Designing Cancer Trials to Accommodate Older Patients

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.

Dr. Hurria reviews the progress of clinical research in geriatric oncology and highlights future directions. With good reason, she emphasizes the integration of a comprehensive geriatric assessment (CGA) into clinical trials. As she highlights with the example of the capecitabine (Xeloda) trials, there is much that the elderly can teach us about the proper use of anticancer drugs in the general population. Several recent studies have demonstrated that geriatric instruments can be independent and sometimes even stronger or more sensitive predictors of outcome than classic tests such as Eastern Cooperative Oncology Group (ECOG) performance status (PS). Such is the case for example with activities of daily living (ADLs), instrumental activities of daily living (IADLs), co-morbidity, depression, and cognitive impairment.[1-4]

Yet many groups are reluctant to integrate these variables into their data collection for fear of the added workload. Can we ignore a potential confounding factor that has as much weight on outcome as ECOG PS? My answer is that if we are serious about increasing the enrollment of elderly patients into clinical trials, we cannot bypass that information. Until now, only the fit elderly have been integrated into regular trials. Trials with broadened inclusion criteria, if they survived multiple reviews by stakeholders, have been hampered by the reluctance of treating oncologists to subject older patients to "toxic" regimens. Are we condemned then to a vicious circle, or are there ways we can square the circle somewhat? I would like to make a few proposals.

Novel Clinical Trials

First, by integrating a CGA in regular trials, we might learn that our "fit patients" may be more diverse than previously thought, as in the example of the capecitabine studies. Second, specific trials aimed at patients deemed unable to tolerate regular chemotherapy can be conducted. The European Organisation for Research and Treatment of Cancer (EORTC), for example, conducted a trial targeting frail elderly patients with non-Hodgkin's lymphoma ineligible for CHOP chemotherapy (cyclophosphamide, doxorubicin HCl, vincristine [Oncovin], prednisone; P. Soubeyran, personal communication, International Society of Geriatric Oncology conference, Geneva, Switzerland, 2005). The lessons learned have led to a follow-up trial for frail patients based on more evidence-based criteria. A logical step would then be to try to escalate the strength of the regimen in the subgroup of patients who tolerate the first treatment well.

Another approach is to translate the phase I/II type of approach to patient enrollment. A trial with progressively increasing inclusion criteria (PIIC) would allow the controlled assessment of tolerance to treatment in progressively impaired cohorts of patients, using phase I-type criteria. The cohorts could then be pursued in a parallel, phase II-style design, to compare the outcome of treatment in patients with a different health status.

All these approaches will require investigators and review boards to dare to move away from deeply embedded clinical trial designs in a cooperative fashion. This will not be easy in these times of tight finances, but we cannot shy away from the task, confronted as we are with the epidemiologic challenge of an aging US population.

—Martine Extermann, MD, PHD

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. Freyer G, Geay JF, Touzet S, et al: Comprehensive geriatric assessment predicts tolerance to chemotherapy and survival in elderly patients with advanced ovarian carcinoma: A GINECO study. Ann Oncol 16:1795-1800, 2005.

2. Frasci G, Lorusso V, Panza N, et al: Gemcitabine plus vinorelbine versus vinorelbine alone in elderly patients with advanced non-small-cell lung cancer. J Clin Oncol 18:2529-2536, 2000.

3. Callen LJ, Vranas P, Overcash J, et al: Survival and patterns of care in older cancer patients with cognitive impairment. Proceedings of the Annual Meeting of the International Society of Geriatric Oncology. San Francisco, 2004.

4. Maione P, Perrone F, Gallo C, et al: Pretreatment quality of life and functional status assessment significantly predict survival of elderly patients with advanced non-small-cell lung cancer receiving chemotherapy: A prognostic analysis of the multicenter Italian lung cancer in the elderly study. J Clin Oncol 23:6865-6872, 2005.