The Prostate Cancer Intervention Versus Observation Trial (PIVOT) should
ing in that the study design will permit observation of the natural history
of a potentially lethal malignant disease, influenced only by palliative
treatments. My comments will focus on the concerns raised by this study
design. I will not address possible biases of the trial introduced by:
(1) enrollment of less than 20% of the eligible population; (2) an enrollment
rate per participating center of less than 3 patients per year;
(3) a 7-year enrollment period; and (4) a 12-year follow-up (for a total
trial duration of 19 years).
The natural history of malignant tumors is characterized by growth by
repetitive cell division at distant sites. The aim of traditional treatment
has been to eradicate the primary tumor by excisional or ablative therapy.
Observation (or expectant) treatment schema logically permit malignant
cells to replicate at a pace dictated by their inherent biology. If prostate-specific
antigen (PSA) levels reflect the tumor volume, then the doubling time of
prostatic tumors is approximately 18 months, with a range of 12 to 24 months.
There is also concern that, over time, malignant tumors show a progressive
loss of cell differentiation. Serial biopsy data from observed Scandinavian
patients demonstrate a shift from diploid to uniploid cells and/or an increase
in Gleason sum in approximately 5% of the residual population each year.
Our data also show a statistically significant increase in Gleason
sum with advancing age.
Cancer-Specific Survival Data
Our data indicate that cancer-specific survival is a function of the
extent of disease, regardless of Gleason sum, PSA level at the time of
treatment, or other factors (Figure 1).
Small-volume tumors, even those with high Gleason sums, can be salvaged
by surgical intervention if the disease is organ- or specimen-confined
Furthermore, our data show that PSA levels at the time of biopsy bear
a direct relationship to the extent of disease (or the number of patients
who are potentially curable). It seems logical to assume, therefore, that
denying patients a proactive treatment option (through random assignment
to observation) will shift these patients, with time, to an extended-disease
category. In other words, their disease will behave as if it were margin-positive.
As all surgically treated margin-positive patients who die from prostate
cancer are exposed to androgen deprivation prior to death (and yet experience
a 55% cancer-specific death rate at 15 years), it seems reasonable to predict
that the patients assigned to observation will approach this figure, even
assuming that all of them have organ-confined disease at entry and all
progress to margin-positive disease in 3 to 5 years after diagnosis.
I hope that my pessimistic projections prove incorrect. Certainly, all
of the observed population will die with prostate cancer. If competing
risks of death are adequately controlled, however, members of the observed
population will also be at risk of dying from prostate cancer.
1. Tribukait B: Eur Urol 23(supp 2):64-76, 1993.
Department of Veterans Affairs, National Cancer Institute and Agency
for Health Care Policy and Research Cooperative Study #407. Supported by
the Department of Veterans Affairs Cooperative Studies Program, the National
Cancer Institute, and the Agency for Health Care Policy and Research.