The Genitourinary (GU) Cancer Committee of the Southwest Oncology Group
in 1978 from a combined Gynecologic-Urologic Cancer Committee. Several
phase II trials in hormone-refractory prostate cancer had been completed,
but growing interest in prostate cancer led to the establishment of a separate
and independent GU cancer committee. Hormone-refractory prostate cancer
remained the primary focus of the newly formed committee in its early years,
but in the mid-1980s the committee's focus broadened to encompass the evaluation
of other therapeutic strategies for newly diagnosed metastatic disease.
The intergroup trial of leuprolide (Lupron) with or without flutamide
(Eulexin)INT 0036proved to be a landmark study of the efficacy of combined
androgen blockade (CAB) for metastatic prostate cancer. Recent SWOG
trials for patients with metastatic prostate cancer have been designed
in the shadow of this trial. Controversy remains as to the universal,
irrefutable benefit of CAB.[3,4] Nevertheless, this therapeutic approach
provides the frame of reference from which clinical trials for metastatic
prostate cancer are designed.[5-7]
Bilateral Orchiectomy With or Without Flutamide in Stage D2Disease
Following the initial study of total androgen deprivation, SWOG investigators
deemed crucial the study of CAB in surgically castrated patients. SWOG-8894/INT
0105, which compared bilateral orchiectomy with or without flutamide in
patients with histologically confirmed stage D2 prostate cancer, was designed
to have adequate power to detect survival differences according to disease
extent (minimal vs severe). It also evaluated various other potential prognostic
factors, including PSA , site of disease, testosterone level, and comorbid
This randomized, placebo-controlled trial was activated in 1989 and
closed in September 1994, after an accrual of 1,387 patients. The objectives
were: (1) to compare overall and progression-free survival in patients
with histologically confirmed stage D2 adenocarcinoma of the prostate who
were treated with either bilateral orchiectomy plus flutamide (250 mg tid)
or bilateral orchiectomy plus placebo (2 capsules tid); and (2) to compare
qualitative and quantitative toxicities associated with the addition of
flutamide following bilateral orchiectomy. Like the INT 0036 protocol,
SWOG 8894/INT 0105 stratified patients according to Eastern Oncology Group
(ECOG) performance status of 0-2 vs 3 and extent of disease. Minimal disease
was defined as pelvic plus axial skeleton and/or soft-tissue nodal metastases,
and extensive disease was defined as appendicular (with or without axial)
skeleton and/or soft-tissue visceral involvement. Good-risk patients had
performance status of 0-2 and minimal disease (Table
The results of the trial in 1,371 eligible patients are shown in Table
2. The trial failed to demonstrate that the addition of flutamide to
bilateral orchiectomy is associated with any therapeutic benefit, despite
differences in prostate-specific antigen (PSA) response.
Toxicity was modest. No treatment-related deaths occurred. The overall
incidence of severe (grades 3-4) toxicity was low. The only significant
differences between flutamide and placebo groups related to the incidences
of diarrhea (3.3% vs 0.8%; P = .007), elevation of aspartate transaminase/alanine
transaminase (1.2% vs 0.8%; P = .027), and anemia (3.0% vs 1.5%;
P = .046).
Need for Novel Therapeutic Approaches
Fifty years have elapsed since the landmark discoveries of Huggins et
al of the effect of castration on advanced prostate carcinoma.[8-10] Despite
improvements in the treatment of metastatic prostate cancer during that
half-century, there have been remarkably few significant advances showing
an impact on survival.
Prognostic differences among patients with metastatic prostatic carcinoma
and their differing treatment responses have led researchers to conceptualize
and design therapeutic protocols accordingly. Thus, patients with a superior
clinical response to androgen ablation have been targeted with trials that
seek to enhance such a response. Patients either unlikely to have such
a response or who initially show an unsatisfactory response may be targeted
for more aggressive chemohormonal approaches. These observations, together
with growing scientific data on the potential mechanisms of progression
to androgen independence, guided the design of the next series of SWOG
trials for untreated patients with stage D2 disease.
Intermittent Androgen Deprivation (Good-Risk Patients)No existing
therapy for metastatic prostatic carcinoma prevents progression to a hormone-refractory
condition. Progression to such an androgen-independent state appears to
be linked to the loss of apoptotic potential in stem cells. This results
in the survival and cloning of androgen-insensitive cells. Research has
investigated methods by which the regeneration of apoptotic potential could
be continued or restored.
Intermittent androgen deprivation (IAD) seems to induce multiple apoptotic
regressions of prostatic tumors, resulting in a threefold prolongation
in the duration of androgen dependence. However, the cyclic effects
of such treatment on prostate cancer can be followed efficiently only by
sequentially measuring serum PSA levels. Only patients whose PSA values
have initially fallen to nadir levels following the institution of hormonal
ablation therapyan indication of androgen dependenceare appropriate candidates
In 1995, SWOG activated a trial to test this therapeutic approach (SWOG
9346). Patients who achieve a PSA nadir within the normal range (0 to 4.0
ng/mL) after an induction period are randomized to either continuous or
intermittent androgen therapy. In addition to the prospect of lengthening
response by IAD, quality of life (QOL) and cost-effectiveness may also
be positively influenced. The trial will use survival and QOL as primary
end point measures. The utility of IAD may be greatest in the long-term
management of patients with a PSA-only relapse after local therapy or as
a primary treatment for selected patients with less than advanced disease.
Suramin and CAB (Poor-Risk Patients)Despite the poor response
of metastatic prostatic carcinoma to chemotherapeutic agents, a greater
understanding of apoptosis and the establishment of hormone resistance
have led to renewed enthusiasm for chemohormonal therapy. The identification
of potentially more active chemotherapeutic agents and combinations provides
an attractive opportunity for evaluating chemohormonal therapy.
A phase II SWOG pilot study of Suramin plus CAB (SWOG 9343) has recently
completed accrual. This trial was implemented as preparation for a phase
III randomized intergroup study of CAB with or without Suramin to be coordinated
Suramin is a polysulfonated naphtylurea that has been used for many
years for the treatment of parasitic diseases. The drug has shown activity
in hormone-refractory prostate cancer. While not completely elucidated,
Suramin's mechanism of action appears to involve inhibition of growth factor
binding. Toxicity is manageable if serum levels are maintained between
narrowly defined limits.
SWOG 9343 will study the efficacy of attempting to eradicate stem cells
by means of chemotherapy in conjunction with CAB in newly diagnosed stage
D2 patients. Interesting observations have been reported in this regard
by the National Prostatic Cancer Project.
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