Will Current Clinical Trials Answer the Most Important Questions About Prostate Adenocarcinoma?

Outlined in the article by Thompson and Seay are a series of questions relevant to the
spectrum of stages of prostate cancer ranging from prevention to the treatment of advanced disease. Given the prevalence of prostate cancer, the morbidity of the disease, and the death rate from prostate cancer of more than 40,000 men in the United States each year, these questions warrant answers as soon as possible.

Accompanying the questions are tables listing existing clinical trials and their sponsors. Although the list seems long, actually there are many more pharmaceutical industry supported trials ongoing which are not listed. Regardless, clinical trials represent the one and only vehicle by which we can answer the important questions posed by Thompson and Seay. Well designed randomized trials are the gold standard by which we determine the efficacy, toxicity and comparative value of two therapeutic approaches. Phase III trials involve hundreds of patients, take years to design, conduct and analyze, they are expensive and they often raise as many questions as they answer. However, for progress to occur, they are critical. All too often, therapies are being applied based on unsubstantiated claims, anecdotes, slick advertising campaigns and the desperate hopes of the disease's victims.

Deterrents to Participation

In the United States, only a small percentage of all cancer patients, including prostate cancer patients, participate in clinical trials thus slowing the accrual and completion of trials. Insurance companies, HMOs and government agencies such as Medicare often balk at covering patients on clinical trials. This lack of coverage or even just the fear of losing coverage are significant deterrents to patient entry in trials. Recent agreements by the NCI with other government enti
ties such as the VA and CHAMPUS are positive steps forward. Medicare, Medicaid, private insurance and HMOs will hopefully follow, for in the long run, evidence based therapy will benefit the insurers, as well as patients.

Another deterrent to patient participation in clinical trials is the all-too-common view that entry in a trial means that they are "guinea pigs." On the contrary, it would seem that receiving "standard" therapies whose efficacy may be marginal or questionable, whose toxicities are significant, and which might actually be inferior to other available therapies, offers greater risks to a larger number of patients than receiving new therapy under controlled conditions in an effort to generate new data upon which better therapies might be based. Since many circumstances in prostate cancer represent unanswered questions for which no "standard" therapy exists, participation in a clinical trial should be the standard of care, not the exception.

For those patients who wish to participate in a trial, availability and access can be a problem. Trials need to be more accessible to patients and their doctors. Although phase I trials usually require intensive monitoring and close interaction with analytical and pharmacology facilities, many phase II and virtually all phase III trials involve therapies familiar to most practitioners. The issues are data collection and quality control, both of which are made easier in the current electronic age. Since complicated designs dampen participation, many crucial questions could be answered with large simple trials made available to as many patients and their caregivers as possible. Coordination between scientific groups, patients, caregivers and insurers would accelerate completion of trials. Realistically, an increase in patient participation to even 10% would result in answers to the questions posed in a much shorter period.

Endpoints and the PSA Controversy

Next, endpoints of clinical trials must be clearly defined, and they must be appropriate for the question being asked. In prostate cancer, we have a disease which is assessable using bidimensional measurements only in the minority of patients. Survival remains an important and definable endpoint, but in studies on early stages of prostate cancer, the use of survival means a conclusive answer to a question can take many years. Quality of life and pain assessments are relevant endpoints with real impact on patient lives. While these endpoints have been traditionally difficult to measure, validated instruments to measure these endpoints are emerging from recently completed trials. The most controversial endpoint is the use of PSA as a surrogate to assess disease state. The use of PSA as a screening tool has been discussed in previous articles in this journal. In addition, it is a useful indicator of recurrent disease after a prostatectomy. However, its use to assess response to therapy in advanced disease can be problematic. Standardization of the use of PSA, the frequency of its measurement, rate of change and extent of rise or decrease as related to treatment response must be carefully and consistently defined to make trials and therapies more comparable.

To complicate issues even further, many new agents, especially those with differentiating properties such as phenyl butyrate, perillyl alcohol(Drug information on alcohol), vitamin D analogs, and retinoids, can modulate
PSA production or secretion by prostate cancer cells in vitro. If these agents are successful in clinical trials, they might actually raise PSA levels in vivo rendering this surrogate marker useless. Thus, for the questions raised by Thompson and Seay to be answered through clinical trials, care must be taken to design trials with endpoints that will answer the questions. More work needs to be done to develop, assess and validate new endpoints.

Summary

Finally, the road to new therapies must be paved with new scientific information and the development of therapies aimed at molecular targets. Funding for prostate cancer research has increased substantially in the past 10 years. New initiatives by the US Army, the American Cancer Society, and other private groups such as Michael Milken's CaPCURE will provide additional momentum to find answers to the questions in the Thompson and Seay article. Even more is needed to accelerate the progress towards finding effective therapies.

Clearly the process from scientific inquiry, to preclinical and clinical testing to clinical application is long and tortuous under the best of circumstances. Efforts to inform patients and practitioners of ongoing clinical trials and the questions they are designed to answer as outlined in the Thompson and Seay article are necessary and laudable.