Working Group 2: Treatment Efficacy and Tolerance

Speaker:
Richard L. Schilsky, M.D., University of Chicago

Co-Chairs:
Richard L. Schilsky, M.D., University of Chicago
Joel E. Tepper, M.D., University of North Carolina School of Medicine

Introduction

Clinical research on cancer is often conducted in individuals who are younger than those in whom the targeted malignancy predominates, and older patients in the NCI Cooperative Group clinical trials represent only a narrow subset of older cancer patients undergoing treatment in the United States. Although information on treatment tolerance and efficacy is very much needed for persons in the age groups in which the cancer primarily occurs (the median age range for most major tumors is 70–74 years at initial diagnosis), the unfortunate reality is that older patients tend not to meet clinical trial eligibility criteria and therefore are not referred to such trials. Other health problems and lack of social support (e.g., transportation, caregiver assistance) also preclude the entry of many elderly patients into these studies. Because so few older patients are enrolled in clinical trials, data from existing trials cannot be generalized to the older population as a whole. As one discussant said, "You have to enter older patients on trial to get data on them; if they do not get on trials, you do not get the data, and therefore, we [i.e., the cooperative groups] undoubtedly do have a very biased subset of elderly patients in clinical trials."

Working Group 2 discussed these issues in the context of promoting collaborative and innovative research and clinical and community applications via the NCI-designated cancer centers on behalf of older persons. With their flexible infrastructure for interdisciplinary research, the cancer centers are an ideal setting for integrating aging and cancer research.

Efforts to obtain information on patient tolerance of cancer therapy can be facilitated through the clinical studies of NCI-designated cancer centers. Some cancer centers have a circumscribed catchment area, virtually all have cancer registries, and all comprehensive cancer centers have an integrated research environment that fosters complex interactions to address the "big picture" problem and specific cancer treatment needs of the elderly.

Research Questions

1. Where, on the spectrum of limited homeostatic mechanisms in older patients, is a particular patient located? How well might a particular patient tolerate the stress induced by prescribed chemotherapy, surgery, or radiation therapy? Are performance status measurement tools available to detect what needs to be known?
2. Are physicians successfully identifying older patients who are more likely to experience toxicity and not entering them in trials? Are older patients treated appropriately with state-of-the-art therapy? Does an age bias exist in the cancer treatment of older patients (i.e., are they medically underserved)?
3. Do ways exist to obtain population-based data on the treatment of older patients? Alternatively, can study parameters be implemented so that patients who are not defined through the trial eligibility criteria are also described? Can the reasons why these patients did not or could not participate in the study (e.g., comorbidity, frailty, lack of functional reserve, doctor and/or patient family decision) be indicated?

Older patients represent a disproportionately large number of those treated for malignancies. Oncologists need to know how therapies will affect older cancer patients with less than ideal health as well as those with good to excellent health. Most older patients have some type of age-related health condition that could affect the cancer course or cancer treatment trajectories. The time course of absorption, distribution, metabolism, and excretion of drugs from the aged host (i.e., pharmacokinetics); the response of the aged host to the anti-cancer drug (pharmacodynamics); the course of radiation treatment; the surgery recommended; and the tolerance of these treatments could be affected by the following:

• The general health status of older patients at the time of cancer diagnosis;
• The presence of moderate to severe comorbid conditions in aged patients; and
• Pathophysiological changes that occur with aging, particularly the decline in functional reserve.

Cancer Center Role

An infrastructure is needed to allow appropriate studies to be conducted in the older population. An organized research structure should incorporate the combined professional skills and experience of gerontologists and oncologists, nurses, social support personnel, and other health professionals. Without this infrastructure, conventional centers are unlikely to be able to perform these studies and the studies' applicability to the population as a whole is likely to be unclear. This effort should also provide the educational programs necessary for a successful research program. Many barriers could be overcome by an organized effort involving the cancer centers.

Research Priorities

1. Develop predictive models for tolerance to therapy. Hypothesis-generating work should be done in focused trials with older cancer patients and should be coordinated by an interdisciplinary team of cancer and aging research specialists in the cancer center research environment.
   • Incremental studies should be organized to focus intensively on issues that are age relevant to toxicities of individual drugs, individual treatment regimens, local therapies, and combinations of therapies to build a knowledge base on functional outcomes of aged patients.
   • Predictive models should incorporate the multiple factors that influence a patient's tolerance for therapy—performance status, preexisting comorbid medical conditions, decreased functional reserve, polypharmacy (i.e., drug-drug interaction), and the social situation (e.g., whether capable caregivers are available).
   • Predictive models should be developed to anticipate adverse effects, such as neurotoxicity from taxanes, renal toxicity, hepatic toxicity, radiation recall, and diarrhea. Better algorithms are needed for prospective dose adjustment for antineoplastic agents in the presence of comorbid conditions and/or age-related physiologic changes.
   • Radiation therapeutic complications associated with dose volume, field size, and scheduling of treatment should be minimized. Predictive methods should be developed to estimate tolerance in older cancer patients based on body composition, size, age, concurrent health problems, kidney function, and other physiologic parameters.
   • Research should be conducted on dose-limiting parameters to predict and avoid risk and severity of short-term and long-term side effects of radiotherapy in older cancer patients.
   • Research on exposure to multiple modalities is needed to assess whether modalities interact to induce increased toxicity.
2. Study tumor-host interactions as a predictor of patient response to therapy. This is complementary to, but distinct from, changes in tumor biology in older patients.
   • What is significant in the older patient's disease and treatment trajectory—such as tumor behavior, treatment-related issues, or unrelated age-associated health problems—needs to be identified. Who should not receive certain types of treatment needs to be determined.
   • Research is needed on how the host reaction to the tumor and/or treatment becomes modified in older patients.
   • Research should address how the tumor reacts to the aged host environment.
   • Key shared predisposing factors to multiple primary tumors should be identified.
   • Phenotypic or genotypic alterations that correlate with therapy resistance or intolerance in older patients should be identified.
3. Develop clinical trials that are specifically designed for older cancer patients. Trials based in cancer centers could address issues that would not (or could not) be addressed in NCI cooperative group randomized clinical trials.
   • A first step is to accept into studies that are solely observational (and, ideally, population based) all patients with certain diseases who are willing, in order to define the issues and acquire valuable baseline data. Investigations could then be broadened to treatment studies that would collect tolerance data and define more precisely the limitations of the present systems. Although certain issues would not be easy to address in the research context of the NCI's large randomized clinical trials, they could be accommodated in the cancer centers environment. Examples include the following:
     • Examine the considerable variations in prostate cancer therapies according to age: younger patients are more likely to receive surgery than older patients, who are more likely to receive radiation treatment. The oldest patients are most likely to receive hormone therapy alone. Data supporting such practices are limited.
     • Ascertain why older glioma patients have poorer outcomes than younger patients.
     • Apply the combined expertise of cancer pharmacology and the physiology of aging to assess the age-dependent differences that influence drug efficacy in selected tumors that primarily affect the elderly.
     • Explore differences in the pharmacokinetics and pharmacodynamics of chemotherapeutic and biologic anti-tumor agents in older and younger patients. Identify the mechanisms for these differences.

Research Barriers

• Insufficient knowledge and bias of medical professionals about proper management of older patients is a barrier to research. Age alone is not a contraindication to standard cancer therapy in most clinical situations.
• Recruiting older patients to clinical trials is difficult.
• Collaboration among gerontologists, geriatricians, and oncologists is limited.
• Research on older patients in clinical practice is time-consuming.
• Social support systems for older cancer patients are inadequate.