Clinical trials of agents to prevent cancer in
populations at risk are relatively recent. To date, these consist of a few large
population-based studies. Trials in this area focus on the prevention of cancer
in individuals with specific predetermined risk profiles. Two large
population-based trials have already been launched and have completed accrual.
These include the Breast Cancer Prevention Trial (BCPT-1, or National Surgical
Adjuvant Breast and Bowel Project [NSABP] P-1 trial) of tamoxifen (Nolvadex) in
women at increased risk for breast cancer, and the Prostate Cancer Prevention
Trial (PCPT-1, or Southwest Oncology Group [SWOG]-9217) using finasteride
(Proscar) as the agent in men at risk for prostate cancer.[2-4]
Findings from the BCPT-1 are among the first to demonstrate the benefit of a
chemopreventive agent in reducing cancer incidence in an otherwise healthy,
at-risk population as determined by the Breast Cancer Detection Demonstration
Project model, sometimes called the Gail model. In this study, increased risk
for breast cancer was defined as age 35 years or greater with histologic
evidence of lobular carcinoma in situ or age 35 to 59 years with a minimum
projected 5-year probability of invasive breast cancer at least equivalent to
that of women 60 years of age. Women aged 60 years or greater were eligible
regardless of other breast cancer risk factors. The PCPT-1, although closed to
accrual, will continue to follow participants for up to 7 years or until the
occurrence of prostate cancer before data will be available for analysis. Risk
of prostate cancer in this trial was defined as age 55 years or older, with a
prostate-specific antigen (PSA) no greater than 3.0 ng/mL.
Smaller trials are being conducted that target the prevention of second
cancers in persons already diagnosed and treated for cancer. Few of these
trials, however, include a health-related quality of life (HRQOL) measure. An
important component of the large population-based primary prevention studies is
the inclusion in the study design of measures to assess the impact of the
preventive agent and knowledge of cancer risk on the participant’s HRQOL.
There are several reasons for the small number of population-based cancer
prevention trials. Primary among these is the limited number of agents available
with properties that prevent or interrupt the carcinogenesis process. In
addition, there is heightened concern in such trials about the safety profile of
the agents to be used. Because these agents will be given to healthy individuals
who do not have cancer, assessment of risk/benefit takes on added importance.
Investigators want to be sure that there will be a low incidence of morbidity
associated with prolonged exposure to any proposed agent. This risk, in turn,
must be balanced against the anticipated efficacy of the drug in reducing cancer
incidence or the burden of cancer to society. Finally, prevention trials are
very costly to conduct. Because the end point is a rare occurrence of cancer,
thousands of subjects must be recruited and followed over long periods of time
to show effectiveness. While there has been much discussion of alternative or
surrogate end points (eg, specific biomarkers) for the actual occurrence of
cancer in these trials, there is no agreement on what valid surrogate end points
should be used.
Just as the basic design concerns of prevention trials are different when the
context is primary prevention (in healthy at-risk groups) vs secondary
prevention (in already diagnosed groups), so too is the approach to HRQOL
assessment. Health-related quality of life measures used in the context of
primary prevention trials are most commonly standardized or developed for use in
healthy populations. Because individuals participating in these studies do not
have cancer, and in some cases, may not be at more than age-appropriate risk for
disease, use of cancer-specific scales are often of limited value. In these
settings, it is important to use instruments that will permit comparison of
participants to other healthy samples or those with diverse (noncancer) chronic
illnesses. In addition, any measures used must be sensitive to change over time
since these trials generally follow participants for several years.
As with many other types of clinical trials, HRQOL questions in these larger,
population-based prevention trials can often be answered with a smaller sample
size than required for the principal prevention hypotheses. Thus, accrual to the
HRQOL component may close before that of the larger study. Moreover, it is often
possible for several HRQOL studies, using different subsets of the larger trial,
to be run in parallel. For example, in BCPT-1, in addition to information
collected on the general HRQOL of participants, ancillary studies exploring
participants’ attitudes about the trial and adherence behavior were also
Finally, prevention trials can offer the opportunity to address the effect of
behavioral interventions on participants’ HRQOL and behavior. Research on
issues related to adherence is one example of this type of research. Because
these population-based studies are, by nature, long-term and longitudinal in
design, ensuring that individuals not only participate in, but also follow the
specified agent dosing across the course of the study is necessary to answer the
research question. Measures of the effectiveness of protocol adherence behavior
of both participants and providers, and interventions to improve these could
help maximize the success of the trial in meeting its aims. At the same time,
this information could inform investigators designing new trials about ways to
maximize accrual and retention.
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