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The Prostate Cancer Intervention Versus Observation Trial (PIVOT)

The Prostate Cancer Intervention Versus Observation Trial (PIVOT)

ABSTRACT: The Prostate Cancer Intervention Versus Observation Trial (PIVOT) is a randomized trial designed to determine whether radical prostatectomy or expectant management provides superior length and quality of life for men with clinically localized prostate cancer. Conducted at Department of Veterans Affairs and National Cancer Institute medical centers, PIVOT will enroll over 1,000 individuals less than 75 years of age. The primary study end point is all-cause mortality. Secondary outcomes include prostate cancer- and treatment-specific morbidity and mortality, health status, predictors of disease-specific outcomes, and cost-effectiveness. Within the first 3 years of enrollment, over 400 men have been randomized. Early analysis of participants' baseline characteristics indicate that enrollees are representative of men diagnosed with clinically localized prostate cancer throughout the United States. Therefore, results of PIVOT will be generalizable. These results are necessary in order to determine the preferred therapy for clinically localized prostate cancer. [ONCOLOGY 11(8):1133-1143, 1997]

Introduction

Despite dramatic efforts to increase early detection and intervention
for prostate cancer, it is
not known whether radical prostatectomy or expectant management provides
superior length and quality of life for men with clinically localized disease.
The Prostate Cancer Intervention Versus Observation Trial (PIVOT) is a
multicenter randomized trial designed to answer the fundamental question,
Does early intervention with radical prostatectomy reduce all-cause and
prostate cancer-specific mortality and morbidity, when compared with expectant
management?

At present, PIVOT is still enrolling patients, with results expected
in 2008. This article discusses the rationale for conducting PIVOT, describes
the trial's study design, and reports early baseline results from the first
group of screened and enrolled men.

Trial Rationale

Many experts have emphasized the importance of conducting randomized
trials to determine whether early intervention with radical prostatectomy
reduces morbidity and mortality in men with clinically localized prostate
cancer, as compared with expectant management.[1-10] In 1997, over 400,000
new cases of prostate cancer and 40,000 deaths due to this disease were
expected among American men.[11] The number of patients diagnosed with
localized prostate cancer has increased dramatically in recent years due,
in large part, to enhanced early detection techniques.

Despite widespread utilization of prostate-specific antigen (PSA) testing
for early detection and a marked rise in the rate of radical prostatectomy,
however, deaths due to prostate cancer have increased. This has led to
scrutiny of the effectiveness of early detection and treatment.

Theoretically, prostate cancer confined within the prostate gland should
be curable with the removal of the entire gland by surgery (radical prostatectomy)
or curative radiotherapy. Screening tests can now detect disease that is
localized to the prostate more often than would be the case among men presenting
with symptoms. Therefore, it is tempting to speculate that screening for
prostate cancer will result in curative treatment of cancers destined to
cause future morbidity and mortality. However, this hypothesis has not
been tested and may or may not be correct.

Barry and colleagues conducted a policy analysis to determine the cost
and effectiveness of early detection and treatment of prostate cancer in
Medicare-aged men.[12] They concluded that a strategy of early detection
(with PSA testing) and treatment (with radical prostatectomy) was cost-effective,
but only if unproven assumptions that were highly favorable with respect
to treatment necessity, efficacy, and morbidity were used.

Lack of Randomized Data

Both the US Preventive Services Task Force and the Canadian Task Force
on the Periodic Health Examination have recommended against routine screening
for prostate cancer, in part, because the effectiveness of treatments in
reducing morbidity or mortality, compared to expectant management, is unproven.[9]
The only randomized controlled trial comparing radical prostatectomy with
expectant management reported no difference in cumulative survival rates
over 15 years.[10] However, this study was conducted in the 1970s and suffered
from several design flaws.

The Clinical Guideline Panel for the Treatment of Early Stage Prostate
Cancer of the American Urological Association (AUA) recently published
the results of a comprehensive survey and analysis of outcomes data for
methods of treating clinically localized prostate cancer.[8] The panel
concluded that the outcomes data were inadequate for valid comparisons
of treatments. In particular, panel members cited major limitations that
hindered their attempts to analyze the data; these included the scarcity
of randomized controlled trials, insufficient data, and data that may not
be representative because many treatment results, especially negative or
equivocal ones, are not published. The data were obtained from case series,
which are confounded by the lack of control groups, the use of older diagnostic
and therapeutic techniques, and variability in patient populations, tumor
grade, and stage. Reports from nonrandomized studies cannot provide the
unbiased information necessary to determine treatment effectiveness.

The panel recommended that treatment alternatives should be presented
as options and should include expectant management, radical prostatectomy,
and radiation therapy. The term "options" was utilized because
the panel concluded that "the health and economic outcomes of the
interventions are not sufficiently well known to permit meaningful decisions,
preferences among the outcomes are not known, patient preferences are divided
among alternative interventions and/or patients are indifferent about the
alternative interventions".[8] They emphasized the need for large
randomized, prospective, controlled studies utilizing modern diagnostic
and therapeutic approaches to investigate surveillance compared to active
treatment of localized prostate cancer.

PIVOT is the only randomized trial currently being conducted in the
United States comparing radical prostatectomy with expectant management.
PIVOT will compare overall and prostate cancer-specific mortality, morbidity,
quality of life, and treatment costs in the two treatment groups.

Radical prostatectomy was chosen as the early intervention to be tested
because it is the most common therapeutic strategy recommended for patients
with clinically localized prostate carcinoma. Almost 100,000 radical prostatectomies
will be performed in 1996. Rates of this procedure have increased by almost
100% from 1984 and can be expected to rise further with earlier and more
frequent prostate cancer detection.[13] In addition, radical prostatectomy
appears to be the early intervention strategy most likely to provide complete
tumor eradication. Radiation therapy was not included as an initial treatment
option because of sample size, cost, feasibility, and data suggesting that
radiation is not superior to prostatectomy in providing prostate cancer-free
survival.[8,14,15]

Early Intervention vs Expectant Management

Both early intervention and expectant management involve potential risks
and benefits. Radical prostatectomy and radiation therapy offer the possibility
of complete tumor eradication and cure. They may reduce patient anxiety,
the likelihood of cancer metastasis, and the need for subsequent interventions
for disease progression. However, prostate cancer may be unique in that
the majority of individuals die "with" not "because of"
cancer. Furthermore, in individuals with poorly differentiated prostate
cancer, early intervention is least likely to completely eliminate cancer.[16,17]
Therefore, although early intervention is often considered curative, it
may not be necessary in many patients and may not be effective in the remainder.

However, refinements in early detection and treatment may now provide
an opportunity for necessary and effective early intervention. Prostate
cancer detection has improved due to the widespread use of PSA testing.
Cancers detected through PSA-based screening programs are more likely to
be confined to the prostate gland than are those detected by digital rectal
examination (DRE).[18] In addition, these tumors exhibit pathologic and
clinical characteristics similar to tumors detected by DRE. Nonetheless,
because of the lead and length biases associated with cancers detected
by PSA testing, it is not known whether early intervention will reduce
mortality and morbidity.[19-21] (see note) Finally,
despite technical advances, early intervention with either radical prostatectomy
or radiation therapy can result in iatrogenic morbidity and mortality,
adversely affecting quality as well as quantity of life.[2,22-24]

In contrast, with the expectant management strategy, palliative therapy
is given only if men develop symptomatic or metastic disease. Thus, in
many men, treatment will not be necessary if expectant management is utilized.
If men develop systems due to local disease progression, relief can be
provided by minor interventions associated with minimal morbidity. Expectant
management may also include hormonal therapy at the time of diagnosis or
upon evidence of disease progression (eg) from PSA testing or physical
examination. While not of proven benefit, such an approach is widely utilized.
The rate of metastasis may also be similar regardless of whether expectant
management may result in improved quality of life, as compared with early
intervention.[20,24,25]

However, expectant management does not attempt to eradicate the tumor
and may miss an opportunity to prevent metastatic disease and prostate
cancer-related death. Morbidity associated with progression of prostate
cancer is substantial and includes urinary tract obstruction, bone pain,
and other sequelae of metastatic disease. Although palliative therapies
generally relieve symptoms, they may only delay disease progression and
are not curative. Palliative therapy can also result in iatrogenic morbidity
and may not have been required if either radical prostatectomy or radiation
therapy had been utilized.

Thus , currently available evidence is consistant with either early
intervention or expectant management being the preferred treatment option.
However, there may be a clinically important difference between the two
options with respect to both quality and length of life. Determining whether
or not such a difference exists would have great implications for a large
segment of society. Because randomized trials are the most scientifically
rigorous, clinically reliable method for evaluating the relative efficacy
of two treatment approaches, such trials are ethical and necessary.

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