High-Dose Estrogen Therapy for Advanced Prostatic Cancer

Jpn. J. Clin. Oncol. 98, () ~ 8 High-Dose Estrogen Therapy for Advanced Prostatic Cancer KENKICHI KOISO, M.D., MIKINOBU OHTANI, M.D., HIROYUKI ASAKAGE, M.D., MAKOTO FUJIME, M.D., HIDEICHI AKIMA, M.D., HIROICHI KISHI, M.D., KAZUKI KAWABE, M.D., AKIRA UENO, M.D. AND TADAO NIIJIMA, M.D. Department of Urology, Faculty of Medicine, the University of Tokyo, Tokyo Abstract To learn whether high-dose estrogen therapy is really effective for advanced prostatic cancer, 5 patients with stage C and stage D disease were retrospectively analyzed. Thirty-nine patients were treated with a high dose of Hexestrol, mg, and patients with the ordinary dose of the drug, mg, daily. In the former group of patients the dosage was reduced to a maintenance level of mg mo after the initiation of therapy. The antitumor effect was evaluated according to the National Prostatic Cancer Project (U.S.) criteria. The follow-up period was at least 5 yr. High-dose therapy was not superior to ordinary therapy in its antitumor effect or in reducing serum phosphatases. Moreover, 5-yr survival rates of the two groups did not differ statistically. However, high-dose estrogen was effective for localizing the metastatic bone lesions. Stage D patients treated with high-dose estrogen showed a lower percentage of patients with "progressive disease" than did those treated with the ordinary dose. There were no statistical differences in adverse effects between the two groups. In conclusion it is indicated that high-dose estrogen therapy should be used for patients with massive bone metastases. Introduction vanced prostatic cancer was increased by estrogen therapy (Murphy, 97). Since the pioneering studies of anti-andro- Recently it was pointed out by the genie treatment for prostatic cancer (Hug- Veterans' Administration Cooperative Urologins and Hodges, 9), estrogen prepara- gical Research (VACURG) that tions, natural or synthetic, have been used survival of prostatic cancer patients in and accepted (Hendry and Furgusson, stage C and stage D was not increased by 976). Synthetic estrogens, such as Hexest- estrogens, and that the causes of poorer rol and diethylstilbestrol-diphosphate, have prognosis in these patients were mainly been reported to be effective for the treat- cardiovascular (Byar, 97). Although the ment of prostatic cancer. However, it is studies made by VACURG are open to doubtufl that survival of patients with ad- criticism, estrogens are now considered to have adverse effects upon the cardiovascular Received March, 98. systems. This study was partially supported by a The mechanism of action of estrogens on Grant-in-Aid from the Ministry of Health and prostatic cancer cells is mainly through Welfare, Japan. hormones, but direct action of estrogens as Reprint requests: Kenkichi Koiso, M.D.,. u...,,, r>». c it i c n t x* J- chemotherapeutic agents 6 has been demon- Department of Urology, Faculty of Medicine, ^ strated University of Tokyo, -, Hongo 7-chome, (Harper et al., 97). From this Bunkyo-ku, Tokyo, Japan. point of view, increase in the normal dosage Downloaded from http://jjco.oxfordjournals.org/ at Pennsylvania State University on September 9, 6

KOISO et al. Jpn. J. Clin. Oncol. August 98 of estrogen was attempted for treating advanced cases of prostatic cancer, with careful observation for these side effects. This paper presents the clinical effects of anti-androgenic therapy given to patients with stage C and stage D prostatic cancer to determine whether high dosage of estrogen is really effective. and Methods One hundred and fifty-two patients with stage C and stage D prostatic cancer who visited the Tokyo University Hospital from January 96 to December 975 were analyzed retrospectively. Seventy-seven patients had stage C disease, while 75 had Croup stage D. All cases were diagnosed as adenocarcinoma histologically. The prostatic cancer cells were classified as welland poorly-differentiated. Staging was performed according to the criteria of Whitmore (96). The patients were divided into four groups according to the stages and to the estrogen doses administered (Table ). Usually the dose was reduced to a maintenance level of mg daily mo after initiation of therapy in the patients in and. They did not receive prior-treatment. The follow-up period was at least 5 yr. Clinical effects of Hexestrol therapy were evaluated on the basis of the following items according to the National Prostatic Cancer Project (U.S.) Table Number of in Each With the Average Age, the Stages, Doses of Hexestrol Administered and Histological Classification 6 7 5 5 Average Age (yr) 6.5 6.5 6. 6.8 6.6 Stage C C D D Doses of Hexestrol Administered (mg) Histological 9 96 Classification Welldifferentiated Poorlydifferentiated There were no statistical differences in the distribution of patients' ages, and histological differentiation among the groups. Table Changes in the Size of Prostatic Tumors Before and After Treatment 6 8 56 Downloaded from http://jjco.oxfordjournals.org/ at Pennsylvania State University on September 9, 6 Shrinkage Changes in the Tumor Size Enlarged 6 7 5 5 (.) 5 (9.) (8.9) (8.) 9 (5.7) (6.7) 6 (5.) (.) 9 (.9) 6 (9.5) 8 (.) 6 (5.) (7.8) 9 (.9) 5 (.8) Numbers in parentheses represent the percentage of the patients with indicated result. Differences between s and, and between s and are not statistically significant.

Vol., No. ESTROGEN THERAPY FOR PORSTATIC CANCER criteria (Murphy, 979). Size of the Prostatic Tumor Tumor size was estimated by rectal palpation. The changes in tumor size were described as shrinkage, unchanged, and enlarged. The term "shrinkage" was used when over 5% regression of the bulk of the tumor mass was observed. Changes of less than 5% of the original tumor were noted as "unchanged." Tumor growth in spite of the treatment was noted as "enlarged." Serum Acid- and Alkali-Phosphatase and ALP) (ACP Serum levels of these phosphatases were measured spectrophotometrically. Their changes were divided into three categories: decreased to normal; decreased, but above normal and unchanged or went to abnormal. However, patients who showed normal levels of these phosphatases during the therapy were excluded from this analysis. Metustuses In stage D patients bone metastases were examined roentgenologically. The changes were evaluated as disappeared, unchanged and developed. Survival of the were followed up for at least 5 yr. Survival rates were calculated by the actuarial method and expressed as percentage ± standard error (Cutler and Ederer, 958). Size of the Tumor Results Changes in the size of prostatic tumors before and after treatment are shown in Table. There was no statistical difference in changes in tumor size between the highdose estrogen group and the ordinary dose group in either stage C or stage D. Stage C prostatic cancer was not shown to respond to the estrogen therapy better than stage D disease. Acid- and Alkali-Phosphatase No statistical differences in the changes in serum ACP levels were demonstrated between s and, and between s and. However, it should be pointed out that Hexestrol was more effective in stage C than in stage D for decreasing the activity of this enzyme (statistically significant, P <.) (Table ). The same phenomena were observed for ALP activity (Table ). Metastases Stage D patients had bone metastases, Table Serum Acid-Phosphatase Changes Before and After Treatment Downloaded from http://jjco.oxfordjournals.org/ at Pennsylvania State University on September 9, 6 Decreased to normal Serum Acid-Phosphatase Change Decreased, but above normal or increased 8 9 (6.5) 5 (.5) II (.9) 5 (6.) (.6) 9 (.) 5 (.7) 7 (56.) (5.6) 6 (5.) ( 9.) (6.6) (.8) (.) (6.) Numbers in parentheses represent the percentage of patients with the indicated change. The differences between.s L and, and between s and are statistically not significant.

KOISO et al. Jpn. J. Clin. Oncol. August 98 9- - Fig. I: Survival rates of the prostatic cancer patients in I and. There were no statistical differences in 5-yr survival rates between these two groups. standard error Survival Fates Actuarial 8 7 " 5- - - - - 5 years 5 years Fig. : Survival rates of the prostatic cancer patients in and. There were no statistical differences in 5-yr survival rates between these two groups. Table Serum Alkali-Phosphatase Changes Before and After Treatment 5 9 Decreased to normal (7.6) 7 (5.) (.) 5 (6.) (.9) Serum Alkali-Phosphatase Change Decreased, but above normal 8 (.9) 5 (8.5) (6.) (6.) 67 (5.) or increased ( 9.5) ( 8.) 8 (6.) (.5) "5 (.ff Numbers in parentheses represent the percentage of patients with the indicated change. The differences between s and, and between s and are statistically not significant. Downloaded from http://jjco.oxfordjournals.org/ at Pennsylvania State University on September 9, 6 Table 5 Change in Bone Metastases in and Before and After Treatment Disappeared Changes in Metastases Newly formed 5 (5.7) (.5) (.) (6.7) 7 (5.9) 7 (.8) Numbers in parentheses represent percentage of the patients with the indicated result. The differences between s and as for the "unchanged" and "newly formed" categories are statistically significant (P <.5).

Vol., No. ESTROGEN THERAPY FOR PORSTATlC CANCER 5 mostly osteoblastic. Changes in these me- as unchanged. Also progressive disease was tastases are summarized in Table 5. High- observed much more frequently in dose estrogen therapy was effective in than in. This difference is statistilocalizing the bone metastases. cally significant (P <.5) (Table 6). Overall Response Survival Rates There were no statistical differences in Five-year survival rates in each group are complete response, partial response, un- shown in Figs. and. s and changed or progressive disease between exhibited 5-yr survival rates of 8 ± 6% s and. No complete response was (M ± SE) and 5.5 ±.5%, respectivefound in stage D patients. Partial response ly. Five-year survival rates in s and rate in was 5.% and in were.6 ± 8.% and. ± 6.%,, 7.% (not significant statistically), respectively. There were no statistical differ- Twenty-five patients (7.%) in ences between these groups, and 5 (68.%) in were evaluated Table 6 Overall Response in Prostatic Cancer G Response CR pr N C p D 6 5 ( 8.) 5 (5.) 5 (.7) 5 (5.) 7 (.8) 6 (5.) (.5) 5 (9.) 5 ( ) 8(5.)* 5(7.)* (7.7)** ( ) 6(7.) 5(68.) (.6) 5 7"(~?6) 5 (.) 69~(5.) (7.) Numbers in the parentheses represent the percentage of patients with the indicated response. *: Difference between s and not significant. **: Difference between s and statistically significant (P <.5). CR complete response NC = no change PR = partial response PD = progressive disease Toxicity Table 7 Incidence of Toxicity Caused by Hexestrol - - Gynecomastia Edema 7 5 (5. ) (5. ) 5 (9. ) (. 5) 9 5 (5 8) (8.) 8 7 (6.) (.8) Hypertension 5 ( 8. ) (. 8) ( 5 7) ( 9.) Cardiovascular Damage ( ) ( ) ( 9) (.5) Liver Damage ( ) ( ) (.8) ( 9.) Exanthema ( ) ( 5 9) ( ( ) Bleeding ( ) ( ) ( ) (.5) Others 5 ( 8 5) (.8) ( 9) ( 9.) 5 - - Downloaded from http://jjco.oxfordjournals.org/ at Pennsylvania State University on September 9, 6 Numbers in parentheses represent the percentage of patients with indicated toxicity.

6 KOISO et al. Jpn. J. Clin. Oncol. August 98 Complication The main complications seen during estrogen therapy were painful gynecomastia, edema and hypertension. Cardiovascular complications were seen in three cases. Sever dysfunction of liver, exanthema and gastrointestinal (Gl) bleeding were seen in low percentages. There were few serious lifethreatening complication. No statistical differences of complications were demonstrated between the high and ordinary dose groups (Table 7). Causes of Death Most of the patients died of prostatic cancer. Senescence and uremia were the causes of death in six patients each. Two patients died of "cardiovascular accidents" during estrogen therapy. The remaining causes of death were cerebral hemorrhage, pneumonia, Gl bleeding, gastric cancer, and ileus (Table 8). Causes of death were classified as '"unknown," when the patients were under the control of the out-patients' clinic and died at home, so that there were no autopsy records (Table 8). Discussion Recent studies have shown that estrogens act synergistically with androgens on the prostate. Moreover, estrogens can inhibit DNA polymerase and 5-reductase, suggesting a direct nuclear site of inhibition (Armstrong and Bashiralahi, 97; Hawkins et al., 976; Shimazaki et al., 97). These facts appear to suggest that estrogens have a direct action on prostatic cancer cells. In the clinical practice of urology high-dose estrogen therapy has been recommended and used in the United Kingdom. Hendry and Fergusson (976) reported that better survival at 6 mo was obtained with a high-dose regimen. These facts led us to compare the results of high-dose estrogen therapy with those of the ordinary dose of estrogen. An anti-tumor effect was observed in % of the stage C patients, but in about 8% in the stage D patients. The effect of high-dose estrogen therapy was considered not to be superior to that of ordinary estrogen therapy. Serum acid-phosphatase levels were elevated in most of the patients under study. The lowering effect of the estrogen preparations on this enzyme was marked in stage C patients, whereas in only about 5% of the stage D patients was there marked reduction. There was no statistical difference in acid-phosphatase changes between the massive and ordinary dose groups. These facts indicate that the lowering effect of estrogens on these phosphatases do not depend upon the dosage administered. In stage D patients changes in bone metastases were examined roentgenologically. Disappearance of the metastases was observed in 5.7% of patients and.5% of patients; the effectiveness of Hexestrol against bone metastases was not striking. Although the percentage of patients in the unchanged bone metastasis category was much higher in than in, newly formed bone metastases in were much fewer than in. From these facts it is assumed that massive-dose estrogen therapy was effective for localizing the metastatic bone lesion. Table 8 Causes of Death During Estrogen Therapy Cause of Death Prostatic Cancer Senescence Cardio-vascular Cerebral Bleeding Pneumonia Gl Bleeding Gastric Cancer Iieus Renal Insufficiency Unknown Cases 8 8 6 9 5 6 6 9 8 Downloaded from http://jjco.oxfordjournals.org/ at Pennsylvania State University on September 9, 6

Vol., No. ESTROGEN THERAPY FOR PORSTATIC CANCER 7 The overall response rates show that the percentage of patients with progressive disease in stage D was.6% in the high-dose group, while it was 7.7% in the ordinary dose group. Five-year survival rates of the patients on ordinary-dose estrogen therapy were lower than in those on high doses. However, there were no statistical differences. Blackard et at. (97) reported that the incidence of cardiovascular death was greatly reduced if the dose of estrogens was cut to a lower level. Therefore, in the case of massive-dose estrogen therapy it should be mentioned that estrogen had an adverse effect on the cardiovascular system. In this study the incidence was extremely low. The cause of death in prostatic cancer was mainly cancer itself. There was no statistical difference in distribution of the causes of death between the high- and ordinary-dose group. These results are in agreement with those so far reported in the literature (Scott and Boyd, 969). References Armstrong, E. G. and N. Bashiralahi, Biochem Biophys Res Commun 6: 68, 97. Blackard, C. E., R. P. Doe, G. T. Mellinger and D. P. Byar, J Urol 6: 79, 97. Byar, D. P., Cancer : 6, 97. Cutler, S. J. and F. Ederer, J Chronic Dis 8: 699, 958. Harper, M. E., A. R. Rahmy and C. G. Pierrepoint, Steroids 5: 89, 97. Hawkins, E. F., M. Nijs and C. Brassinne, Biochem Biophvs Res Commun 7: 85, 976. Hendry, W. F. and F. D. Furgusson, Recent Advances in Urology (edited by W. F. Hendry). Churchill Livingstone, Edinburgh, London and New York, p. 9, 976. Huggins, C. and C. V. Hodges, Cancer Res : 9, 9. Murphy, G. P., Cancer : 8, 97. Murphy, G. P., Prostatic Cancer (edited by G. P. Murphy). PSG Publishing Co., Inc., Littleton, Massachusetts, p., 979. Scott, W. W. and H. L. Boyd, J Urol : 86, 969. Shimazaki, J., T. Horaguchi and Y. Ohki. Endocrinol Jpn 8: 79, 97. Whitmore. W. F. Jr.. Cancer 6: 9, 96. Downloaded from http://jjco.oxfordjournals.org/ at Pennsylvania State University on September 9, 6