Should Hormonal Therapy Be Started Early?
Patrick C. Walsh

An article published in the December 8, 1999 New England Journal of Medicine¹ stimulated a great deal of interest in starting hormonal therapy immediately after radical prostatectomy in men who had cancer in the lymph nodes removed at the time of surgery. This, indeed, has been extrapolated to suggest that other men with adverse findings should follow this lead. What are the facts and who should receive hormonal therapy?

Theoretical considerations

Prostate cells require male hormones for their growth and development. If the supply of hormones is shut off, the normal prostate shrinks but does not disappear. Thus, even normal prostate cells can survive without hormones. Prostate cancers are made up of a mixture of hormone-sensitive and insensitive cells. When prostate cancer is deprived of male hormones, the hormone-sensitive cells shrink away but the hormone independent cells are unaffected. These are the cells that eventually progress and cause death in men with prostate cancer. Thus, on a theoretical basis, hormone deprivation can shrink prostate cancer but cannot eliminate the cells that will ultimately prove to be lethal. Experimental studies in animal tumors support these observations. In animals with established tumors, similar to the clinical state of men who are candidates for early hormonal therapy, survival is the same in those animals that receive treatment early as in those animals that are treated later in the course of their disease.

Clinical trials that have demonstrated no benefit

In the 1960s the Veterans Administration Cooperative Urological Research Group (VACURG) carried out a Comprehensive study of hormonal therapy ². Men with locally advanced disease and men with metastatic disease to bone were randomized to be treated with castration, estrogen, and estrogen plus castration. The long-term survival of these men was compared to a group of men who were followed carefully and treated when they developed progression of their disease and/or symptoms. This study went on for a decade and clearly showed no benefit for early immediate treatment with hormonal deprivation in either the men with locally advanced disease or men with metastatic cancer. It is reasonable to question whether this study is still pertinent 30 years after its completion. It is. Why? Because we know very well that there has been no improvement in the survival of patients treated with hormonal deprivation over the past 50 years since Charles Huggins made his Nobel Prize winning discovery on the influence of castration in men with prostate cancer.

Studies that have demonstrated a benefit from early hormonal therapy

The Veterans Administration undertook a second study in which they tried to determine the optimal dose of estrogen. In this study, they randomized patients to a low dose of estrogen that was ineffective, a high dose that caused cardiovascular toxicity, and an intermediate dose. These 3 groups of men were then compared to placebo treated patients. In this study, patients receiving immediate treatment with the intermediate dose of estrogen had improved survival. However, approximately 50% of the patients on placebo (no treatment) and on the lowest dose of estrogen that had no effect, never received hormonal therapy. This policy was followed because many investigators in this study interpreted the first Veterans Administration study incorrectly. They interpreted that study to show that treatment with hormonal therapy did not prolong life; they did not understand that the men in the placebo treated group were ultimately treated. More recently the Medical Research Council (MRC) in Great Britain carried out a study similar to the first Veterans Administration study, which looked at the influence of early versus late treatment in men with locally advanced and metastatic disease ³. However, this study was rather loosely organized and there was no defined interval for followup. Indeed, bone scans were not even available for many patients. In this study, men with locally advanced cancer who received early hormonal therapy survived longer. However, in men assigned to the delayed treatment group, treatment was often not instituted until the patients developed a pathologic fracture or spinal cord compression. There were 54 more deaths in the delayed treatment group than in the patients who received hormonal deprivation up front. However, of these 54 patients 29 never received hormonal therapy before their death from prostate cancer! Thus, this study does not compare early versus late treatment. Rather, it compares early versus no treatment or treatment that was administered too late.

The study in the New England Journal by Messing et al looked at men who underwent radical prostatectomy and were found to have positive lymph nodes. These patients were randomly assigned to treatment early with hormonal therapy or treatment that was delayed until the patients developed signs or symptoms of metastatic disease. After a relatively short followup interval, the authors were able to show a survival benefit in the patients receiving early hormonal therapy. The results are somewhat surprising because there are at least 2 other studies that have not replicated these results. One of these is a European study carried out by the EORTC, in which 304 men with positive lymph nodes who did not undergo radical prostatectomy were randomly assigned to early or delayed therapy⁴. In this much larger study where patients have been followed for an equal length of time, there is still no significant difference in survival. The Mayo Clinic has a rather large group of men with positive lymph nodes, many of whom were treated with hormonal therapy. In a retrospective review of these data, they were not able to demonstrate an overall cancer survival benefit for men receiving early hormonal therapy. However, after 10 years they were able to show some significant effect in a subset of men who had diploid tumors. Thus, the findings of Messing are somewhat surprising and it is reasonable to question whether one can totally rely upon this single study to direct therapy. What could be wrong? In carrying out a randomized study, one needs to have comparable groups of patients in both arms of the study. The study was originally designed to evaluate 240 patients. However, they had problems recruiting that number and were only able to randomize 98 patients. This leaves a smaller number of men in each group making it possible that unintentional bias might have been introduced. The most powerful predictor of outcome is the Gleason score on the radical prostatectomy specimen.^5,6. Unfortunately, they did not have a central place where all pathologic specimens were analyzed, and in this study they were unable to show that their Gleason scores had any association with the ultimate outcome. This suggests that the Gleason scores were not performed accurately. Thus, it is possible that there was an unequal distribution of patients with more adverse pathologic features in the delayed group. For example, in men with positive lymph nodes who have Gleason 8-10 disease, 82% will have metastatic disease within 5 years.⁷ Conversely, in men with Gleason 5-7 disease, only 15% will develop metastatic disease in 5 years. In the Messing study, 37% of the patients had metastatic disease by 5 years. This is much higher than in 3 other series, including the Hopkins series, in which only 20% of patients would be expected to have metastasis at 5 years.^7,8,9 Thus, unintentional bias in the randomization process may explain the results.

Risk benefit analysis

Why not begin hormonal therapy early? The side effects of hormonal therapy in men are profound. It is not like adjuvant hormonal therapy in women who take a tamoxifen pill a day following breast cancer surgery. In men, hormonal deprivation has a profound impact on quality of life: hot flashes, weight gain, loss of muscle mass, osteoporosis, anemia, and decreased mental acuity, not to mention loss of libido and impotence. It is also expensive -$5,000.00 - $10,000.00 a year. Thus, before embarking upon this treatment, one needs to understand the scientific evidence that supports early treatment and compare it to the potential risks. To reduce side effects, some physicians recommend intermittent hormonal therapy where hormones are administered for a while and once the PSA level falls they are discontinued. There is no evidence that this is safe and effective. Indeed, in one animal study, intermittent hormonal therapy reduced survival by 50%.

My philosophy

As I look at the scientific evidence, I am not convinced that early hormonal therapy prolongs life. There are many men with prostate cancer who have adverse flndings on their radical prostatectomy specimen or an elevated PSA following surgery who live a high quality of life for many many years without receiving hormonal treatment. In the May 5, 1999 issue of the Journal of the American Medical Association we looked at the outcome of 304 men who developed an elevated PSA following radical prostatectomy.¹⁰ These men were followed expectantly until they developed metastasis. The average time from development of the first PSA elevation to the development of bony metastasis was 8 years. We were able to construct an algorithm which helped patients and their physicians estimate more accurately when metastasis to bone might show up. The factors that we found to be most useful were the Gleason score on the radical prostatectomy specimen (more or less than 8), the time following radical prostatectomy when the PSA level first increased (more or less than 2 years), and the time it took the PSA to double (more or less than 10 months). Using this information, a patient can quickly determine his risk for developing metastatic disease. For example, in one of the most common scenarios, a man with Gleason 7 disease who developed a PSA elevation more than 2 years following surgery, who had a PSA doubling time longer than 10 months, had an 82% likelihood of being metastasis free at 7 years. In contrast, if the PSA had gone up within the first 2 years and the PSA doubling time was less than 10 months, then the freedom from metastatic disease at 7 years would be only 15%. Using information like this, one can have a better understanding of the risk benefit ratio, i.e. how long will I be off hormones until I need them. Finally, one must understand the true value of hormonal therapy. There is no good scientific evidence that hormonal therapy prolongs life. It is effective in men with symptoms from prostate cancer progression because it can shrink the tumor. However, ultimately the androgen independent cells win out. For this reason, if patients want to aggressively attack their tumor, they should consider enrolling in clinical trials, of which there are many, which are directed at eliminating the androgen insensitive cell population.

    References

1. Messing, E.M., Manola, J., Sarosdy, M., Wilding, G., Crawford, E.D., Trump, D.: Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N. Engl. J. Med. 341:1781-1788, 1999.

2. Byar, D.P.: Proceedings: the Veterans Administration Co-operative Urological Research Group's studies of cancer of the prostate. Cancer 32:1126-1130, 1973.

3. Byar, D.P.: Proceedings: the Veterans Administration Co-operative Urological Research Group's studies of cancer of the prostate. Cancer 32:1126-1130, 1973.

4. Schroeder, F.H.: Personal communication.

5. Scrignoli, A.R., Walsh, P.C., Steinberg, G.D., Steiner, M.S., Epstein, J.I.: Prognostic factors in men with stage D1 prostate cancer: identification of patients less likely to have prolonged survival after radical prostatectomy. J. Urol. 152:1077-1081, 1994.

6. Cheng, L., Bergstralh, E.J., Cheville, J.C., et al. Cancer volume of lymph node metastasis predicts progression in prostate cancer. Am. J. Surg. Pathol. 22:1491-1500, 1998.

7. Cadeddu, J.A., Partin, A.W., Epstein, JI, Walsh, P.C.: Stage D1 (T1-3,N1-3,MO) prostate cancer: a case-controlled comparison of conservative treatment versus radical prostatectomy. Urology 50:251-255, 1997.

8. Zincke, H., Bergstralh, E.J., Larson-Keller, J.J., et al.: Stage D1 prostate cancer treated by radical prostatectomy and adjuvant hormonal treatment: evidence for favorable survival in patients with DNA diploid tumors. Cancer 70:Suppl:311-323, 1992.

9. deKemion, J.B., Neuwirth, H., Stein, A., et al.: Prognosis of patients with stage D1 prostate cancer following radical prostatectomy with and without early endocrine therapy. J. Urol. 144:700-703, 1990.

10. Pound, C.R., Partin, A.W., Eisenberger, M.A., Chan, D.W., Pearson, J.D.: Walsh, P.C.: Natural history of progression after PSA elevation following radical prostatectomy. JAMA 281:1591-1597,1999.