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
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,
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.
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
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.