How Do We Get More Older Patients Into Clinical Trials?

March 1, 2007

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.

The aging of the population and the resultant increase in older cancer patients will necessitate a change in the design, implementation, and reporting of clinical cancer trials. Dr. Hurria's paper touches on a number of key points illustrating the important issues involved. As has been amply demonstrated, older patients are underrepresented in clinical trials. Reports from the Southwest Oncology Group, the National Cancer Institute of Canada Clinical Trials Group, and the Food and Drug Administration have shown that older patients are disproportionately underrepresented in clinical trials of diseases that primarily affect them. The reasons for this are multifactorial.

Reasons for Underrepresentation

In the seminal trial evaluating barriers to participation, Kemeny et al in the Cancer and Leukemia Group B found that physician reluctance to enter patients on clinical trials was due to the perception that older patients would experience excessive toxicity.[1] Additional issues were lack of awareness of an available trial, eligibility issues, comorbidity, and tolerance. It has been reported that when older patients are eligible for clinical trials, they do not experience excessive toxicity and they do benefit as much as younger patients.[2-4] The study also showed the need for new clinical trial designs that take into account the problems that are particular issues for the elderly, such as complicated treatment regimens, comorbidity, decline in function, polypharmacy, and the need for increased social supports.

Pharmacologic Considerations

One area of need is the evaluation of the pharmacology of anticancer therapy. The underrepresentation of older patients on trials also has been reflected in the lack of data available on the pharmacology of chemotherapy in the elderly. The importance of these studies is that as we age, a number of physiologic changes occur that can affect pharmacokinetics. The most clinically relevant is the change that occurs in renal function with aging independent of comorbidity.

Dr. Hurria points out problems that can ensue when renal function is not evaluated carefully in the older-patient group. One very important point is that serum creatinine should not be used to evaluate renal function. Various formulae are available for this determination, and a recent review summarizes the data.[5] Comorbidity with advancing renal insufficiency magnifies this problem. A number of excellent studies have evaluated chemotherapy with end-organ dysfunction (renal and hepatic), but more work needs to be done in this setting.[6]

Bone marrow reserve and hematopoietic toxicity has long been an issue in the elderly. The efficacy of hematopoietic growth factors and their incorporation into treatment guidelines have mitigated this problem. Their use has shifted the parameter of dose-limiting toxicity toward nonhematologic events such as neurotoxicity and cutaneous toxicity. The standard toxicity assessments need to be altered in evaluating the older patient.

The future of clinical trials for older patients is strongly tied to the development of simple, easily administered, and predictive comprehensive geriatric assessments (CGAs). Dr. Hurria's paper examines the traditional comprehensive geriatric assessment as it applies to the elderly cancer patient. The author provides detailed coverage of functional status, comorbidity, nutritional status, cognition, social support, psychological state, and polypharmacy. She points out that CGA can be predictive of survival, chemotherapy toxicity, and pain management requirements, and most importantly, uncovers problems not recognized by routine history and physical examination.

Recommendations for Change

The question confronting the entire oncology community is, where do we go from here? Age-specific clinical trials are a necessity. Preliminary work has shown the advantages of this approach.[7] Is this discrimination against younger patients, or a different level of care? I do not think so. While older patients are theoretically eligible for trials, they are not entered, and therefore the data are lacking. We need to think about clinical trials differently. As the paper states, we need to establish novel endpoints for clinical trials. In addition, the entire process needs to be altered. Suggestions to consider include the following measures:

(1) Conduct randomized phase II trials of new agents in groups of patients divided by age. Drugs, which will be primarily used by older patients, should be studied in older patients. These studies should involve pharmacokinetic analysis, and oral medication should include measurements of compliance.

(2) Study using a dose-modification scheme in a phase I fashion, using progressive changes in functional impairment and increasing comorbidity.

(3) Include functional independence as a clinical benefit of cancer treatment in older individuals.

(4) Consider studying long-term functional and medical consequences of cancer treatment in long-term older cancer survivors.

(5) Use some form of CGA, which should be done prospectively and over the course of treatment to correlate with outcome and therapy toxicity.

(6) Eligibility should be altered to include varying degrees of functional limitations, end-organ dysfunction, prior malignancy, and other factors specific to the elderly.

(7) Reporting of all clinical trials needs to be altered. Journal editors should encourage the inclusion of age-related analyses in the reporting of appropriate clinical trials, to provide meaningful information for clinicians caring for older patients.

Much work needs to be done. The epidemiologic shift is upon us, and we must move forward to optimize care for the most vulnerable members of our population and to plan for the further increase in older cancer patients.

—Stuart M. Lichtman, MD, FACP

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.

References:

1. Kemeny MM, Peterson BL, Kornblith AB, et al: Barriers to clinical trial participation by older women with breast cancer. J Clin Oncol 21:2268-2275, 2003.

2. Goldberg RM, Tabah-Fisch I, Bleiberg H, et al: Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol 24:4085-4091, 2006.

3. Sargent DJ, Goldberg RM, Jacobson SD, et al: A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med 345:1091-1097,
2001.

4. Borkowski JM, Duerr M, Donehower RC, et al: Relation between age and clearance rate of nine investigational anticancer drugs from phase I pharmacokinetic data. Cancer Chemother Pharmacol 33:493-496, 1994.

5. Lichtman SM, Wildiers H, Launay-Vacher V, et al: International Society of Geriatric Oncology (SIOG) recommendations for the adjustment of dosing in elderly cancer patients with renal insufficiency. Eur J Cancer 43:14-34, 2007.

6. Ratain MJ, Miller AA, McLeod HL, et al: The Cancer and Leukemia Group B pharmacology and experimental therapeutics committee: A historical perspective. Clin Cancer Res 12:3612s-3616s, 2006.

7. Jatoi A, Hillman S, Stella P, et al: Should elderly non-small-cell lung cancer patients be offered elderly-specific trials? Results of a pooled analysis from the North Central Cancer Treatment Group. J Clin Oncol 23:9113-9119, 2005.