In this issue of oncology, Dr. Moul provides the rationale for a more
contemporary definition of advanced prostate cancer. He
also provides a concise overview of the growing role of hormonal
therapy in the management of patients with advanced disease. I
wholeheartedly agree with his general thesis. However, I also feel
that the term cure has been given far too much attention
in the urologic literature. The fact of the matter is that the vast
majority of men diagnosed with prostate cancer are not
cured, but does that mean that they have advanced
prostate cancer? Since approximately 40,000 men die of prostate
cancer each year, but more than five times that number are diagnosed,
there is a large discrepancy between the common diagnosis of advanced
prostate cancer and prostate mortality. Based on these observations,
it appears to be premature to recommend that most men with newly
diagnosed prostate cancer undergo long-term castration for advanced
Flaws of the Medical Research Council Study
In making his arguments for early vs delayed hormonal therapy, Dr.
Moul refers to the 1995 Medical Research Council (MRC) study.
Again, although I agree with the principles he alludes to, close
inspection of this study reveals several flaws that call into
question whether the conclusions can be applied to men with prostate
cancer in this country.
In general, the men included in the MRC study were diagnosed prior to
the advent of prostate-specific antigen (PSA) testing and probably
had fairly advanced disease. A total of 174 men were entered into
this study from facilities at which bone scans were not routinely
available. Although this shortcoming can be adjusted for
statistically, it certainly suggests that the standards of practice
in the institutions where the study was conducted differ from the
standards in this country. Furthermore, although most of the study
participants were not offered local therapy, some were, but no
information was provided regarding the impact of such treatment.
This study is flawed in other ways as well. Among the group who did
not receive initial treatment, 29 patients died of prostate cancer
without ever having received hormone suppressive therapy. It is
doubtful that this situation would have occurred in the United
States. Clearly, men with advanced prostate cancer who receive
treatment should do better than those who receive none. The question
is not whether hormonal therapy should be given, but rather when.
Which End Points Warrant Greater Emphasis?
Dr. Mouls review overemphasizes the finding of positive margins
and PSA failure while underemphasizing survival as the most important
end point. This is understandable. We want to be able to tell our
patients now what to expect later.
Unfortunately, PSA testing has been available for only about 10
years, and we currently have very limited information on which to
model survival using this marker.
Based on a review of Radiation Therapy Oncology Group (RTOG) data,
which represents the oldest and largest available database of men
with locally advanced prostate cancer, it is clear that Gleason score
is a major predictor of survival. For this reason, I believe that the
value of this prognostic factor was underemphasized in Dr. Mouls
review. Patients with Gleason scores of 8 to 10 have a 75% failure
rate 4 years after radical prostatectomy even if they have early
clinical stage disease (T1, T2).[2,3] Even patients with
pathologically confined disease have a failure rate exceeding 50% at
5 years if their Gleason score is 8 or above.
These observations support the need to redefine advanced
prostate cancer in such a way as to give greater emphasis to
the Gleason score. This is particularly true in an era in which more
men are being screened with PSA but less of them are being found to
have high PSA levels. The need to emphasize Gleason score is further
supported by the results of RTOG 85-31. This study demonstrated a
survival benefit associated with adjuvant hormonal suppression only
for men with high Gleason scores confirmed by central pathologic review.
Role of Local Therapy in Advanced Disease
It appears that hormonal therapy will play an important role in the
treatment of many men with advanced prostate cancer.[5,6] The
remaining question in the minds of most oncologists relates to the
role of local therapy in patients with advanced disease. Although
very few patients with advanced solid tumors are cured,
we have learned that the optimal treatment for unresectable non-small-cell
lung cancer, small-cell lung cancer, esophageal cancer, anal cancer,
nasopharyngeal cancer, postoperative rectal cancer, brain tumors, and
other solid tumors involves the combined use of chemotherapy and
radiation. These tumors share several features: (1) the
availability of chemotherapeutic agents with at least modest
activity; (2) a site that can be easily incorporated into a
radiotherapy portal; and (3) the presence of locally advanced disease
that is not well suited to curative surgery.
Along the same lines, the response rates of prostate cancer to
androgen suppression equal (or exceed) the activity of chemotherapy
in many of these other solid tumors, and the prostate is easily
included in a radiotherapy ports. The absence of overlapping
toxicities when androgen ablation is added to radiation also suggests
that there is unlikely to be a major down side to the
concomitant use of these modalities.
The results of two recent prospective randomized trials provide
support for this combined-modality approach in advanced prostate
cancer.[6,8] Based on these data, I believe that the standard of care
for advanced prostate cancer should be hormonal therapy plus
radiotherapy, until proven otherwise.
As Dr. Moul suggests, there is a need to redefine the term
advanced prostate cancer. However, I believe that this
new definition should be based on survival and quality-of-life end
points. In the absence of survival data, it is premature to routinely
castrate men with prostate cancer. Hopefully, some of the innovative
approaches discussed in this review article will resolve many of
these problems and questions.
1. The Medical Research Council Prostate Cancer Working Party
Investigators Group: Immediate versus deferred treatment for advanced
prostate cancer: An overview of 22 randomized trials with 3283 deaths
in 5710 patients. Lancet 346:265-269, 1995.
2. Partin AW, Lee BR, Carmichael M, et al: Radical prostatectomy for
high grade disease: A reevaluation in 1994. J Urol 151:1583-1586, 1994.
3. Ohori M, Goad JR, Wheeler TM, et al: Can radical prostatectomy
alter the progression of poorly differentiated prostate cancer? J
Urol 152:1843-1849, 1994.
4. Lerner SE, Blute ML, Zincke H: Risk factors for progression in
patients with prostate cancer treated with radical prostatectomy.
Semin Urol Oncol 14(suppl):12-21, 1996
5. Pilepich MV, Caplan R, Byhardt RW, et al: Phase III trial of
androgen suppression using goserelin in unfavorable-prognosis
carcinoma of the prostate treated with definitive radiotherapy:
Report of Radiation Oncology Group Protocol 85-31. J Clin Oncol 15:3:1013-1021,1997.
6. Bolla M, Gonzalez D, Warde P, et al: Improved survival in patients
with locally advanced prostate cancer treated with radiotherapy and
goserelin (abstract 591197). N Engl J Med 337:295-300, 1996.
7. Roach M: Neoadjuvant total androgen suppression and radiotherapy
in the management of locally advanced prostate cancer. Semin Urol
Oncol 14:2:32-38, 1996.
8. Laverdiere J, Gomez JL, Cusan L, et al: Beneficial effect of
combination therapy administered prior and following external beam
radiation therapy in localized prostate cancer. Int J Radiat Oncol
Biol Phys 37:2:247-252, 1997.