In 1941, Charles Huggins, Clarence Hodges, and R. E. Stevens reported
on the beneficial effects
of orchiectomy in 21 men with advanced prostate cancer. Fifty-five years
later, Southwest Oncology Group (SWOG) investigators were able to confirm,
in a 1,387-patient intergroup comparative trial of bilateral orchiectomy
with or without flutamide (Eulexin), that we still have nothing better
to offer these men. This fact alone should underscore the critical need
for well-planned, well-executed clinical trials in prostate cancer. The
incidence and death rates continue to rise, and even today too few men
are being enrolled in studies designed to alter these statistics.
The current and recently completed SWOG clinical trials cover the broad
spectrum of this disease from prevention to hormone-refractory prostate
Trials in Untreated Metastatic Disease
In the arena of previously untreated metastatic prostate cancer, there
are currently two large intergroup trials. The SWOG trial of intermittent
androgen deprivation (IAD) assumes that this approach will result in prolongation
of androgen dependence, and hence, response to androgen deprivation. This
trial has accrued patients at a far slower rate than anticipated. This
poor accrual has been attributed to the fact that fewer men present with
untreated metastatic disease. However, the true reason is probably multifactorial.
There may be disbelief by both investigators and patients that prescribing
or receiving less hormonal therapy is better or even equal to continuous
androgen deprivation. Unfortunately, there are scant published clinical
results supporting this approach.[2,3]
Furthermore, the expected improvements in quality of life (QOL) during
the time off hormonal therapy must be balanced against the potential decreased
QOL resulting from the anxiety of following a rising prostate-specific
antigen (PSA) without restarting treatment. In this trial, treatment is
not restarted until the PSA is less than 20 ng/mL or there is clinical
If accrual does not increase, completion of this trial is in jeopardy.
Possible ways to improve accrual would include lowering the PSA required
to restart therapy and providing the drugs free of charge.
The second large intergroup trial for this patient population is being
spearheaded by the Eastern Cooperative Oncology Group (ECOG). This randomized
phase III trial of combined androgen blockade (CAB) with or without suramin
is based on a pilot trial conducted by the Clinical Pharmacology Branch
of the National Institutes of Health showing excellent survival in poor-risk
patients. Suramin in this trial is given at a fixed dose and schedule,
avoiding the need to closely monitor serum levels. Unfortunately, reluctance
by some investigators and patients to add a potentially toxic additional
drug to CAB may hinder accrual to this study.
In the future, potential trial designs should include the testing of
novel agents prior to the initiation of hormonal therapy, as well as the
use of concomitant chemotherapy, such as mitoxantrone (Novantrone), to
target both the androgen-sensitive and -insensitive prostate cancer cell
Trials in Hormone-Refractory Prostate Cancer
Current or recent trials in hormone-refractory prostate cancer divide
between those with primary palliative end points, ie, improved pain control,
and those with primary end points of objective response, ie, tumor shrinkage,
decline in PSA, and prolonged survival. The serial phase II studies conducted
by SWOG have had the same disappointing results as those reported by other
investigators, with no new treatment resulting in prolongation of survival.
Although not employed in the SWOG trials, the use of a decline in PSA
as a surrogate end point in clinical trials in hormone-refractory prostate
cancer is being widely adopted, and is based on analyses demonstrating
a correlation between PSA decline and prolonged survival.[5-7] Using this
end point, some promising approaches, such as the combination of estramustine
(Emcyt), vinblastine, and strontium-89, are emerging and are progressing
to the cooperative group setting.
Results have been far more encouraging in trials that used QOL as the
primary end point. In a recently completed phase III trial of prednisone
with or without mitoxantrone, pain reduction was significantly better for
the combination-therapy arm. The Cancer and Leukemia Group B (CALGB)
conducted a similar large phase III trial with mitoxantrone and hydrocortisone
instead of prednisone. Again, patients receiving the combination achieved
greater palliative benefit.
Nonetheless, in the absence of therapies that prolong survival in hormone-refractory
disease, the initiation of serial phase II trials that seek to identify
new active agents will remain the backbone of clinical research in this
Trials in Locally Advanced Disease
As pointed out in this review, locally advanced T3 disease (cT3 and
pT3) is becoming the most common stage of prostate cancer. Patients with
locally advanced disease are at high risk for recurrence and may benefit
from early systemic therapy.
SWOG has taken a leadership role with its phase II trials of continuous-infusion
fluorouracil and radiation and of neoadjuvant CAB preprostatectomy, as
well as its large randomized trial of adjuvant radiation for pT3 disease.
The results of these studies are anxiously awaited.
The European Organization for Research and Treatment of Cancer (EORTC)
recently reported on the results of its randomized phase III trial of radiotherapy
with or without concurrently initiated monthly goserelin (Zoladex) continued
for 3 years and cyproterone acetate (Androcur) orally for 1 month in patients
with T1-4, N0 or NX disease. This trial demonstrated not only better local
control but also improved disease-free and overall survival favoring the
It is plausible that given the high rate of relapse and occult metastatic
disease in this patient population, hormonal therapy alone is adequate
to control local and distant disease. This idea leads to the very important
National Cancer Institute of Canada (NCIC) trial of hormonal therapy with
or without radiation. Facilitated by the GU Global Group of SWOG, this
international intergroup trial will assess the possibility of managing
locally advanced disease with systemic therapy alone.
Similar to therapy for previously untreated metastatic disease, future
trials in locally advanced prostate cancer will need to focus on innovative
ways to target both androgen-sensitive and -insensitive prostate cancer
cells. In addition, correlative science studies evaluating new biologic
markers, androgen receptor mutations, reverse transcriptase-polymerase
chain reaction, and so on, need to be incorporated into all studies to
better identify subsets of patients who are more likely to benefit from
different therapeutic approaches.
Trials in Early-Stage Disease
Moving to earlier-stage disease, one of the most critical questions
being raised is the necessity for local therapy in patients with stage
T1 or T2 disease. Many men are currently choosing the watchful waiting
approach. The Prostate Intervention vs Observation Trial (PIVOT) was designed
to determine the crucial comparative value of intervention (prostatectomy)
vs no intervention. It is unfortunate that a third arm of radiation could
not have been included. A future intergroup trial is being planned to compare
cryosurgery and external-beam radiation.
Moving even earlier in the disease process is the 18,000-patient Prostate
Cancer Prevention Trial (PCPT). Even if finasteride (Proscar) is not shown
to lower the incidence of prostate cancer, this trial will provide a tremendous
wealth of information, including the impact of diet and body habitus. It
will also provide a tissue and serum bank for future research. This trial
accrued patients quickly and demonstrated both the feasibility of and interest
in large-scale preventive trials.
Future preventive trials under consideration include an assessment of
soy supplements and selenium.
1. Huggins C, Stevens RE, Hodges CV: Studies on prostatic cancer. II:
The effects of castration on advanced carcinoma of the prostate gland.
Arch Surg 43:209-223, 1941.
2. Goldenberg SL, Bruchovsky N, Gleave ME, et al: Intermittent androgen
suppression in the treatment of prostate cancer: A preliminary report.
Urology 45:839-845, 1995.
3. Klotz LH, Herr HW, Morse MJ, et al: Intermittent endocrine therapy
for advanced prostate cancer. Cancer 58:2546-2550, 1986.
4. Dawson NA, Figg WD, Cooper MR, et al: A phase II trial of suramin,
leuprolide and flutamide in previously untreated metastatic prostate cancer.
J Clin Oncol 15:1470-1477, 1997.
5. Kelly WK, Scher HI, Mazumdar M, et al: Prostate-specific antigen
as a measure of disease outcome in metastatic hormone-refractory prostate
cancer. J Clin Oncol 11:607-615, 1993.
6. Smith DC, Dunn RL, Strawderman MS, et al: Change in serum prostate
specific antigen as a marker of response to cytotoxic therapy for hormone-refractory
prostate cancer. J Clin Oncol, 1997 (in press).
7. Dawson NA: Eligibility and response criteria in hormone refractory
prostate cancer (RPC): A need for consensus (abstract). Proc Am Soc
Clin Oncol 17, 1997 (in press).
8. Wehbe T, Akerley W, Sloan L, et al: Strontium-89, estramustine and
vinblastine (SEV) in hormone-refractory prostate carcinoma (RPC): concurrent
chemoradiotherpay. Proc Amer Soc Clin Oncol 15:262, 1996.
9. Tannock IF, Osoba D, Murphy K, et al: Chemotherapy with mitoxantrone
plus prednisone or prednisone alone for symptomatic hormone-resistant prostate
cancer: A Canadian randomized trial with palliative endpoints. J Clin
Oncol 14:1756-1764, 1996.
10. Kantoff PW, Conaway M, Winer E, et al: Hydrocortisone with or without
mitoxantrone in patients with hormone-refractory prostate cancer: Preliminary
results form a prospective randomized Cancer and Leukemia Group B Study
(9182) comparing chemotherapy to best supportive care. Proc Am Soc Clin
Oncol 15:25, 1996.
11. Bolla M, Gonzalez D, Warde P, et. al: Immediate hormonal therapy
improves locoregional control and survival in patients with locally advanced
prostate cancer: Results of a randomized phase II clinical trial of the
EORTC radiotherapy and genitourinary tract cancer cooperative groups. Proc
Amer Soc Clin Oncol 15:238, 1996.