Lack of elderly patients in cancer trials leads to inadequate treatment guidance

Older patients largely have been underrepresented in clinical oncology trials in the United States for several decades.

The shortfall became so concerning that the FDA published guidelines in 1989 that emphasized "the population studied should reflect the population likely to be treated."

Despite that guidance, study results suggest the trend has continued.

Patients aged at least 65 years accounted for 61% of new cancer cases between 1997 and 2000, yet that population accounted for only 32% of the 59,000 patients who participated in oncology trials during that time period, according to results of a study by Kemeny and colleagues published in the Journal of Clinical Oncology.

A subsequent retrospective study by Talarico and colleagues, also published in the Journal of Clinical Oncology, reviewed 55 registration trials that included 28,766 patients with cancer. Researchers discovered trial representation was significantly lower than the corresponding rates of the US cancer population for those aged 70 years and older (20% vs. 46%; P<.001) and those aged 75 years and older (9% vs. 31%; P<.001).

"Although the overt exclusion of elderly patients in these trials has improved, the median age of patients has not changed significantly," Adrian G. Sacher, MD, of Princess Margaret Hospital and University Health Network at the University of Toronto, said in an interview. "Greater awareness of the need to include elderly patients in oncology clinical trials has the potential to improve the lives of many elderly patients."

Federal reforms — such as the decision by CMS in 2000 to authorize Medicare payment of routine care costs for beneficiaries enrolled in clinical trials — have paved the way for the inclusion of more elderly patients. However, experts agree much more work is needed to inform physicians, patients and policymakers of the need for clinical trial enrollment to accurately reflect the overall patient population.

"The number of people over age 65 with solid tumors is growing daily, but we have limited data on how they respond to our chemotherapy regimens," Channing Paller, MD, assistant professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital and Sibley Memorial Hospital, told HemOnc Today. "Some clinicians often dose-reduce for octogenarians or don’t give chemotherapy at all, as they believe octogenarians may have surpassed their estimated life expectancy and they don’t want to cause any harm. Eliminating this well-meaning bias and replacing it with data is important to effective care for an increasingly aging population."

Low numbers in NSCLC

In 2010, about 5.8 million Americans were aged at least 85 years. That number is expected to reach 19 million by 2050, according to the US Census Bureau.

Consequently, clinicians will need to know more about how to treat and care for this segment of the population, Dale R. Shepard, MD, PhD, co-director of the Taussig Oncology Program for Seniors and staff physician in the department of solid tumor oncology at Cleveland Clinic’s Taussig Cancer Institute, said in an interview.

"The primary problem is that when you look at who gets cancer, particularly solid tumors, it’s older people," Shepard said. "But we end up developing drugs in younger people to give to older people, and often times we don’t fully understand the side effects and how effective these drugs are in the elderly."

An FDA review published in 2011 evaluated trial data submitted to the FDA between 2000 and 2010 for the treatment of non–small cell lung cancer.

Shakun Malik, MD,  medical officer in the FDA’s Center for Drug Evaluation and Research, and colleagues assessed whether the demographics of all 10 trials accurately reflected the patient populations who were expected to receive the drugs under investigation.

They found elderly patients were significantly underrepresented. Thirty-six percent of trial participants were aged 65 years or older, yet data culled from the SEER database showed 73% of patients diagnosed with lung cancer are in that age bracket. Moreover, the median age at lung cancer diagnosis is 71 years.

"Clinical trials, in general, exclude patients with comorbid conditions and enroll patients with a good performance status only, resulting in lower numbers of elder patient enrollment," Malik told HemOnc Today. "However, cancer incidence increases with age. Thus, a significant number of patients receiving approved therapies will be elderly."

In a report published earlier this year in the Journal of Thoracic Oncology, Sacher and colleagues pooled data from 248 phase 3 trials conducted between 1980 and 2010 that assessed systemic therapy alone for patients with advanced NSCLC.

The median patient age among the 100 most cited studies was 60.9 years. By design, 33% of studies excluded patients aged older than 75 years, and several of those excluded anyone aged older than 65 years.

Better representation of the elderly in trials will help researchers and clinicians better understand evidence-based standards in the aging population of cancer patients, Sacher said.

"Elderly patients remain underrepresented in practice-changing clinical trials in advanced NSCLC," Sacher said. "The elderly are in many ways different from younger patients — their renal, hepatic and bone marrow reserve is often poorer than in younger patients, and thus they often experience increased toxicity from cancer treatments. As such, the balance of toxicity vs. the antitumor effect of the treatments being examined in clinical trials may be significantly altered when a treatment that benefits younger patients is used on elderly patients."

Breast cancer trials

There is significant interest from oncology cooperative groups for the inclusion of the elderly in breast cancer trials, yet underrepresentation remains a problem in that specialty, too, Shepard said.

"[One study] looked at three different breast cancer trials that included about 6,000 patients, and only 3% of the study population was aged 70 and older," Shepard said. "However, when you look at the median age for breast cancer, it’s the mid-60s. The majority of patients are in this older age group, yet only about 3% are represented in trials. This population has been misrepresented for a long time. Even in a clinical trial setting with groups who are mindful of these issues, it’s still happening."

M. Margaret Kemeny, MD, FACS, director of the Queens Cancer Center at Queens Hospital Center in New York, and colleagues conducted a retrospective case-control study across 10 CALGB institutions to assess the barriers to trial participation among older women with breast cancer.

The study included 77 pairs of women who were eligible for an open treatment trial. Each pair — matched by disease stage and treating physician — included one woman aged younger than 65 years and one woman aged 65 years or older.

The researchers interviewed patients about their reasons for participating in or refusing to participate in a trial. Investigators also distributed questionnaires to physicians to evaluate their reasons for offering or not offering patients the option to participate in a trial.

The researchers found 68% of younger women with stage II breast cancer were offered participation in a breast cancer trial, whereas 34% of older women were offered participation (P=.0004).

Results of multivariate analysis demonstrated patient age and disease stage were significant predictors for whether physicians offered participation in a trial (P=.0008). Presence of comorbid conditions also served as a predictor.

"The greatest impediment to enrolling older women onto trials in the setting of this study was the physicians’ perceptions about age and tolerance of toxicity," Kemeny and colleagues concluded.

Informed decisions

An increasing number of research studies have focused on whether elderly individuals who are otherwise healthy often undergo unnecessary cancer screenings, as well as whether those already diagnosed with cancer are subjected to too many potentially highly toxic treatments that offer little or no benefit in terms of length or quality of life.

Cary P. Gross, MD, associate professor of internal medicine at the Yale School of Medicine, said this is the exact reason why the elderly population should be represented in clinical trials.

"If we don’t study the effect of different treatment strategies in the older population, clinicians and patients are left without adequate guidance to inform their decisions about screening, as well as treatment," Gross told HemOnc Today.

In a study published in the Archives of Internal Medicine, Gross and colleagues pooled data from Medicare records between 1998 and 2007 on more than 39,000 men aged 67 years and older with prostate cancer.

The researchers observed an increase in intensive cancer treatment in older patients, increasing their risk for reduced quality of life, further complications and increased health care costs.

"We found that there was actually an increase in the use of curative treatment among men who were least likely to benefit from treatment, such as those with less aggressive cancers," Gross said. "Although it is unclear what is driving this trend, we need to do a better job of explaining the treatment alternatives — including active surveillance — to older men with prostate cancer."

Reasons for underrepresentation

The experts who spoke with HemOnc Today proposed several reasons why the elderly are significantly underrepresented in clinical trials. They range from physical challenges, such as the presence of comorbid conditions, to socioeconomic obstacles, such as the cost of health care and the lack of mobility.

Another significant contributing factor is reluctance on the part of some health care providers to suggest intensive treatments or even screening for older patients.

"Elderly patients don’t go into trials because, for the most part, they are not asked by their physicians," Kemeny said.

Shepard agreed.

"At my institution, we have a geriatric oncology clinic. We treat patients aged 75 and older whose physician may have become uncomfortable in terms of what to do for them regarding treatment," he said. "Part of this is not wanting to harm their patients, and so those physicians are then even less likely to want to offer the patient participation in a clinical trial."

That mindset can have consequences, however.

A study published earlier this year in JAMA Internal Medicine was one of the first to examine elderly patients’ perceptions of recommendations to halt cancer screenings as they age.

The findings indicate these patients feel strong moral obligations to continue with cancer screenings, despite their physicians’ recommendations to forgo screening due to the potential harm or lack of benefit.

Patients also may begin to lose trust in physicians who recommend they stop undergoing screenings, researcher found.

"In this era of attention to overtesting, there is a growing recognition in the medical community that some older adults are screened for cancer when it is not beneficial or even potentially harmful to that person," researcher Alexia Torke, MD, an assistant professor of medicine at the Indiana University School of Medicine, said in a press release. "Each patient is different, but when speaking with older adults or the caregivers of those who can no longer make decisions for themselves about reducing screenings, the discussion needs to clearly outline the balance of risks and benefits for the specific individual. This approach has the greatest chance of building trust and understanding."

The fact that many elderly patients with cancer have comorbidities also represents another significant barrier. For example, trials are currently designed to exclude older patients with a previous heart arrhythmia or impaired kidney and liver functions.

"I had a phase 1 trial specifically designed for patients aged 75 years and older that ended up not accruing patients because of the requirement to not allow patients with any previous heart arrhythmia. This was maddening," Shepard said. "If you are looking for patients aged 75 and older without even a remote history of heart arrhythmia, you cannot find patients. Despite initial concerns based on preclinical studies, there was no reason for this from a safety and medical judgment standpoint. It’s these artificial-type things that we often do in trials that negatively impact clinical trial options for our elderly patients."

The elderly may have comorbid conditions and their risk–benefit ratio may be different compared with younger patients, Malik said.

"[However], the pharmaceutical industry should make an effort to enroll elderly patients with performance status that represents the actual patient population and include patients with acceptable comorbid conditions, since these are the types of patients who will receive these therapies if they eventually are approved," Malik said.

Paller agreed.

"Patients with comorbidities such as liver or kidney problems, who might have been excluded from trials in the past, should be included in clinical trials of cancer drugs," Paller said. "Oncologists should study different doses and schedules of chemotherapy drugs in those patients, and in patients over age 70, as they may have different side effects."

Potential solutions

Although previous efforts have focused on improving the representation of elderly patients in clinical trials, the problem has never gone away, experts said.

One solution is to better educate physicians about cancer in the elderly, Kemeny said.

When she and colleagues investigated the barriers to trial participation among older women with breast cancer, they reported "two particular areas of interest" — physicians’ lack of knowledge about open trials, as well as the perception that older patients would not be eligible.

"With the increase in physicians’ caseloads, and in academic centers where there are multiple protocols to consider, it has become extremely hard for oncologists to match available protocols to eligible patients without additional staff," Kemeny and colleagues wrote.

Increased availability and use of technology designed to help clinicians match patient information with trial eligibility criteria "might dramatically increase oncologists offering trials to their older, as well as younger, patients," the researchers concluded.

In a paper published in The Journal of Nutrition, Health & Aging, Habicht and colleagues suggested legislation should be enacted to ensure older people are adequately represented in clinical trials. A similar effort helped to increase participation of women in clinical trials, they said.

"In tandem with such legislation, changes need to be implemented in the regulatory frameworks controlling pharmaceutical and medical device licensing," they wrote." It should not be possible for new interventions to obtain a license unless evidence is submitted of their effectiveness in the population likely to receive them most commonly, namely older people with comorbid disease."

Habicht and colleagues also suggested ethics committees play a greater role in ensuring trial eligibility criteria do not support direct exclusion of older people based solely on age, or indirectly based on comorbid disease.

Shepard, who was recently appointed to the Alliance Cancer Control Program’s Cancer in the Elderly Committee, also said changes must be made regarding clinical trial design.

"It is important to have the right eligibility criteria," he said. "I have a prostate cancer trial going on right now for cabazitaxel (Jevtana, Sanofi-Aventis) in men with prostate cancer aged 75 years and older. When I was writing the trial, the company that sponsored the trial wanted to make sure the patients were not ‘too unfit.’ They wanted to include activities of daily living, which is a standard geriatric measure, as an inclusion criteria."

Although this makes sense in general clinical settings, it is not appropriate in this patient population for determining eligibility for a clinical trial, Shepard said.

"It is likely inappropriate to use activities like shopping, doing laundry and cooking meals as inclusion/exclusion criteria in men who are 75 years and older. These are things that many of these men aren’t doing, not because they can’t but they never did because their wives had always done them," he said. "These types of ‘artificial barriers’ are placed on elderly populations in clinical trials and need to be eliminated."

Trial schedules also must be re-evaluated, Shepard said. Even if older patients can tolerate the regimen under investigation, the frequency and duration of tests as part of a clinical trial are sometimes too intense for them to endure.

"If you are requiring the patient to be at an institution for 12 hours at a time, running from building to building, this is a lot more than many elderly patients can tolerate," Shepard said. "We need to change the way we think about trials in terms of designing them so that older people can actually participate. Solutions to the problem are out there, but it’s the implementing part that’s hard." – by Jennifer R. Southall

References:

Habicht DW. J Nutr Health Aging. 2008;12:194-196.

Kemeny MM. J Clin Oncol. 2003;21:2268-2275.

Malik S. Abstract #O44.06. Presented at: The 14th World Conference on Lung Cancer; July 3-7, 2011; Amsterdam.

Ross JS. Arch Intern Med. 2012;172:1601-1603.

Sacher AG. J Thorac Oncol. 2013;8:366-368.

Talarico L. J Clin Oncol. 2004;22:4626-4631.

Torke A. JAMA Intern Med. 2013;doi:10.1001/jamainternmed.2013.2903.

For more information:

Cary P. Gross, MD, can be reached at The Yale School of Medicine, 333 Cedar St., New Haven, CT 06510; email: cary.gross@yale.edu.

M. Margaret Kemeny, MD, FACS, can be reached at Queens Cancer Center of Queens Hospital Center, 82-68 164th St., New-Bldg., 5th Floor, Jamaica, NY 11432.

Shakun Malik, MD, can be reached at Food and Drug Administration, Center for Drug Evaluation and Research, 10001 New Hampshire Ave., Room 4175, Silver Spring, MD 20903; email: CDERTradePress@fda.hhs.gov.

Channing Paller, MD, can be reached at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital and Sibley Memorial Hospital, 1800 Orleans St., Baltimore, MD 21287; email: cpaller1@jhmi.edu.

Adrian G. Sacher, MD, can be reached at Princess Margaret Hospital and University Health Network, University of Toronto, 610 University Ave., Toronto, ON M5T 2M9, Canada; email: adrian.sacher@mail.utoronto.ca.

Dale R. Shepard, MD, PhD, can be reached at Department of Solid Tumor Oncology, Cleveland Clinic, Mail Code R35, 9500 Euclid Ave., Cleveland, OH 44195.

Disclosure: Gross, Kemeny, Malik, Paller, Sacher and Shepard report no relevant financial disclosures.

Should the federal government require the percentage of elderly patients enrolled in clinical trials match the treatment’s target population?

Clinical trials should enroll the target population that eventually will be treated with the drugs or interventions being developed.

Although numerous studies have shown that the fit older population derives as much survival benefit from various therapies as their younger counterparts, we typically see increased toxicities among older patients.

It thus becomes imperative to establish whether such toxicities eventually will negate any potential survival benefit, as exemplified by the subset analysis of data pertaining to older patients enrolled in the study on bevacizumab (Avastin, Genentech) in combination with carboplatin and paclitaxel in the treatment of non–small cell lung cancer.

The importance of enrolling sufficient numbers of participants or designing a separate study targeting the geriatric population applies, particularly if cardiovascular, myelosuppressive and neurotoxic toxicities are anticipated — effects that the older population may be more susceptible to based on expected comorbidities typical for this age group.

I don’t foresee a major issue in implementing such a mandate, even though there may be concerns over poor accrual. Studies with good rationale and hypothesis that have specifically included only a geriatric population have historically accrued well.

Nonetheless, the caveat will be that even if the FDA issues a mandate to increase the number of geriatric patients enrolled in studies, other clinical-trial eligibility criteria will likely not be representative of the typical older patient with multiple comorbidities or borderline status. Such patients are typically not included in clinical trials.

Grace Dy, MD, is associate professor in the department of medicine at Roswell Park Cancer Institute. She specializes in lung cancer, mesothelioma and thymic malignancies. She can be reached at Roswell Park Cancer Institute, Elm and Carlton streets, Buffalo, NY 14263. Disclosure: Dy reports no relevant financial disclosures.

The notion that age representation on clinical trials should mirror the age distribution of that diagnosis in the general population, while laudable, is simply unachievable and may ultimately backfire.

Unfortunately, this approach — if it turns into a mandate — runs the risk of holding a trial hostage to unrealistic accrual goals, potentially sabotaging or delaying the development of promising new therapies.

Eligibility criteria for phase 2 and phase 3 clinical trials are usually quite stringent, often leading to a disproportionate exclusion of older patients, who tend to have more comorbidities or compromise in baseline organ function. Even if older patients are eligible, new treatments are frequently quite toxic, and they need to be developed first in a younger, potentially fitter population.

If the newer but more toxic treatment results in a survival advantage in the general population, it may be preferable to evaluate that regimen prospectively and separately in a modified or a dose-attenuated form in the elderly. That would require careful attention to comorbidities, which tend to be more common as patients age, as well as to polypharmacy, which can lead to toxic interactions.

By the same token, regardless of therapeutic venue, clinical trials — when feasible — should stratify by age, with nested analyses of outcome, including response rates, PFS, OS and toxicity based on age distribution.

Ultimately, to address the under-representation of the elderly on clinical trials, it is probably best to launch elderly-specific trials, since the established standard of care in older, more vulnerable populations often differs from the population at large.

Corey J. Langer, MD, FACP, is director of thoracic oncology at the Abramson Cancer Center and professor of medicine at the University of Pennsylvania. He can be reached at Abramson Cancer Center, Hematology/Oncology Division, 3400 Spruce St., 12 Penn Tower, Philadelphia, PA 19104. Disclosure: Langer reports grant/research support from, scientific advisory and speakers’ bureau roles with, and data and safety monitoring committee service with Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Lilly, Merck, Pfizer, Sanofi-Aventis and other pharmaceutical companies.