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Contemporary Hormonal Management of Advanced Prostate Cancer

Contemporary Hormonal Management of Advanced Prostate Cancer

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 prostate cancer.

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.[1] 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. Moul’s 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. Moul’s 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.[4]

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.[5]

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.[7] 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.

Summary
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.

References

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.

 
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