Ernest T. Hawk, MD, MPH
Chief
Ellen S. Richmond, MS, RN
Clinical Trials Nurse Specialist
Jaye L. Viner, MD, MPH
Program Director
Gastrointestinal & Other Cancers Research Group
Division of Cancer Prevention
National Cancer Institute
National Institutes of Health
Bethesda, Maryland
Clinical trials for cancer prevention pose unique challenges. In addition to the usual uncertainties of clinical research - including timely accrual of appropriate cohorts, access to promising interventions, and rigorous collection of efficacy and safety data - cancer prevention faces other challenges as well. Foremost among these is the controversy surrounding short- and long-term goals of cancer prevention trials, which arises in part from the probabilistic nature of biology and the length of time required to observe "hard" clinical endpoints. Although these and other hurdles limit commercial interest and investment in cancer prevention, they are readily offset by opportunities arising from our growing understanding of molecular carcinogenesis. This knowledge - once translated into clinical trials and then into medical practice - will revolutionize the way we define and manage carcinogenesis.
In light of their projected impact on clinical care and public health, clinical prevention trials are critical to our progress against cancer. Clinical intervention trials are designed to demonstrate a significant difference in the number of events per time period, either within a group treated with an investigational agent (i.e., before versus after treatment) or across different treatment arms. Investigators exploit the three cardinal elements of trial design - cohorts, endpoints, and agents - in order to reveal such differences. Among these three elements, a focus on cohorts and endpoints has the best likelihood of accelerating near-term progress in clinical cancer prevention and to stimulate commercial investment.
Cohorts
Cohorts for clinical prevention trials include persons at risk for cancer owing to endogenous and/or exogenous risk factors. Trials in high-risk individuals focused on biology intrinsic to carcinogenic progression are critically needed to identify and prioritize promising leads before embarking on larger and longer-term trials. For example, studying individuals with germline mutations that place them at high cancer risk may achieve statistical significance with fewer than 100 participants exposed to an investigational agent for as little as a few months. By contrast, demonstrations of agent efficacy in more heterogeneous or lower-risk cohorts typically require larger sample sizes and/or longer observation periods. These broad-scale trials may better reflect the general population, but at a prohibitive cost. In effect, the costs (i.e., staff, infrastructure, available cohort, and research opportunities) and time required for such studies limit our options to conduct other studies. In an environment of increasingly limited resources, studies of heterogenous cohorts require massive trials that preclude the conduct of several smaller trials in more homogeneous cohorts. Keeping pace with the growing number of competing hypotheses requires focused research informed by biologic principles that determine risk and disease and which should logically drive agent development as well.
Endpoints
Long follow-up times provide an effective though costly and cumbersome approach to acquiring the requisite number of neoplastic events. Alternative approaches exist, but may require different infrastructures for clinical research. For example, rather than waiting for clinical declarations of disease, sensitive technologies such as endoscopy offer opportunities to identify disease earlier in the course of carcinogenesis. In addition, within-person (rather than between-person) comparisons may provide important efficiencies in terms of disease homogeneity and trial cost. Intermediate endpoints arguably offer the most important insights and efficiencies. Although they remain a surprisingly contentious issue, biologically mature lesions such as intraepithelial neoplasia (IEN) have been conclusively established as a legitimate focus of screening, intervention, and medical reimbursement in many settings. Indeed, more than 10 drugs have been approved for the treatment of IEN - mostly within the last 5 years.(2) Therefore, while an element of uncertainty remains, a path forward is suggested.
Conclusion
Associations between early and late neoplastic events are probabilistic, owing to the temporal nature of biology. Consequently, useful chemopreventives are likely to achieve relative and partial effects, which nevertheless may represent clinically meaningful gains for individuals as well as for the general population. One of the greatest challenges facing cancer prevention is its acceptance as an achievable goal on a par with - if not preferable to - cancer treatment. This acceptance will entail commitment from the general public, investigators, medical practitioners, regulators, industry, and third-party payers.
Compelling scientific evidence for cancer prevention argues for implementing today's technologies while recognizing their limitations. The challenge, of course, is knowing which technologies to use and when; and accepting that certain transitional tools offer valuable - albeit incomplete - solutions, along with incentive for iterative improvements. Other medical disciplines have implemented reasonably validated technologies, rather than waiting for reductions in late events. Clinical prevention in cardiovascular disease is the classic demonstration of this principle. By employing progressively better tools for the treatment of risk factors for late-stage events (i.e., myocardial infarction [MI] or MI-related death, cerebrovascular accidents [CVA] or CVA-related death), rather than exclusively treating late events, they successfully shifted emphasis from treatment to prevention. This approach is described in the following report from 1981:
"This committee previously recommended, and the Food and Drug Administration (FDA) concurred, that approval of lipid altering agents should be based on a drug's biochemical efficacy in decreasing serum lipids. Attempts to establish clinical efficacy in the prevention of coronary artery disease or other manifestations of atherosclerosis, would require prolonged observations and hamper research and development of this class of drugs."(3)
Through the use of emerging technologies, certain risk factors such as hypertension, hyperlipidemia, and asymptomatic stages of atherosclerosis became accepted by medical practitioners and the public as subclinical diseases worthy of identification, intervention, and reimbursement in and of themselves. Indeed, data show that cardiovascular mortality has been dropping since this approach was adopted a decade ago.
The central tenet of the Hippocratic oath - "first, do no harm" - is generally assumed to refer to action, however it clearly applies to inaction as well. This principle is most readily evident in clinical practice, however it applies equally well to the research enterprise. Each insight into carcinogenesis and advance in cancer prevention demands careful reassessment of the next generation of clinical trials. Our challenge is to capitalize on this tension, rather than allow it to inhibit our innovation.
References
- Weinstein MC, Fineberg HV. Clinical Decision Analysis. Saunders, London, 1980.
- Viner JL, Hawk E, Lippman SM. Cancer chemoprevention. In Cancer Epidemiology and Prevention (David Schottenfeld and Joseph F. Fraumeni, Jr. eds). Oxford University Press, New York, 2004; (In press)
- Minutes of the Endocrinologic and Metabolic Drug Advisory Committee - 10/15/81. Rockville, MD, Food and Drug Administration, 1981, p 16, FDA Document No. F82-25307.
