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Hormonal Therapy of Advanced Prostatic Cancer
0022-534 7/86/1363-0653$02.00/0
Vol. 136, September
THE JOURNAL OF UROLOGY
Copyright © 1986 by The Williams & Wilkins Co.
Printed in U.S.A.
Editorial HORMONAL THERAPY OF ADVANCED PROSTATIC CANCER This issue of the Journal contains 2 articles that detail the results of studies done by the Urological Group of the European Organization for Research on Treatment of Cancer (EORTC) on hormonal therapy of advanced prostatic cancer (stages C and D or T3T4NxMo and TanyNxMl lesions). These important multi-institutional investigations have added to our knowledge of the relative merits of diethylstilbestrol, cyproterone acetate, medroxyprogesterone acetate and estramustine phosphate in the treatment ofprostatic cancer. The conclusions reached are likely to add more fuel to the controversy regarding the appropriate timing of hormonal treatment. In the EORTC study 30762 (page 619) the effect of diethylstilbestrol was compared to that of estramustine phosphate, a compound claimed to possess hormonal and cytotoxic effects. There were 227 evaluable patients randomized to receive either 3 mg. diethylstilbestrol daily or 560 mg. estramustine phosphate daily for 8 weeks and 280 mg. daily thereafter. At the outset it should be noted that the currently recommended dose of estram:ustine phosphate is 140 mg./10 kg. or approximately 980 mg. daily for a 70 kg. man. Thus, the dosage used in the study is on the order of 30 to 60 per cent of the dose now deemed appropriate. The best local response, as determined by digital rectal examination, was seen in patients receiving diethylstilbestrol. No significant differences were noted between treatments with respect to response rate of metastases, time to local progression, time to distant progression, survival or death of carcinoma of the prostate. In the accompanying EORTC study 30761 (page 624) the group compared diethylstilbestrol, cyproterone acetate and medroxyprogesterone acetate in 210 eligible patients. No significant differences in response were noted in patients receiving either diethylstilbestrol or cyproterone acetate. Patients treated with medroxyprogesterone acetate had a shorter time to progression and a shorter over-all survival than those treated with either of the other 2 agents. Based on these observations, the authors indicate the need to reconsider the appropriateness of delayed hormonal therapy in the management of advanced disease; the implication is that the results may support those who advocate early (at time of diagnosis) intervention. In both studies approximately half of the patients had advanced local disease (T3T4Mo) and the remainder had metastatic disease (Ml) at the start of therapy. In essence then, the patients with nonmetastatic disease may be considered as receiving early hormonal therapy and those with Ml disease receiving late therapy, although not all of the latter patients were symptomatic with disease. The over-all response to hormonal therapy was lower than the reported 80 per cent response to estrogen or castration. 1 Of 156 patients receiving diethylstilbestrol in both studies a significant local response to therapy was noted in 82 (53 per cent). Marked improvement in distant metastases was noted in fewer than 20 per cent of the treated patients (21 of 124). In the 30762 study the time to progression of disease was not different between the 2 treatments and those patients with stage C (T3T4Mo) disease at the initiation of treatment had a time to progression similar to that of placebo-treated patients in the Veterans Administration Co-operative Urological Research Group study. 2 The marked variation in local and distant response rates 653
plus the observation that local response does not necessarily predict distant response suggests that local and distant responses are independent parameters. Another explanation to be considered is that the multitude of known (not to mention unknown) variables and the wide variation in the behavior of prostatic cancer plus the softness on the response criteria, that is digital rectal examination and bone scan, render even the significant differences questionable. These data together with the lack of any statistically significant differences in the overall survival of patients with Mo disease receiving diethylstilbestrol or medroxyprogesterone acetate (in contrast to the improved survival of subjects with Ml disease given diethylstilbestrol versus medroxyprogesterone acetate) weaken the argument for early hormonal manipulation in patients who present with extensive local or asymptomatic metastatic disease at the time of diagnosis. To my interpretation, the use of hormonal manipulation at the time of diagnosis of stage C or D lesions in an attempt to improve over-all survival, instead of awaiting the development of symptomatic metastatic disease, does not appear to be supported by the data presented, although no untreated controls were included in the study. In the 30761 study the implication that the marked difference observed between medroxyprogesterone acetate and the other 2 agents occurred because the weak estrogenic effect of medroxyprogesterone acetate essentially results in a comparison of diethylstilbestrol and cyproterone acetate against a no-treatment arm. As discussed by the authors while the dosage of medroxyprogesterone acetate used in the trial may be inadequate and the medroxyprogesterone acetate-treated patients presented with a higher percentage of unfavorable prognostic indicators than patients in the other treatment groups 1 these factors do not appear to be responsible for the significant differences observed. The possibility that medroxyprogesterone acetate may function as an androgen is real and may in some measure account for the difference noted in response to treatment. In addition to the study quoted, in which medroxyprogesterone acetate restored sexual potency in some patients,3 there are experimental data supporting the assumption that medroxyprogesterone acetate may possess androgenic activity. Chief among these are the observation that medroxyprogesterone acetate binds to the androgen receptor in the kidney,4 and will stimulate development of the external genitalia and, to a lesser extent, the prostate in some species. Thus, it is possible that survival may be influenced unfavorably by medroxyprogesterone acetate and the data observed here do not unequivocally represent a comparison of diethylstilbestrol and cyproterone acetate against no treatment but they may compare an antiandrogen with a weak androgen. Whatever the explanation it is clear that hormonal manipulation, while superior to no active treatment in patients with advanced prostatic cancer, provides benefit for a limited period with approximately 40 per cent of the patients with Mo disease and 60 per cent bf those with metastatic disease dying within 3 years of initiating treatment. The spectacular results of chemotherapy and surgery in the treatment of Wilms and testicular tumors, and the cautious optimism being expressed with the encouraging early results of
654
FAIR
combined therapy in the management of patients with invasive bladder cancer have yet to be approached in prostatic cancer, despite the similar observations of Huggins and Hodges in patients with prostatic cancer who founded the field of solid tumor chemotherapy. 5 In addition to the timing of therapy recently the clinician has been faced with a variety of options for effective hormonal manipulation. In these EORTC studies bilateral orchiectomy was not a treatment consideration but the data appear to indicate that diethylstilbestrol is equivalent to other, more expensive, and perhaps equally toxic forms of therapy. In comparison with estramustine phosphate approximately a third of the patients treated with diethylstilbestrol had cardiovascular complications with the 3 mg. daily dose. This dose is superior to 1 mg. diethylstilbestrol in consistently suppressing testosterone levels to the castrate range 6 but there are no convincing data to indicate that 3 mg. are superior to 1 mg. in affecting clinical response rates. It may be that 2 mg. diethylstilbestrol daily would lower predictably testosterone levels to the castrate range without the cardiovascular toxicity associated with the higher doses, although studies addressing this issue are not available. Estramustine phosphatase appears to have little advantage over diethylstilbestrol in terms of therapeutic effectiveness. In addition, the cost of treatment, which in the New York City area is approximately $600 per month, can be prohibitive. The response to estramustine phosphate in patients who have failed prior endocrine therapy, currently being evaluated in clinical trials, may determine the eventual role of this agent in the clinician's armamentarium. Cyproterone acetate and the other antiandrogens also are being evaluated in a number of studies and appear to be as effective as estrogen in untreated patients. However, they offer no significant benefit to hormonal refractory patients. Although use of the antiandrogens conceptually is appealing in that sexual potency may be maintained while the effect of testosterone on the prostate is inhibited, considerations of cost and availability currently limit their use to experimental situations. The concept of total androgen blockade, as a more effective way of controlling the growth of prostatic cancer, with a combination of LHRH agonist plus an antiandrogen has been proposed recently as a more effective method of controlling or reversing the growth of prostatic cancer. Although the initial results appeared to be encouraging,7 to date no data. are available that confirm those observations, although randomized trials to test this hypothesis currently are being conducted in Canada, Europe and the United States.
In summary, effective hormonal manipulation of prostatic cancer can be accomplished with 1 to 3 mg. diethylstilbestrol daily. Presently, there are no data to indicate that other agents that alter the hormonal milieu of the tumor or the host are any more effective in controlling the clinical manifestations of the disease. Likewise, no data exist to support unequivocally the concept that hormonal manipulation is more effective in terms of over-all survival when given at the time of diagnosis as opposed to waiting until the symptoms dictate therapy. Thus, the last sentence in the 30761 study seems to be unsupported if not unwarranted. William R. Fair Department of Urology Memorial Sloan-Kettering Cancer Center New York,New York
REFERENCES
1. Morse, M. J. and Whitmore, W. F., Jr.: Clinical management of advanced prostatic cancer. In: Hormonally Responsive Tumors. Edited by V. P. Hollander. New York: Academic Press, Inc., part II, chapt. 16, pp. 431-468, 1985. 2. The Veterans Administration Co-operative Urological Research Group: Treatment and survival of patients with cancer of the prostate. Surg., Gynec. & Obst., 124: 1011, 1967. 3. Fossil, S., 0greid, P., Karlsen, F. S., Haveland, H., Jansen, J. and Trovilg, A.: High-dose medroxy-progesterone acetate (MPA) versus prednisolone (P) in hormone-resistant prostatic cancer. In: Advances in Urological Oncology and Endocrinology. Edited by V. Bracci and F. Di Silveris. Rome: Acta Medica, pp. 433-437, 1984. 4. Bardin, C. W., Bullock, L. P., Mills, N. C., Lin, Y. C. and Jacob, S. T.: The role of receptors in the anabolic action of androgens. In: Receptors and Hormone Action. Edited by B. W. O'Malley and L. Birnbaumer. New York: Academic Press, vol. 2, pp. 83103, 1978. 5. Huggins, C. and Hodges, C. V.: Studies on prostatic cancer; the effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res., 1: 293, 1941. 6. Shearer, R. J., Hendry, W. F., Sommerville, I. F. and Fergusson, J. D.: Plasma testosterone: an accurate monitor of hormone treatment in prostatic cancer. Brit. J. Urol., 45: 668, 1973. 7. Labrie, F., Dupont, A., Belanger, A., Lacoursiere, Y., Raynaud, J. P., Husson, J. M., Gareau, J., Fazekas, A. T. A., Sandow, J., Monfette, G., Girard, J. G., Emond, J. and Houle, J. G.: New approach in the treatment of prostatic cancer: complete instead of only partial withdrawal of androgens. Prostate, 4: 579, 1983.
Vol. 136, September
THE JOURNAL OF UROLOGY
Copyright © 1986 by The Williams & Wilkins Co.
Printed in U.S.A.
Editorial HORMONAL THERAPY OF ADVANCED PROSTATIC CANCER This issue of the Journal contains 2 articles that detail the results of studies done by the Urological Group of the European Organization for Research on Treatment of Cancer (EORTC) on hormonal therapy of advanced prostatic cancer (stages C and D or T3T4NxMo and TanyNxMl lesions). These important multi-institutional investigations have added to our knowledge of the relative merits of diethylstilbestrol, cyproterone acetate, medroxyprogesterone acetate and estramustine phosphate in the treatment ofprostatic cancer. The conclusions reached are likely to add more fuel to the controversy regarding the appropriate timing of hormonal treatment. In the EORTC study 30762 (page 619) the effect of diethylstilbestrol was compared to that of estramustine phosphate, a compound claimed to possess hormonal and cytotoxic effects. There were 227 evaluable patients randomized to receive either 3 mg. diethylstilbestrol daily or 560 mg. estramustine phosphate daily for 8 weeks and 280 mg. daily thereafter. At the outset it should be noted that the currently recommended dose of estram:ustine phosphate is 140 mg./10 kg. or approximately 980 mg. daily for a 70 kg. man. Thus, the dosage used in the study is on the order of 30 to 60 per cent of the dose now deemed appropriate. The best local response, as determined by digital rectal examination, was seen in patients receiving diethylstilbestrol. No significant differences were noted between treatments with respect to response rate of metastases, time to local progression, time to distant progression, survival or death of carcinoma of the prostate. In the accompanying EORTC study 30761 (page 624) the group compared diethylstilbestrol, cyproterone acetate and medroxyprogesterone acetate in 210 eligible patients. No significant differences in response were noted in patients receiving either diethylstilbestrol or cyproterone acetate. Patients treated with medroxyprogesterone acetate had a shorter time to progression and a shorter over-all survival than those treated with either of the other 2 agents. Based on these observations, the authors indicate the need to reconsider the appropriateness of delayed hormonal therapy in the management of advanced disease; the implication is that the results may support those who advocate early (at time of diagnosis) intervention. In both studies approximately half of the patients had advanced local disease (T3T4Mo) and the remainder had metastatic disease (Ml) at the start of therapy. In essence then, the patients with nonmetastatic disease may be considered as receiving early hormonal therapy and those with Ml disease receiving late therapy, although not all of the latter patients were symptomatic with disease. The over-all response to hormonal therapy was lower than the reported 80 per cent response to estrogen or castration. 1 Of 156 patients receiving diethylstilbestrol in both studies a significant local response to therapy was noted in 82 (53 per cent). Marked improvement in distant metastases was noted in fewer than 20 per cent of the treated patients (21 of 124). In the 30762 study the time to progression of disease was not different between the 2 treatments and those patients with stage C (T3T4Mo) disease at the initiation of treatment had a time to progression similar to that of placebo-treated patients in the Veterans Administration Co-operative Urological Research Group study. 2 The marked variation in local and distant response rates 653
plus the observation that local response does not necessarily predict distant response suggests that local and distant responses are independent parameters. Another explanation to be considered is that the multitude of known (not to mention unknown) variables and the wide variation in the behavior of prostatic cancer plus the softness on the response criteria, that is digital rectal examination and bone scan, render even the significant differences questionable. These data together with the lack of any statistically significant differences in the overall survival of patients with Mo disease receiving diethylstilbestrol or medroxyprogesterone acetate (in contrast to the improved survival of subjects with Ml disease given diethylstilbestrol versus medroxyprogesterone acetate) weaken the argument for early hormonal manipulation in patients who present with extensive local or asymptomatic metastatic disease at the time of diagnosis. To my interpretation, the use of hormonal manipulation at the time of diagnosis of stage C or D lesions in an attempt to improve over-all survival, instead of awaiting the development of symptomatic metastatic disease, does not appear to be supported by the data presented, although no untreated controls were included in the study. In the 30761 study the implication that the marked difference observed between medroxyprogesterone acetate and the other 2 agents occurred because the weak estrogenic effect of medroxyprogesterone acetate essentially results in a comparison of diethylstilbestrol and cyproterone acetate against a no-treatment arm. As discussed by the authors while the dosage of medroxyprogesterone acetate used in the trial may be inadequate and the medroxyprogesterone acetate-treated patients presented with a higher percentage of unfavorable prognostic indicators than patients in the other treatment groups 1 these factors do not appear to be responsible for the significant differences observed. The possibility that medroxyprogesterone acetate may function as an androgen is real and may in some measure account for the difference noted in response to treatment. In addition to the study quoted, in which medroxyprogesterone acetate restored sexual potency in some patients,3 there are experimental data supporting the assumption that medroxyprogesterone acetate may possess androgenic activity. Chief among these are the observation that medroxyprogesterone acetate binds to the androgen receptor in the kidney,4 and will stimulate development of the external genitalia and, to a lesser extent, the prostate in some species. Thus, it is possible that survival may be influenced unfavorably by medroxyprogesterone acetate and the data observed here do not unequivocally represent a comparison of diethylstilbestrol and cyproterone acetate against no treatment but they may compare an antiandrogen with a weak androgen. Whatever the explanation it is clear that hormonal manipulation, while superior to no active treatment in patients with advanced prostatic cancer, provides benefit for a limited period with approximately 40 per cent of the patients with Mo disease and 60 per cent bf those with metastatic disease dying within 3 years of initiating treatment. The spectacular results of chemotherapy and surgery in the treatment of Wilms and testicular tumors, and the cautious optimism being expressed with the encouraging early results of
654
FAIR
combined therapy in the management of patients with invasive bladder cancer have yet to be approached in prostatic cancer, despite the similar observations of Huggins and Hodges in patients with prostatic cancer who founded the field of solid tumor chemotherapy. 5 In addition to the timing of therapy recently the clinician has been faced with a variety of options for effective hormonal manipulation. In these EORTC studies bilateral orchiectomy was not a treatment consideration but the data appear to indicate that diethylstilbestrol is equivalent to other, more expensive, and perhaps equally toxic forms of therapy. In comparison with estramustine phosphate approximately a third of the patients treated with diethylstilbestrol had cardiovascular complications with the 3 mg. daily dose. This dose is superior to 1 mg. diethylstilbestrol in consistently suppressing testosterone levels to the castrate range 6 but there are no convincing data to indicate that 3 mg. are superior to 1 mg. in affecting clinical response rates. It may be that 2 mg. diethylstilbestrol daily would lower predictably testosterone levels to the castrate range without the cardiovascular toxicity associated with the higher doses, although studies addressing this issue are not available. Estramustine phosphatase appears to have little advantage over diethylstilbestrol in terms of therapeutic effectiveness. In addition, the cost of treatment, which in the New York City area is approximately $600 per month, can be prohibitive. The response to estramustine phosphate in patients who have failed prior endocrine therapy, currently being evaluated in clinical trials, may determine the eventual role of this agent in the clinician's armamentarium. Cyproterone acetate and the other antiandrogens also are being evaluated in a number of studies and appear to be as effective as estrogen in untreated patients. However, they offer no significant benefit to hormonal refractory patients. Although use of the antiandrogens conceptually is appealing in that sexual potency may be maintained while the effect of testosterone on the prostate is inhibited, considerations of cost and availability currently limit their use to experimental situations. The concept of total androgen blockade, as a more effective way of controlling the growth of prostatic cancer, with a combination of LHRH agonist plus an antiandrogen has been proposed recently as a more effective method of controlling or reversing the growth of prostatic cancer. Although the initial results appeared to be encouraging,7 to date no data. are available that confirm those observations, although randomized trials to test this hypothesis currently are being conducted in Canada, Europe and the United States.
In summary, effective hormonal manipulation of prostatic cancer can be accomplished with 1 to 3 mg. diethylstilbestrol daily. Presently, there are no data to indicate that other agents that alter the hormonal milieu of the tumor or the host are any more effective in controlling the clinical manifestations of the disease. Likewise, no data exist to support unequivocally the concept that hormonal manipulation is more effective in terms of over-all survival when given at the time of diagnosis as opposed to waiting until the symptoms dictate therapy. Thus, the last sentence in the 30761 study seems to be unsupported if not unwarranted. William R. Fair Department of Urology Memorial Sloan-Kettering Cancer Center New York,New York
REFERENCES
1. Morse, M. J. and Whitmore, W. F., Jr.: Clinical management of advanced prostatic cancer. In: Hormonally Responsive Tumors. Edited by V. P. Hollander. New York: Academic Press, Inc., part II, chapt. 16, pp. 431-468, 1985. 2. The Veterans Administration Co-operative Urological Research Group: Treatment and survival of patients with cancer of the prostate. Surg., Gynec. & Obst., 124: 1011, 1967. 3. Fossil, S., 0greid, P., Karlsen, F. S., Haveland, H., Jansen, J. and Trovilg, A.: High-dose medroxy-progesterone acetate (MPA) versus prednisolone (P) in hormone-resistant prostatic cancer. In: Advances in Urological Oncology and Endocrinology. Edited by V. Bracci and F. Di Silveris. Rome: Acta Medica, pp. 433-437, 1984. 4. Bardin, C. W., Bullock, L. P., Mills, N. C., Lin, Y. C. and Jacob, S. T.: The role of receptors in the anabolic action of androgens. In: Receptors and Hormone Action. Edited by B. W. O'Malley and L. Birnbaumer. New York: Academic Press, vol. 2, pp. 83103, 1978. 5. Huggins, C. and Hodges, C. V.: Studies on prostatic cancer; the effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res., 1: 293, 1941. 6. Shearer, R. J., Hendry, W. F., Sommerville, I. F. and Fergusson, J. D.: Plasma testosterone: an accurate monitor of hormone treatment in prostatic cancer. Brit. J. Urol., 45: 668, 1973. 7. Labrie, F., Dupont, A., Belanger, A., Lacoursiere, Y., Raynaud, J. P., Husson, J. M., Gareau, J., Fazekas, A. T. A., Sandow, J., Monfette, G., Girard, J. G., Emond, J. and Houle, J. G.: New approach in the treatment of prostatic cancer: complete instead of only partial withdrawal of androgens. Prostate, 4: 579, 1983.