Improved trial design, education needed to optimize geriatric oncology care

In the United States, the 65-and-older demographic — which accounts for 56% of cancer diagnoses and 70% of cancer deaths — is projected to nearly double from 43.1 million in 2012 to 83.7 million in 2050, according to census bureau estimates.

That trend poses formidable challenges to the oncology community.

“We are in the midst of a rise in the number of individuals who will be diagnosed with cancer,” Arti Hurria, MD, director of the Cancer and Aging Research Program at City of Hope Comprehensive Cancer Center and HemOnc Today’s geriatric oncology section editor, said in an interview. “This rise in cancer incidence is primarily driven by the aging of the U.S. population and the association of cancer with aging. Hence, oncologists in everyday practice are caring for more and more older adults.”

Consequently, geriatric oncology “is no longer a niche field,” Stuart M. Lichtman, MD, medical oncologist at Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, wrote in Journal of Clinical Oncology. Instead, “all adult oncologists are now geriatric oncologists,” Lichtman wrote.

However, most oncologists are not adequately trained to address the more specialized treatment older patients require.

HemOnc Today spoke with several leading geriatric oncologists about the lack of clinical trial data for older patients with cancer, methods used to avoid the risks associated with polypharmacy and inappropriate medication use in this population, and how the crucial differences between actual and functional age should influence treatment options.

Geriatric assessment

Because cancer care for the geriatric population — typically defined as those aged 65 years and older — is particularly nuanced, each patient requires an individualized treatment plan.

“At every stage in the treatment of older adults, a personalized treatment plan needs to be devised in the context of someone’s preferences, goals and values,” Hurria said. “Without that discussion — and understanding the risks and benefits of a specific treatment — it is very hard to understand why one treatment might be right for one older patient and completely wrong for another. The value they might place on one outcome or another might be very different.”

Photo by Matt Wittmeyer

The care older patients with cancer receive can vary considerably based on whether they are treated by a trained geriatric oncologist or a non-geriatrician, especially regarding supportive care interventions, according to Supriya G. Mohile, MD, MS, associate professor of medicine and director of the geriatric oncology clinic at James Wilmot Cancer Center at University of Rochester.

“Although we are making some progress in the treatment of older adults, there are some significant disparities that persist,” Mohile told HemOnc Today. “Oncologists need to be better equipped to manage not only how to make treatment decisions, but how to offer day-to-day care.”

The geriatric assessment is a key component; however, its use may not be uniform due to time constraints or a lack of resources and expertise.

In an article published in American Family Physician, Elsawy and Higgins outlined how the geriatric assessment differs from standard patient assessments due to the inclusion of nonmedical domains, emphasis on quality of life and functional capacity, and evaluation by a multidisciplinary team. They created a guide to measure an older patient’s functional ability, physical health, nutrition and wellness, cognition and mental health.

The geriatric assessment — which should be used by all physicians who treat older patients with cancer — helps identify a patient’s functional age, which may differ from their chronological age, according to Holly M. Holmes, MD, MS, associate professor and division director of geriatric and palliative medicine at The University of Texas Health Science Center at Houston.

“When an oncologist sees an older patient, the very first paradigm shift they need to consider is that difference between chronological age and physiological or functional age,” Holmes said in an interview. “Older patients are not simply adults who have aged. They are actually patients who have a complete set of challenges that affect their ability to safely complete therapy and their likelihood of benefiting from — or being harmed by — a treatment. At minimum, the ability to use an existing validated tool like those that are part of the geriatric assessment is the way to approach a daily practice that will include a lot of older patients.”

Identification of a geriatric patient’s functional age also may help a physician understand what the patient hopes to achieve through treatment, Peggy Burhenn, RN, MS, CNS, AOCNS, a professional practice leader at City of Hope who specializes in geriatric oncology nursing, told HemOnc Today.

“We sometimes focus on the cancer as if it were the only issue,” Burhenn said. “With geriatric patients and the higher presence of comorbidities and the risk for other geriatric syndromes, that is far from the only issue. I teach nurses to look at the individual and assess what issues are going to matter for that individual, and I hope that will heighten their awareness that caring for older adults involves much more than just managing the cancer.”

The geriatric assessment should be an ongoing process due to issues that may affect a patient’s quality of life throughout treatment.

“Older adults are more prone to issues such as sleep problems, skin breakdown and incontinence than a younger patient, and that is something we need to be aware of and try to intervene to improve care,” Burhenn said. “There are also issues of care that might require more effort from an older patient — or more help from a caregiver — that we wouldn’t normally consider. An older patient may not be able to manage care alone at home, or keep up with medications and appointments.”

The need for specialized care requires the presence of oncologists who are experts in geriatric medicine, according to William Dale, MD, PhD, associate professor of medicine and chief of geriatric and palliative medicine at University of Chicago.

“By necessity, all oncologists have to take care of patients over 65,” Dale told HemOnc Today. “But having said that, there is a select group of patients who are much older, much frailer, or have specific geriatric conditions or functional losses, who are better served by specialists in the field. It functions the same way that other fields need specialists and generalists.”

Polypharmacy and medication use

Older patients often take many prescriptions, and the risks associated with polypharmacy and complications due to inappropriate medication use are magnified among those with cancer.

Clinicians also need to be aware of how different patient populations respond to certain agents.

“There are so many medications that we commonly give in oncology that may not be appropriate for older adults,” Burhenn said. “They can lead to confusion or falls in older patients, but they are commonly ordered by oncologists who may not realize the potential for adverse events in this patient population.”

Ginah Nightingale, PharmD, BCOP, assistant professor of pharmacy practice at Jefferson College of Pharmacy, Thomas Jefferson University, and colleagues assessed medication use among older patients with cancer. Their findings, published this year in Journal of Clinical Oncology, showed more than half of patients included in their study used potentially inappropriate medications — which significantly increased comorbidities (P = .005) — and polypharmacy occurred among 41%. The mean number of drugs taken by study participants was 9.23 (range, 1-30).

“This is a significant geriatric issue,” Nightingale told HemOnc Today. “The more medication a patient takes, the more likely he or she is to be on a potentially inappropriate medication. Oncologists and frontline pharmacists need to conduct comprehensive medication management interventions in this population.”

Dale endorsed what Nightingale called “the brown bag method” of medication management.

“When I meet a patient for the first time, I tell them that the next time I see them, I want them to come in with all of their pill bottles in a bag,” Dale said. “We spend a whole visit lining them up and talking through them. That way, I can say why I would recommend stopping a certain drug or which drug needs to be made a high priority.”

The appropriateness of drug regimens evolves throughout the cancer treatment process.

“Medications that used to be appropriate may no longer be appropriate [after someone is diagnosed] with advanced cancer,” Dale said. “For example, a patient may be taking statin medications for cholesterol issues. If a patient had, say, advanced lung cancer, there is no evidence that keeping them on statins will have any clinical benefit. An aggressive diabetes management regimen may make sense in a patient with a longer life expectancy, but not necessarily among patients whose life expectancy is reduced.”

Other factors related to older age — such as decreased appetite or mobility — may contribute to drug interactions, Mohile added.

“In clinical practice, I may have an older patient with advanced cancer who is on three drugs for blood pressure and a diabetes drug, and maybe he is not eating very well,” Mohile said. “They can become hypertensive or hypoglycemic and eventually wind up in the ER. We have to be aware of those issues.”

Because older patients sometimes have underlying cognitive impairment, common drugs administered during chemotherapy may trigger adverse events.

“Medicines that we use as standard of care for nausea during chemotherapy, like Benadryl, could cause delirium,” Mohile said. “It is standard protocol to administer these drugs, but many of our patients encounter problems. Unfortunately, in these cases we just do not have a lot of other options.”

Incorporating oncology pharmacists into decision-making processes can improve medication management.

“Oncology care is undergoing significant transformation in the delivery of effective clinical services and is ripe for greater engagement of pharmacists to reduce drug-related problems and unnecessary medications, optimize medication prescribing and provide patient medication counseling,” Nightingale said. “Well-designed, interprofessional, collaborative medication management interventions are needed to continuously manage medication use in this population.”

Mohile acknowledged this is not always realistic in community practices.

“In many of the geriatric oncology clinics in academic centers, there is an integrated pharmacist who reviews the drugs to make sure that there are no interactions,” she said “We discuss management, adherence and compliance, as well as a host of other issues with the patient. In the community, there are not necessarily available pharmacists to do this, or the pharmacists are separated and it does not happen as often. In those cases, it is important for the oncologist to know what drugs their patients are on and what could become an issue.”

Clinical trials

Existing data may not be generalizable to geriatric patients with cancer because they often are inadequately represented in clinical trials.

FDA guidelines released in 1989 stated “the population studied should reflect the population likely to be treated.” However, multiple studies suggest that rarely is the case.

Talarico and colleagues retrospectively reviewed demographic data of 55 registration trials conducted between 1995 and 2002 that included more than 28,000 patients with cancer. Their findings, published in Journal of Clinical Oncology, showed trial representation was significantly lower than corresponding rates of the U.S. cancer population for patients aged 65 years and older (36% vs. 60%), 70 years and older (20% vs. 46%), and 75 years and older (9% vs. 31%; P < .001 for all).

A paper by Hurria and Kevin S. Scher, MD, MBA, published in 2012 in Journal of Clinical Oncology, showed the trend has continued. Twenty-four drugs received approval for cancer treatment between 2007 and mid-2010. Package inserts showed only one-third of patients included in registration trials for those agents were aged 65 years or older, even though individuals in that age group accounted for an estimated 59% of patients with cancer during that time.

Researchers have provided several explanations — including comorbid conditions, lack of understanding, lack of social and home support, and unfavorable risk–benefit ratios — but experts suggest the disparities will continue until clinical trial design changes dramatically.

“We often don’t aggressively push our clinical trial designs in a way that helps us specifically answer the question of how treatment will be received by older patients,” Holmes said. “The approach has been that we should encourage factors like broader inclusion criteria. But, our strategy should be to simply say that the clinical trial world is best suited to help us address the questions for which we need answers to have good evidence for treating older patients. Really, it is a philosophical shift.”

ASCO issued two position statements — published in July in Journal of Clinical Oncology — regarding the inclusion of older adults in clinical trials. Hurria, Dale and Mohile served as authors on the statements.

The recommendations included the use of clinical trials to improve the evidence base for treating older adults; the use of research design and infrastructure to improve the evidence base; increasing the FDA’s authority to incentivize and require research that includes older adults; using clinician recruitment to enroll older adults in clinical trials; and using journal policies to incentivize researchers to consistently report on age distribution and health-risk profiles of trial participants.

The limited enrollment of older patients in FDA registration trials leads to a dearth of data in the package insert about the risks and benefits of that drug in older adults, Hurria said. The ASCO position statements sought to correct this and improve the information available that is used to recommend therapies for FDA approval.

“If a drug is going to be approved based on study results from a younger population than those with the disease, there needs to be additional studies to inform the data on geriatric usage. Often that section of the package insert has very limited data,” Hurria said. “The call to action here is an improvement on the data that is used to get drugs approved, so that doctors know the proper dosage and toxicity profile for an older patient.”

Similar research guidelines have been successful in improving the information about cancer therapies in pediatric patients, Hurria said.

“The Pediatric Research Equity Act provided drug companies with the incentive to study their drugs in pediatric patents to gain patent extensions, which led to improvements in evidence-based data for treating pediatric patients,” Hurria said. “The same is needed for geriatrics. If all oncologists are geriatric oncologists, then we need the education and training as well as the dosing information for commonly used drugs, because geriatric patients — like pediatric patients — are a vulnerable population.”

Clinical trial endpoints also are a factor, because those typically used may not be as relevant to the older population.

In a joint position article prepared by three entities — European Organization for Research and Treatment of Cancer, Alliance for Clinical Trials in Oncology and International Society of Geriatric Oncology — Wildiers and colleagues wrote that disease-specific survival should be included in oncology clinical trials of older adults to account for deaths due to other causes. The statement also recommended the use of composite endpoints, randomized or phase 2 studies that focus on efficacy and toxicity in older patients, and the requirement of a geriatric assessment for all patients.

“For young patients with familial/social obligations (eg, toward young children), prolongation of life might be the most important endpoint; however, older adult patients with incurable disease may prefer quality of life above quantity of life, especially if treatment also has an impact on their functional capacity and ability to carry out daily tasks, their cognitive function, their social situation/capability to stay at home, or their caregiving abilities,” Wildiers and colleagues wrote. “Therefore, there is a need for delineation of relevant clinical endpoints for older individuals, which can then be uniformly incorporated into future clinical trials.”

FDA regulations to address these issues could broadly and permanently change the landscape of oncology trials.

“We should use [the existing] infrastructure to conduct trials using older patients, whether the trial is specifically geared toward older patients or whether we are adding on companion arms,” Holmes said. “The ASCO recommendation asking the FDA to require older patient participation would be the most effective way to change how industry-funding bodies think about studying and releasing new agents. It would be a big step to change this culture if the FDA would say that it is not enough to relax criteria or not be exclusionary, but that we want to incentivize trial design to benefit older patients.”

The position statement, although ambitious, represents an essential turning point, Hurria said.

“Our recommendations are very achievable,” Hurria said. “However, their implementation is going to require patients and the oncology community banding together to make them a reality.”

Education, advocacy

As the population continues to age, concerns regarding the treatment of older patients with cancer likely will only grow. Better understanding of the needs of older patients — and how they differ from the general adult population — will continue to be vital to effective cancer care.

Education can help meet this need.

“Additional training is needed across the board,” Hurria said. “It is needed in the entire spectrum of care, not just when we are faced with end-of-life decisions.”

Mohile agreed.

“A younger trainee might get a boards or exam question about treatment options for a patient with colon cancer, and in the question scenario, the patient is 50 years old,” Mohile said. “But that question does not represent the majority of patients with colon cancer. So, we should write the question as someone who is 75 years old. Those kinds of simple things will make people more aware of what they are going to have to do in clinical practice.”

The engaged treatment and monitoring required for older patients may necessitate patient advocate networks.

“Some of our patients may not have family support, or they may live in a remote community that makes it difficult for them to get to treatment or undertake simple everyday tasks,” Burhenn said. “Sometimes older patients may be lonely and need someone to talk to and check up on them, whereas younger patients might have a more central family structure. It is important to focus on the social situations of these patients, as well as their medical care.”

Part of understanding geriatric oncology practice is recognizing which patients require extra care due to cognitive or physical deficits, Holmes said. Professional systems designed to help advocate for older patients may address this unique problem.

“Patients who can advocate for their own unique care are probably the least vulnerable,” Holmes said. “I worry about the patients who are unable to advocate for unique care, because they are the most likely to not receive personalized geriatric care. For a patient who is unable to advocate for themselves, it is critical to have a family member or representative with them at appointments to help them understand what the treatment plan is, or what the outcomes might be. Whether there are systems in place that can assist in patient advocacy is an area of extreme variation, but it is an area of need.”

Moving forward, the best treatment outcomes will occur when general oncologists and geriatric specialists work together.

“The oncology community sometimes is not aware of what is available in the aging community,” Dale said. “All oncologists should have basic skills for taking care of these patients, but I don’t know that we can expect them to be experts in every cognitive impairment or geriatric syndrome.” – by Cameron Kelsall

References:

Elsawy B and Higgins KE. Am Fam Physician. 2011;83:48-56.

Hurria A, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2015.63.0319.

Jemal A, et al. CA Cancer J Clin. 2011;doi:10.3322/caac.20107.

Lichtman SM. Am Soc Clin Oncol Educ Book. 2015;doi:10.14694/EdBook_AM.2015.35.e127.

Lichtman SM. J Clin Oncol. 2015;doi:10.1200/JCO.2014.60.3548.

Magnuson A, et al. Curr Geriatr Rep. 2014;doi:10.1007/s13670-014-0095-4.

Mohile S, et al. Cancer Forum. 2013;37:216-221.

Nightingale G, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2014.58.7550.

Scher KS and Hurria A. J Clin Oncol. 2012;doi:10.1200/JCO.2012.41.6727.

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

U.S. Census Bureau. An aging nation: The older population in the United States. Available at: www.census.gov/library/publications/2014/demo/p25-1140.html. Accessed on Sept. 11, 2015.

Wildiers H, et al. J Clin Oncol. 2013;doi:10.1200/JCO.2013.49.6125.

For more information:

Peggy Burhenn, MS, RN, CNS, AOCNS, can be reached at City of Hope, 1500 E. Duarte Road, Duarte, CA 91010; email: pburhenn@coh.org.

William Dale, MD, PhD, can be reached at The University of Chicago Medicine, 5841 S. Maryland Ave., MC 6098, Chicago, IL 60637; email: wdale@medicine.bsd.uchicago.edu.

Holly M. Holmes, MD, MS, can be reached at The University of Texas Health Science Center, 6431 Fannin, MSB 5.116, Houston, Texas 77030; email: holly.m.holmes@uth.tmc.edu.

Arti Hurria, MD, can be reached at City of Hope, 1500 E. Duarte Road, Duarte, CA 91010; email: ahurria@coh.org.

Supriya G. Mohile, MD, MS, can be reached at University of Rochester Medical Center, School of Medicine and Dentistry, 601 Elmwood Ave., Box 704, Rochester, NY 14642; email: supriya_mohile@urmc.rochester.edu.

Ginah Nightingale, PharmD, BCOP, can be reached at Thomas Jefferson University, 130 S. 9th St., Suite 1540, Philadelphia, PA 19107; email: ginah.nightinhale@jefferson.edu.

Disclosure: Hurria reports research funding from Celgene and GlaxoSmithKline, as well as consultant roles with Boehringer Ingelheim, GTx and OnQ Health. Burhenn, Dale, Holmes, Mohile and Nightingale report no relevant financial disclosures.

 

 

Should older patients with colorectal cancer undergo adjuvant chemotherapy?

Selected elderly patients with stage III colon cancer benefit from adjuvant chemotherapy.

Colorectal cancer (CRC) is one of the leading causes of cancer-related death in the elderly. Because there are no clear treatment guidelines, however, elderly patients with CRC tend to be understaged and undertreated. Adjuvant chemotherapy has a role in patients with stage III and high-risk stage II colon cancer. However, older patients are less likely to receive postoperative chemotherapy than younger patients because of the concern for toxicity.

Between 1990 and 2004, postoperative chemotherapy with leucovorin-modulated 5-FU (5-FU/LV) was the standard of care for stage III colon cancer, based on a 26% relative reduction in mortality compared with surgery alone (Gill S, et al. J Clin Oncol. 2004;doi:10.1200/JCO.2004.09.059.). Further, 5-FU/LV adjuvant chemotherapy seems to be as beneficial in older patients in terms of DFS and OS as it is in younger patients. In a population-based cohort study of patients aged older than 67 years with stage III colon cancer, the survival benefit of 5-FU/LV adjuvant chemotherapy did not diminish with chronologic age (Iwashyna TJ, et al. J Clin Oncol. 2002;doi:10.1200/JCO.2002.03.083.). In a pooled analysis of patients with resected colon cancer, the relative benefit on both OS and time to tumor recurrence from adjuvant chemotherapy was similar across all age groups, with no increased incidence of toxicities among patients 70 years or older, except for leukopenia in one study (Sargent DJ, et al. N Engl J Med. 2001;doi:10.1056/NEJMoa010957.). Oral fluoropyrimidine capecitabine can be an effective alternative to 5-FU/LV in the adjuvant setting. In a randomized phase 3 study of capecitabine vs. bolus 5-FU/LV (Mayo Clinic regimen), capecitabine showed an equivalent DFS to 5-FU/LV and was associated with significantly fewer adverse events (Twelves C, et al. N Engl J Med. 2005;doi:10.1056/NEJMoa043116.).

In 2004, the MOSAIC trial demonstrated that the addition of oxaliplatin to 5-FU/LV improved DFS and OS in patients with stage III colon cancer. However, the benefit of adding oxaliplatin to 5-FU/LV (FOLFOX) for elderly patients is controversial. The subset analyses of the NSABP C-07 trial found that the addition of oxaliplatin to 5-FU/LV yielded no survival benefit in patients aged older than 70 years with stage II or III colon cancer, with a trend toward decreased survival (Yothers G, et al. J Clin Oncol. 2011;doi:10.1200/JCO.2011.36.4539.). In the subset analyses of the MOSAIC trial, patients aged 70 to 75 years with stage II or III colon cancer showed a lack of survival benefit from the addition of oxaliplatin (Tournigand C, et al. J Clin Oncol. 2012;doi:10.1200/JCO.2012.42.5645.). With no data from prospective studies, adjuvant chemotherapy with oxaliplatin-containing regimens needs to be considered on an individual basis for elderly patients.

Overall, selected elderly patients with stage III colon cancer can obtain the same benefit from adjuvant chemotherapy with 5-FU/LV or capecitabine as their younger counterparts, without a significant increase in toxicities. Therefore, advanced age alone should not be the only criteria to preclude effective adjuvant chemotherapy in elderly patients with CRC.

 

Jung Han Kim, MD, PhD, is associate professor in the division of hemato-oncology in the department of internal medicine at Kangnam Sacred-Heart Hospital and Hallym University Medical Center in Seoul, South Korea. He can be reached at harricil@hallym.or.kr. Disclosure: Kim reports no relevant financial disclosures.

The evidence base for therapeutic decision-making in older patients remains limited.

Along with the ever-increasing number of elderly patients in routine practice, there is an increasing proportion who are fit for treatment and an increasing expectation that standard treatments will be offered. Although oncologists are well aware that therapies shown to improve outcomes in the carefully selected patient population enrolled on clinical trials should be offered to older patients, they are also acutely aware that these treatment options may not benefit or may even harm the individual elderly patient in front of them.

Subset analyses of clinical trials indicate that elderly patients with colon cancer benefit from adjuvant 5-FU to a similar extent as younger patients and that treatment is reasonably well tolerated (Sargent DJ, et al. N Engl J Med. 2001;doi:10.1056/NEJMoa010957). More recent studies, where oxaliplatin was added to 5-FU, found no benefit from the addition of oxaliplatin in patients aged older than 70 years (Andre T, et al. N Engl J Med. 2004;doi:10.1056/NEJMoa032709.; Yothers G, et al. J Clin Oncol. 2011;doi:10.1200/JCO.2011.36.4539.), suggesting 5-FU alone is the standard for adjuvant therapy treatment in older patients. Despite this, routine care studies have repeatedly shown that a significant proportion of elderly patients do not receive treatment. Many have interpreted this as under-treatment driven by age alone; however, 92.6% of surveyed U.S. oncologists indicated they would recommend treatment for a fit 80-year-old patient with stage III colon cancer (Keating NL, et al. J Clin Oncol. 2008;doi:10.1200/JCO.2007.15.9434.). There was much less enthusiasm for treatment in the presence of comorbidities. Consistent with this, a series analyzing prospectively collected point-of-care data found that comorbidity was the dominant reason older patients were not offered treatment in a routine care setting (Moore M, et al. J Clin Oncol. 2010;28:e36-e37.). Overall, it appears that comorbidity — which increases with age — is the dominant driver of non-treatment rather than age itself. Also in the series by Moore and colleagues, older patients were more likely to decline a recommended treatment, including 20% of those older than 75 years, so patient preference is also a significant contributor to non-treatment.

Although including more elderly patients on clinical trials is critical, conducting adjuvant therapy studies that are limited to the elderly population and have broader entry criteria should also be strongly considered, as has been done in the advanced disease setting (Seymour MT, et al. Lancet. 2011;doi:10.1016/S0140-6736(11)60399-1.; Aparicio T, et al. J Clin Oncol. 2013;doi:10.1200/JCO.2012.42.9894.). Such studies ensure adequate sample sizes and sufficient statistical power to carefully examine treatment impact. Molecular analysis should also be routinely included in any future studies — of particular relevance to the elderly are the increasing rates of microsatellite instability and BRAF mutations associated with advancing age, with both appearing to impact prognosis and treatment benefit.

The value of multidisciplinary care in medical oncology is increasingly recognized, reflecting that input from multiple experts and disciplines provides the optimal method of tailoring treatment advice to individual patients. In the elderly patient, comprehensive geriatric assessment could inform the multidisciplinary team decision by predicting life expectancy and the potential benefit and risk from a selected intervention, including adjuvant chemotherapy. Working alongside disease subspecialists as part of the multidisciplinary team, the geriatric oncologist could make a major contribution to improving the care of each elderly individual.

Peter Gibbs, MBBS, MD, is a medical oncologist and senior staff specialist at Royal Melbourne Hospital and Western Hospitals in Australia. He can be reached at peter.gibbs@mh.org.au. Disclosure: Gibbs reports no relevant financial disclosures.