/m² over 3 hours every 3 weeks demonstrated a decrease in clearance and an increase in the area under the curve (AUC) of the drug with increasing age.[33] In comparison, a study of the pharmacokinetics of docetaxel (Taxotere) delivered at 75 mg/m² every 3 weeks reported no age-related differences in the AUC or clearance of this agent.[40] However, both studies demonstrated that older patients are at increased risk for myelosuppression.

• Impact of Age on Bone Marrow Reserve-Bone marrow reserve decreases with aging,[40-44] placing older patients at increased risk for myelosuppression and associated complications. In a study of older patients (median age 70) receiving CHOP (cyclophosphamide, doxorubicin HCl, vincristine [Oncovin], and prednisone), 35 of 267 suffered a toxic death; 82% of the deaths were due to infection, with 63% occurring after the first cycle.[45]

Therefore, the American Society of Clinical Oncology (ASCO) guidelines for the use of white cell growth factors acknowledge that older patients receiving moderately toxic chemotherapy (ie, similar dose intensity to CHOP) are at increased risk for neutropenia and neutropenia-associated complications and recommend initiation of white blood cell growth factor support with the first cycle of treatment.[46] In addition, the ASCO and National Comprehensive Cancer Network (NCCN) guidelines for the use of myeloid growth factors acknowledge that the age of 65 or older is a risk factor for febrile neutropenia.[47]

The age-related increased risk of myelosuppression also places the older patient at increased risk for anemia. In the older population, anemia has been associated with increased risk of mortality, functional dependence, cardiovascular complications, fatigue, and an increase in the volume of distribution of chemotherapy drugs, which are heavily bound to red cells.[48-51] Careful attention to anemia and initiation of red cell growth factors can decrease the risk of anemia-associated complications.

Incorporating a Geriatric Assessment

Aging is a heterogeneous process, and cancer treatment must be addressed with this in mind. While certain declines in organ function are universal as the human body ages, the rate of this decline and the consequences of this decline on everyday function proceeds at a unique pace in each individual. Therefore, chronologic age tells us relatively little about the specific individual. A more detailed evaluation of an older adult patient is needed in order to capture factors other than chronologic age that predict for morbidity and mortality. A comprehensive geriatric assessment (CGA) may serve this purpose. The CGA includes an evaluation of functional status, comorbid medical conditions, cognitive function, nutritional status, social support, and psychological state, as well as a review of medications. Here we review each domain of a geriatric assessment and discuss its utility in the older patient with cancer.

Components of a Geriatric Assessment

• Functional Status-The need for functional assistance is predictive of morbidity and mortality in the geriatric population. The need for this assistance increases in older patients with cancer.[52] The oncologist's evaluation of functional status typically consists of rating a patient's -Karnofsky or Eastern Cooperative Oncology Group (ECOG) performance status.[53,54] These brief assessments predict treatment morbidity and mortality regardless of age. However, they do not provide details regarding the impact of functional decline on everyday activities required to maintain independence at home or in the community. In addition, these performance scales have not been validated in the geriatric population, where functional decline may come from medical conditions unrelated to cancer.

A geriatrician's assessment of functional status typically consists of evaluating an individual's ability to complete activities of daily living (ADLs) and instrumental activities of daily living (IADLs). ADLs are basic self-care skills needed to maintain independence at home; IADLS are skills needed to maintain independence at home and in the community (Table 2). Literature is emerging that cites the importance of ADL and IADL abilities in the cancer population. These scales provide information about physical functioning above and beyond that provided by the Karnofsky or ECOG performance status.

In a study of patients aged 65 and older with cancer with a good ECOG performance status (defined as < 2), 37.7% had limitations in IADLs and 9.3% had limitations in ADLs.[55] Functional limitations in ADLs and IADLs predict morbidity and mortality among the geriatric population.[56,57] In a study of 566 patients aged 70 and older with non-small-cell lung cancer, those who did not require assistance in performing instrumental activities of daily living had an improved overall survival (P = .04).[58]

• Comorbidity-A common reason why physicians do not offer clinical trials to an older patient is a concern for the impact of comorbid medical conditions on toxicity, even if these medical conditions are not among specific exclusion criteria for the clinical trial.[4,11] Indeed, the number of competing comorbid medical conditions increase with age, making an understanding of the impact of comorbid medical conditions on overall life expectancy and the ability to tolerate cancer therapy highly relevant to the geriatric population.[59]

Comorbid medical conditions can impact life expectancy apart from a cancer diagnosis.[60] For example, in a study of older patients with breast cancer, patients with three or more comorbid medical conditions compared to no comorbid medical conditions had a 20-fold increased risk of dying from a medical condition other than breast cancer and a 4-fold increased risk of overall mortality.[61] The presence of comorbid medical conditions may also affect a patient's ability to tolerate chemotherapy. In a study of older patients with lung cancer, patients with a higher comorbidity score, as measured by the Charlson scale, were more likely to discontinue therapy early.[62] Although, intuitively, one might assume that functional status and comorbidity are linked, studies have shown that these two variables are independent, and therefore, each is important to assess.[63]

• Nutritional Status-In the geriatric population, unintentional weight loss is associated with poorer survival. In a study of over 4,714 individuals aged 65 and older, weight loss greater than 5% of body weight was associated with increased mortality.[64] Among patients with cancer, unintentional weight loss is also associated with poorer performance status, decreased response to chemotherapy, and poorer survival.[65]

A low body mass index is similarly associated with poorer survival in the geriatric population. In a study of over 7,500 patients aged 70 and older, a body mass index < 19.4 kg/m² was associated with poorer survival.[66] Other studies suggest that the definition of a "low" body mass index does not need to be stringent, and that even patients with a body mass index < 22 or 23 kg/m² are at increased risk for mortality.[67,68]

• Cognition-Impairment in cognitive function is an independent predictor of mortality.[69,70] The incidence of dementia rises with increasing age, and older patients with dementia are more likely to be diagnosed with cancer at an advanced stage and less likely to receive standard cancer therapies.[71,72] With increasing use of oral chemotherapy and supportive care measures, an understanding of the patient's cognitive capacity is essential to ensuring that the patient can recognize signs of toxicity and seek help when needed. Little is known about the impact of cancer therapy on the older patient's cognitive function, although a small study suggested that a subset is at risk for cognitive decline.[73] This is a fertile area for future research.

• Social Support and Psychological State-Social isolation is an independent predictor for mortality in the geriatric population.[74] Studies demonstrate that, in general, older patients with cancer experience similar or less psychological distress than younger patients.[75,76] However, older individuals who are most vulnerable to psychological distress are usually socially isolated.[77] Depression in the geriatric population is associated with functional decline and increased need for informal caregiving.[78,79] From a practical standpoint, because older patients with cancer are more likely to require functional assistance, an assessment of social support is essential to determining health-care needs and planning for the resources required during cancer therapy.

• Medication Review-Age-related changes in physiology may affect a drug's pharmacokinetics and pharmacodynamics, placing the older patient at increased risk for adverse drug events.[20,80] During cancer therapy, several additional medications such as antiemetics or other supportive care agents are often prescribed. Moreover, older individuals are often already taking several prescribed medications as well as over-the-counter drugs, leading to a risk for drug interactions.[80-82] An important component of the geriatric assessment is a review of the patient's list of medications in order to evaluate for potential drug interactions and to discontinue any nonessential medications.

Benefits of a CGA in Oncology Practic

Conclusions from several studies are emerging regarding the benefits of performing a CGA for older patients with cancer:

(1) CGA predicts survival.[58]

(2) CGA predicts toxicity to chemotherapy.[83]

(3) CGA uncovers problems not detected by routine history and physical in initial consultation and in follow-up care.[55,84,85]

(4) CGA can improve pain control.[86]

(5) CGA improves an older patient's mental health and well-being.[86]

Consensus guidelines recognize these benefits and recommend the inclusion of a geriatric assessment as part of the evaluation of an older patient.[51,87] However, to date, there is no standard geriatric assessment measure available for oncologists. The assessment must take into account the limited time and resources available in a subspecialty practice. Novel approaches are being developed, such as a mailed geriatric assessment or abbreviated geriatric assessment, with the more detailed assessment reserved for patients identified as vulnerable.[88,89] Other investigators are working on developing a geriatric assessment that would be feasible to incorporate in cancer clinical trials.[90]

Using a CGA to Establish Novel Endpoints for Clinical Trials

The traditional endpoints for clinical trials of therapeutic drugs include disease-free and overall survival. While these end points are important in the geriatric population, the quality of survival, including the preservation of functional independence, is also important to measure. Older patients report a willingness to undergo toxic, life-sustaining therapies as long as there is no long-term impact on functional status, cognitive function, or quality of life.[91] Inclusion of a geriatric assessment and quality-of-life assessment at serial time points during cancer therapy can provide valuable data on the longitudinal impact of cancer therapy on these parameters. In addition, as the number of cancer survivors grows, we will be better able to understand the unique problems faced by these patients and to develop interventions to minimize the long-term consequences of potentially life-sustaining therapy in order to preserve the independence of older adults.

Research Priorities at the Cancer-and-Aging Interface

The National Institute of Aging (NIA) and the National Cancer Institute (NCI) recognized the need to address the gap in knowledge regarding older adults with cancer. In 2001, Rosemary Yancik, PHD (on behalf of the NIA) and Margaret E. Holmes, PHD (on behalf of the NCI) convened a workshop titled "Exploring the Role of Cancer Centers for Integrating Aging and Cancer Research."[92] The goal of this multidisciplinary workshop was to identify research priorities at the interface of cancer and aging. Seven research themes and priorities were identified[92]:

• Patterns of care

• Treatment efficacy and tolerance

• Effects of comorbidity on cancer

• Prevention, risk assessment, and screening

• Psychosocial, social, and medical issues

• Palliative care, end-of-life care, and pain relief

• Biology of cancer and aging

In addition, in 2002 the NCI and NIA funded eight US cancer centers for a 5-year period with the purpose of integrating cancer and aging research into their cancer center support grants (Table 3). This support will provide a solid foundation for established research programs in cancer and aging at each of these institutions.

Conclusions

In this article, we review the statistics regarding the growing geriatric cancer population and discuss the current underrepresentation of older adults in clinical trials, as well as potential barriers to enrollment of older adults in cancer clinical trials. We discussed factors to consider when developing clinical trials for older adults including age-related changes in physiology and pharmacokinetics, factors that may affect treatment tolerance and efficacy, as well as the role of geriatric assessment in identifying factors other than chronologic age that may have an impact on morbidity and mortality. In order to provide optimal care for this growing cancer population, it is necessary to increase the enrollment of older adults in clinical trials and design trials that explore the specific issues facing the geriatric population. National efforts to address these research priorities are already underway.

Disclosures:

The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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