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

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

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

Deterrents to Participation

In the United States, only a small percentage of all cancer patients,including prostate cancer patients, participate in clinical trials thusslowing the accrual and completion of trials. Insurance companies, HMOsand government agencies such as Medicare often balk at covering patientson clinical trials. This lack of coverage or even just the fear of losingcoverage are significant deterrents to patient entry in trials. Recentagreements 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 theall-too-common view that entry in a trial means that they are "guineapigs." On the contrary, it would seem that receiving "standard"therapies whose efficacy may be marginal or questionable, whose toxicitiesare significant, and which might actually be inferior to other availabletherapies, offers greater risks to a larger number of patients than receivingnew therapy under controlled conditions in an effort to generate new dataupon which better therapies might be based. Since many circumstancesin prostate cancer represent unanswered questions for which no "standard"therapy exists, participation in a clinical trial should be the standardof care, not the exception.

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

Endpoints and the PSA Controversy

Next, endpoints of clinical trials must be clearly defined, and theymust be appropriate for the question being asked. In prostate cancer, wehave a disease which is assessable using bidimensional measurements onlyin the minority of patients. Survival remains an important and definableendpoint, but in studies on early stages of prostate cancer, the use ofsurvival means a conclusive answer to a question can take many years. Qualityof life and pain assessments are relevant endpoints with real impact onpatient lives. While these endpoints have been traditionally difficultto measure, validated instruments to measure these endpoints are emergingfrom recently completed trials. The most controversial endpoint is theuse of PSA as a surrogate to assess disease state. The use of PSA as ascreening 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 canbe problematic. Standardization of the use of PSA, the frequency of itsmeasurement, rate of change and extent of rise or decrease as related totreatment response must be carefully and consistently defined to make trialsand therapies more comparable.

To complicate issues even further, many new agents, especially thosewith differentiating properties such as phenyl butyrate, perillyl alcohol,vitamin D analogs, and retinoids, can modulate
PSA production or secretion by prostate cancer cells in vitro. If theseagents are successful in clinical trials, they might actually raise PSAlevels in vivo rendering this surrogate marker useless. Thus, for the questionsraised by Thompson and Seay to be answered through clinical trials, caremust 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 scientificinformation and the development of therapies aimed at molecular targets.Funding for prostate cancer research has increased substantially in thepast 10 years. New initiatives by the US Army, the American Cancer Society,and other private groups such as Michael Milken's CaPCURE will provideadditional momentum to find answers to the questions in the Thompson andSeay article. Even more is needed to accelerate the progress towards findingeffective therapies.

Clearly the process from scientific inquiry, to preclinical and clinicaltesting to clinical application is long and tortuous under the best ofcircumstances. Efforts to inform patients and practitioners of ongoingclinical trials and the questions they are designed to answer as outlinedin the Thompson and Seay article are necessary and laudable.