Hematology/Oncology

Approximately 60% of all new cases of cancer occur in patients aged 65 years or older, according to a 1997 report in Cancer. However, research into treating cancer in this age group is sparse, especially since older patients are underrepresented in clinical trials. Defining terms such as “elderly” and “frailty” can even be difficult.

According to the results of a 2004 study published in The Journal of Clinical Oncology, patients aged 65 and older comprised 36% of patients enrolled in clinical trials for cancer, but this age group represents 60% of the total population with cancer.

Older patients often present with comorbidities that affect treatment decisions and prohibit their participation in clinical trials. Diabetes or congestive heart failure are adequate comorbidities to withhold certain treatments from any patient with cancer, regardless of age, according to Lodovico Balducci, MD, division chief of the Senior Adult Oncology program at the H. Lee Moffitt Cancer Center in Tampa, Fla. Age alone, however, is not a comorbid condition.

“Unfortunately, in the past, many older patients have received less treatment than younger patients despite being in overall good health,” Balducci told HemOnc Today. “This is changing due to the recognition that age is a functional aspect, not just a chronological aspect.”

HemOnc Today has spoken with several leaders in senior adult oncology to discuss issues in treating older patients, including what defines elderly, the need for more data and ways to improve overall treatment for the elderly.

According to Balducci, age is defined by physiological and functional changes, rather than by a chronological event. Although the majority of people who are physiologically old are older than 70, not all people older than 70 are elderly, he said.

There are no absolute age cutoffs to define elderly patients, according to Stuart Lichtman, MD, an associate attending physician at the Memorial Sloan-Kettering Cancer Center. It is a matter of differentiating between patients who are resilient enough to receive active therapy as opposed to best supportive care.

“If a patient is older than 80, then most of us will agree that he or she is elderly,” Lichtman said in an interview. “The gray area is patients aged 70 to 80 years.”

Medicare currently defines elderly by age, at 65 years. Sixty-five is also used to define elderly patients in various research databases such as the SEER database.

According to Gary Lyman, MD, a professor of medicine in the division of medical oncology at Duke University, the definition of elderly continues to change, however.

“It is apparent that as populations age, in general, people are more health-conscious, people continue to work and are active well into their 70s,” Lyman said in an interview. “There is no uniform definition of elderly. Many of us use age 70 to define a time where significant physiologic changes start to take place, but the definition of elderly really is a continuum.”

A person is not considered elderly until they have reached a point where they cannot function independently, according to Balducci. He said that age 70 is typically a landmark when many people begin to develop severe comorbid conditions that decrease life expectancy, including the symptoms of geriatric syndrome.

Comorbidities

According to Arti Hurria, MD, the director of the Cancer and Aging Research Program at the City of Hope Cancer Center in Duarte, Calif., many studies have shown that older adults are less likely to receive different types of cancer therapy compared to younger patients. She said there are many possible reasons for this, including patient choice, physician bias about the risks and benefits of therapy, and the concerns regarding increased toxicity.

“A number of factors could come into play here, and the reasons for the disparity in treatment require additional studies,” Hurria told HemOnc Today. “One important variable to consider is access to care.”

Comorbid conditions play a large role in determining treatment for older patients because they can have an effect on life expectancy, Hurria said. The challenge lies in weighing the risk of dying of the cancer vs. the risk of dying from another comorbid illness.

Although heart disease, diabetes and renal insufficiency, among others, have clear influence on determining cancer treatment, frailty is a comorbidity that is difficult to define and often overlooked, according to Lichtman.

Frailty can be defined in several ways, including presentation with geriatric syndromes such as dementia, Lichtman said. Other signs of frailty include a deficiency in the instrumental activities of daily living and changes in gait and/or balance.

“Frailty is the comorbidity that affects this age group the most,” Lichtman said. “The important issue is whether being frail makes an elderly person more vulnerable to the toxicities of chemotherapy. Rudimentary geriatric principles can be incorporated into practice to determine the frailty of a patient.”

According to Hyman Muss, MD, a professor of medicine at the University of Vermont, oncologists need to be trained to recognize the special issues that pertain to older patients. These include frailty and the capability to carry out activities of daily living.

“I always try to make sure I know what my patients can do,” Muss told HemOnc Today. “Do they live by themselves? Do they drive? Can they cook? What is the family structure? The average physical does not encompass these things, but they influence treatment decisions also. A lot of oncologists have not learned this.”

According to Muss, comprehensive geriatric assessments have been helpful in predicting mortality in patients and at finding interventions to help people who have lost certain functions. These assessments evaluate a variety of domains in an older patient: comorbidities, physical function, medications, nutrition, psychological state and social support. According to the CALGB, a self-administered assessment is currently being evaluated in clinical trials, Muss said.

“We hope this is a valid instrument to apply to older patients on a regular basis that may help us predict which older patients are going to have adverse effects to chemotherapy,” Muss said. “If we can predict, we can do more to prevent.”

Comorbidities will weigh treatment decisions regardless of the tumor type, Hurria said. For more aggressive cancers that severely limit a person’s life expectancy, the effects of comorbidity on life expectancy may not be as significant when considering treatment options. With a lesser-risk cancer, comorbid illnesses may have a greater effect on life expectancy than the cancer, Hurria said.

“How do we really counsel patients about their risk for toxicity because of their comorbidities?” Hurria said. “We need to do more research within the older patient population so we can really understand the short- and long-term survivorship issues.”

Clinical trial participation

Despite comprising the majority of the population with cancer, older patients are severely underrepresented in clinical trials, according to Balducci. He said there are two primary reasons for this. First, the inclusion criteria of clinical trials often make an older patient ineligible. Second, there is little motivation to enroll older patients into trials.

In a 2003 study published in The Journal of Clinical Oncology, Lewis et al found that 32% of participants in phase-2 and phase-3 trials were older adults, compared with the 61% of patients with cancer who are older adults. The researchers estimated that if the inclusion criteria of clinical trials were more relaxed and included more patients with comorbidities, the older adult participation in clinical trials would be 60%.

According to Hurria, many physicians are concerned about subjecting their older patients to the potential toxicity related to treatment during a clinical trial. They want to ensure that the treatment risks do not outweigh the potential benefits, Hurria said. As a result, they do not offer clinical trial enrollment to their older patients.

Older patients want to participate, however. According to data published in The Journal of Clinical Oncology in 2003, Kemeny et al found that women older than 65 who had breast cancer were just as likely to accept participation in a clinical trial as women younger than 65. However, only 34% of the older patients were offered clinical trial participation vs. 68% of the younger patients.

“We sometimes forget that cancer is a disease that increases progressively with age,” Lyman said. “If we are not including these patients in the clinical trials, then we are getting a biased picture of proper treatment for the older patients. It is imperative for us to enroll older patients because the results in younger patients may not be generalizable to the majority of older patients.”

Barriers to enrolling older patients in clinical trials range from ineligibility due to comorbidities, to physician bias, to lack of patient understanding. According to a study recently published in the Journal of Oncology Practice, 60% of patients older than 65 reported one or more barriers to enrolling in clinical trials.

The most common barriers were logistical ones, such as traveling to the cancer center. Patients older than 75 were also concerned about being treated in a university cancer center and losing continuity with their oncologist.

“Many older patients are treated in community-oriented settings, so participation in clinical trials can be more of a social issue,” Lichtman said. “The nearest cancer center may not be local, so traveling to participate in a clinical trial is a major burden. The burden is placed not only on the patient but also the patient’s caregivers.”

As for physician bias, this is likely related to physician concerns about protecting their older patients from toxicity and the rigors of clinical trial treatment, according to Hurria.

“In this situation, the physicians are just trying to be good doctors and not cause harm to their patients,” Hurria said. “But the studies show that many older adults want to participate in trials. We need to build safety parameters into our clinical trials so that older adults have access to the same studies that younger patients do.”

Elderly-specific trials

According to Martine Extermann, MD, an associate professor of oncology and medicine at the H. Lee Moffitt Cancer Center and also the president-elect of the International Society of Geriatric Oncology, clinical trials including only older patients are more common in Europe, where age is permitted to be an exclusion criterion for clinical trials.

In the United States, carrying out elderly-specific trials is more of a challenge, but may be the best way to identify ideal treatments for the typical older population, she said.

“If we only do all-age inclusive clinical trials, we ignore a large number of older patients with comorbidities,” Extermann told HemOnc Today. “We currently extrapolate those data into practice, but what we need are trials that lead to real data in real people with the same comorbidities. There is a clear role for elderly-specific trials, especially since the population of older people will only continue to grow.”

Balducci said that one solution is for the FDA to require drug companies to conduct smaller phase-2 studies in older patients as a condition of drug approval. If approximately 30 patients were enrolled in such trials, it would be possible to determine whether a drug is effective and safe in that age group.

Elderly-specific clinical trials are feasible. At the 2008 ASCO Annual Meeting, Muss presented data from the CALGB 49907 trial, one of the largest trials ever conducted in the United States specifically in patients older than 65. The trial included 633 patients, although it did take longer than usual to reach accrual goals, Muss said.

According to Hurria, the questions to be addressed in elderly-specific trials include: What effect does the treatment have on the remaining quality of life? What does the older adult really experience when undergoing treatment? How does the treatment affect their ability to function?

“There are many clinically important questions that can be asked in an elderly-specific trial that can help us guide treatment decisions for our older patients,” Hurria said. “Furthermore, if we found a treatment that is efficacious and had great short-term and long-term tolerability in older patients, we would want to try that treatment in younger patients as well. The idea is that we want every age group to have tolerable and efficacious therapies.”

Nevertheless, older adults should also be enrolled more frequently on non–age-specific trials to make results more generalizable, Hurria said.

Education and future directions

Awareness and training are critical to improving the care of elderly and to increase their enrollment in clinical trials.

“It is a challenge to overcome, but we are doing better,” Muss said. “We need more education for our doctors to make them aware that older patients benefit from treatment and clinical trials. Our younger doctors in fellowship need to learn as well.”

Education, both in medical school and continuing medical education, is necessary for physicians to evaluate patients for physiological age vs. chronological age, according to Balducci. Lyman also said this is a “two-pronged approach.”

Extermann said that all oncologists need to learn at least the basic principles of geriatrics. She suggested cross-training and multidisciplinary efforts between oncologists and geriatricians.

Hurria said that all oncologists are also geriatricians, since the majority of patients with cancer are older adults. Therefore, incorporating elements of the geriatric curriculum in oncology training and CME activities would be invaluable.

Balducci, who is chairman of the panel for the NCCN Senior Adult Oncology Guidelines, said that one of the recommended updates to the guidelines is to recommend that every patient older than 70 undergo a geriatric assessment to assess their physiological age.

“This would be a simple way to help determine whether a patient is fit enough for routine treatment,” Balducci said. “It is a very simple process, and research is being conducted to see if it can serve as a predictor of treatment response as well.”

Lichtman said that all older patients should be initially evaluated just like younger patients, and this should include some form of geriatric assessment. “At the end of the day, you may want to treat the patient differently, but they still need to be evaluated just like a young patient,” Lichtman said. “I see a lot of older patients who are not evaluated properly. Once the diagnosis is made, then you can delve into geriatric issues and determine whether they will tolerate therapy options.”

According to Lyman, continuing research in elderly patients, especially the use of novel targeted agents that are specifically designed to treat with less toxicity, is also crucial to improving elderly care. According to Hurria, the most important thing is to increase clinical research from several perspectives, to understand what is the most efficacious treatment with the least toxicity. The only way to do this is by increasing the enrollment of older adults on clinical trials.

“We are facing a growth in the number of older adults with cancer in the next 30 years,” Hurria said. “We want to make decisions about their treatment in an evidence-based manner. The only way to do that is by rapidly increasing our collaborative research efforts.” – by Emily Shafer

Should there be more elderly-specific clinical trials?

For more information:

• Basche M, Barón AE, Eckhard SG, et al. Barriers to enrollment of elderly adults in early-phase cancer clinical trials. Journal of Oncology Practice. 2008;4:162-170.
• Edwards BK, Howe HL, Ries LAG, et al. Annual report to the nation on the status of cancer, 1973-1999, featuring implications of age and aging on U.S. cancer burden. Cancer. 2002;94:2766-2792.
• Kemeny MM, Peterson BL, Kornblith AB, et al. Barriers to clinical trial participation by older women with breast cancer. J Clin Oncol. 2003;21:2268-2275.
• Lewis JH, Kilgore ML, Goldman DP, et al. Participation of patients 65 years of age or older in cancer clinical trials. J Clin Oncol. 2003;21:1383-1389.
• Talarico L, Chen G, Pazdur R. Enrollment of elderly patients in clinical trials for cancer drug registration: A 7-year experience by the US Food and Drug Administration. J Clin Oncol. 2004;22:4626-4631.