- Email: [email protected]
Estramustine phosphate-hormone, chemotherapeutic agent, or both?
ESTRAMUSTINE
PHOSPHATE-HORMONE,
CHEMOTHERAPEUTIC YAIR WALZER,
AGENT, OR BOTH?*
M.D.
JOYE OSWALT, R.N. MARK S. SOLOWAY M.D. From the Department of Urology, University of Tennessee Center for the Health Sciences, and the Memphis Veterans Administration Hospital, Memphis, Tennessee
ABSTRACT-Estramustine phosphate, a combination steroid and alkylating agent, has been used for treatment of cancer of the prostate since 1969. We treated 32 patients with Stages C and D prostate cancer with this compound. Using the National Prostatic Cancer Project criteria of response, no patient achieved complete or partial objective response. Sixty-two per cent of the patients without prior hormonal manipulation and 12 per cent of those who were progressingfollowing hormonal therapy met the criteria for a stable response. Both Stage C patients, 50 per cent of Dl and 28 per cent of 02 patients achieved disease stabilization for a mean duration of 14.8 months. There was no correlation between tumor grade and response to treatment. Fifty per cent of the patients whose elevated acid phosphatase declined remain stable, whereas 80 per cent in whom the acid phosphatase did not decline have progressed. Estramustine is effective in patients without prior hormonal manipulation. In those refractory to hormones, the prognosis is poor yet data exist to support the superiority of estramustine phosphate over conventional therapy.
Estramustine phosphate (EP), a conju,gate of 17-beta estradiol and nitrogen mustard, is a synthetic agent first manufactured in Sweden and introduced into clinical use in 1969.’ It is one of a series of synthesized agents linking steroids and alkylating moieties evaluated for initial therapy of metastatic and hormonerefractory prostate cancer. Despite extensive clinical trials and laboratory investigations over the last decade, there are conflicing views regarding its mode of action and effectiveness. Since 1979 we have treated 32 patients as part of ongoing protocols of the National Prostatic Cancer Project (NPCP). These patients form the basis of this report. *Supported by PHS Grant CA20618 awarded by The National Prostatic Cancer Project.
UROLOGY
i
JULY 1984
i
VOLUME
XXIV, NUMBER
1
Material and Methods Thirty-two patients with Stage C-D histologically confirmed cancer of the prostate were entered into NPCP protocols. Their ages ranged from fifty-five to eighty-two. Patients were admitted to the study between February, 1979, and August, 1982. Patients received EP either as initial therapy or as a crossover at progression of other modes of therapy as per Protocols 1000, 1300, or 1500 of the NPCP. Table I lists the patients according to prior therapy. Eight patients received EP as initial treatment. All patients were expected to survive ninety days on entry into the study. All had a minimal white blood count of 3,OOO/cu mm and a platelet count greater than 1OO,OOO/cumm. Pretreatment studies included an SMA-12, prostatic acid phosphatase, and alkaline phosphatase. A bone
53
TABLE I.
Initial therapy
Treatment
No. of Patients 8 7
Estracyt Radiation Radiation + orchiectomy Orchiectomy + TUR Orchiectomy + stilbestrol Orchiectomy Radical prostatectomy Radical prostatectomy + orchiectomy + radiation
5
5 3 2 1 1
TOTAL
32
TABLE II. Group I II III IV TOTAL
Response to estracyt Category
No. of Pts.
Stable Progressed Died Off protocol
12 5 12 3 32
scan and appropriate x-ray films were performed prior to entry into a protocol. Blood studies and pertinent physical findings were assessed every three weeks. The bone scan was repeated every three months. At the twelveweek interval, response was determined. If there was objective tumor regression or stabilization, EP was continued. At progression, patients received other antitumor agents as per protocol. Criteria of response have been previously reported.2 Complete objective regression, all of thefollowing: 1. Absence of any clinically detectable soft tissue tumor mass which must include the primary tumor. 2. Return of elevated acid phosphatase to normal. of osteolytic lesions, if 3. Recalcification present. 4. No evidence of progression of osteoblastic lesions, if any. 5. If hepatomegaly is present, there must be complete reduction in liver size and normalization of all pretreatment abnormalities of liver function. Partial objective regression, all of the following: 1. A 50-per cent reduction in measurable or palpable soft tissue tumor mass when present.
54
2. Return of an elevated acid phosphatase to normal. 3. Recalcification of some osteolytic lesions, if present. 4. If hepatomegaly is a significant indicator, there must be reduction in liver size and at least a 30-per cent improvement of all pretreatment abnormalities of liver function 5. There may be no increase in any other lesion and no new areas of malignant disease. * 6. No significant deterioration in weight (> 10 % ), symptoms, or performance status (one score level). * Objectively stable, all of the following: 1. Insufficient regression of indicator lesion to meet aforementioned criteria. 2. Less than 25-per cent increase in any measurable lesion. 3. No significant deterioration in weight (> 10 % ), symptoms, or performance status (one score level). Objective progression, any of following: deterioration in symptoms, 1. Significant decrease in weight or performance status. 2. Appearance of new areas of malignant disease. 3. Increase in any previously measurable lesion (soft tissue and lung, exclude bone) by greater than 50 per cent in two perpendicular diameters. 4. Increase in acid phosphatase alone is not considered an indication of progression; these should be used in conjunction with other criteria. Two patients in this study cannot be fully evaluated. One patient moved away and a second refused treatment at one and thirty-one months, respectively. An additional patient was removed because of toxicity (severe nausea and vomiting). Results No patient had a complete or partial objective response (Table II). Twelve patients have remained stable after initiation of treatment from one to forty months with a mean of 14.8 months and a median duration of thirteen months. Five patients progressed from one to eighteen months following EP These patients continue to be followed and are receiving other *Criteria sion.
applicable
to complete and partial objective
regres-
UROLOGY / JULY 1984 / VOLUMEXXIV, NUMBER1
TABLE III.
No. of Pts. 8
No previous therapy
16
No previous hormonal therapy Hormonal manipulation f anything else
16
Results related to previous therapy
Stage
Stable*
8 Dz 2c 4 D, 10 Dz 16 De
62.5%/11
Lost to F/U
Progressedt 37.5%/2.7 (3) 31% 17.4 (5) 75 % 13.4 (12)
62 *0. 5?7?4 1 (IO) 12.5% 130 (2)
. *
*Mean interval on therapy in months. fMean interval to progression in months.
therapy. Twelve patients died of carcinoma of the prostate from one to five months after beginning EP. Three patients were removed from the protocol at one, six, and thirty-one months for reasons already mentioned. Subjective response was evaluated primarily in terms of decreased bone pain and need for analgesics and was found in 7 patients, 5 in the stable category and 2 in those with objective progression. Since any prior therapy (e.g., radiation, hormonal) may affect response to subsequent EP, response was correlated with types of prior therapy (Table III). Eight patients qualify as both having had no previous therapy and no previous hormonal manipulation and thus appear twice. Eight patients with Stage D2 prostate cancer received EP as initial therapy. Five (62.5%) remain stable for a mean duration of eleven months. Three progressed at a mean of 2.7 months. Sixteen patients received either no treatment, radiation, or radical prostatectomy. Thus, this group did not have prior hormonal manipulation. Two patients in this group were Stage C; four, Dl; and 10, D2 when EP was initiated. Ten (62.5%) patients in this group remain stable for between one and forty-one months with a mean duration of 14.1 months. The remaining six progressed after an average of 7.4 months. Sixteen patients received some form of hormonal manipulation as part of their primary therapy and were placed on EP after documented progression. All patients were D2. Two patients (12.5%) in this group were stable on EP for a mean of thirty months. The remaining 14 patients progressed despite EI? The mean interval to progression was 3.4 months. Table IV reviews patient response according to tumor stage when patients began receiving EI! Two, 4, and 25 patients were Stages C, Dl, D2, respectively. Both Stage C patients have re-
UROLOGY
/ JULY 1984
/
VOLUME XXIV, NUMBER 1
TABLE IV.
Stage c
D, D, ?
No. of
Pts.
2 (6)
4 (12) 25 (78) I (3)
TABLE V.
Stable (%) 2 (100) 2 (50) 7 (28) I
to stage
Progression (%)
Lost to F/U (%)
l’(25) 16 (64)
l(25) 2 (8)
. .
. .
Response according to dijferentiation of primary tumor
Degree of Differentiation Well Moderately well Poor TOTALS
Response according
No. of
Pts. (%)
Stable (%)
Progression (%)
5 (19) 12 (44) 10
I (26) 5 (42) 5 (56)
4 (86) 7 (58) 5 (56)
27
11
16
mained stable. Two of 4 (50%) Stage Dl patients remain stable. Seven of 25 (28%) Stage D2 patients have remained stable. Table V presents patient response according to differentiation of the primary tumor. Five were welldifferentiated tumors, 12 were moderately well differentiated, and 10 were poorly differentiated. Twenty per cent of patients with well differentiated tumors, 42 per cent with moderately well differentiated tumors, and 50 per cent of patients with poorly differentiated tumors have remained stable. In 29 patients the effect of therapy on prostatic acid phosphatase and alkaline phosphatase could be evaluated. Figure 1 presents the data in the 23 patients (79 per cent) who had an elevated prostatic acid phosphatase at initiation of therapy. In 12, the prostatic acid phosphatase level decreased, and one half of these patients have remained stable for a mean duration of
55
5 4 (23%)
l’-”
6 STABLE (50%) MEAN :
18.8
‘~~%~RESSED
MONTHS
(50%) 6.8
MONTHS
2 STABLE “~)PRcIGRESSED (18%) (82%) 4.5
FIGURE 1. Patient with originally tatic acid phosphatase.
MONTHS
2.1
elevated
MONTHS
2 STABLE ’ (40%) MEAN :
17
MONTHS
\
17-/t (77%)
3 PROGRESSED (60%) 7.7
MONTHS
5 STABLE’ (29%) 16
MONTHS
’
12 PROGRESSED (71%) 3.6
MONTHS
pros-
FIGURE 2. Patients with originally elevated alkaline phosphatase.
18.8 months. The remaining patients progressed after a mean interval of 6.8 months. In 11 patients the prostatic acid phosphatase remained stable or continued to increase and only 2 of these patients remained stable for a mean duration of 4.5 months. The remainder progressed after a mean interval of 2.1 months. Figure 2 presents the data in the 22 patients who had an elevated alkaline phosphatase at initiation of therapy. In 5 patients the alkaline phosphatase decreased, and 2 of these remained stable for a mean duration of seventeen months. The remainder have progressed at a mean interval of 7.7 months. In 17 patients the alkaline phosphatases remained the same or increased, and 5 of these remained stable for a mean duration of sixteen months. The remainder have progressed at a mean of 3.6 months. Toxicity was noted in 18 of 32 patients and consisted of mild to severe nausea and vomiting, 1 transient decrease in platelets, 1 increase in bilirubin (2.4) which reversed with temporary discontinuation of therapy. Only 1 patient had therapy discontinued because of toxicity.
peutic regimens do show some promise yet often at the expense of toxicity in this elderly group of patients who frequently have little bone marrow reserve.4,e*7 In an effort to improve on this, estramustine phosphate was designed and manufactured in the hope of carrying the cytotoxic agent directly to hormone-dependent cells. The metabolism of EP involves initial dephosphorylation to estramustine which is then oxidized to estromustine. Estromustine is then hydrolyzed to 17-beta estradiol and the nitrogen mustard moiety. * It is believed that the prostate as well as the liver is capable of hydrolyzing EP thus releasing the alkylating agent inside the cancer cell9 The major circulating metabolite is estromustine, followed by estramustine phosphate, estramustine, estrone, and 17-beta estradiol. The considerable amount of parent compound and its immediate metabolites present in the plasma explains the reportedly low levels of clinical feminization, In vitro, EP was localized originally to both estradiol and dihydrotestosterone receptor sites. lo More recent work has revealed a protein localized in the human, baboon, and rat prostate with a high affinity for estramustine phosphate. This has been named estramustine binding protein (EBP) and is likely similar to other previously described prostatic proteins such as alpha protein, prostatic binding protein, and prostatein. r1 Intracellular binding to such a high-affinity specific protein and hydrolysis with release of the nitrogen mustard directly in the tumor cell could result in a clinical effect after failure of conventional estrogens. An additional theoretical advantage of EP is that the estrogenic component of the compound results in both a depressed serum testosterone as well as a markedly elevated level of testosterone estradiol binding globulin and consequently less available free testosterone than is seen following orchiectomy.12 Several studies have been done using EP as primary therapy. It might be expected that the
Comment The inaccuracies in monitoring tumor status in patients with carcinoma of the prostate make it difficult to assess the results of any currently available therapy. Most patients with Stage D2 disease have bone metastases as the indicator lesion, and thus it is often difficult objectively to monitor response to therapy. The fact remains, however, that this is the primary and usually the only available site of metastases in patients with metastatic prostate cancer. Thus lack of progression, i, e., stable disease and survival, are important parameters for evaluation of therapy.3 The mean survival of patients with metastatic cancer of the prostate resistant to hormonal therapy is approximately twelve months.4.5 Single and multi-agent chemothera.. 56
UROLOGY
i ~u~yi984 / v~LuMEXXIV,N~MBER~
results would be better than with conventional hormones because of theoretical effectiveness against a hormone-resistant tumor cell population. Objective response rates of 60 to 94 per cent have been reported.4x13-1s In our experience, 62 per cent of the patients who received EP as primary hormonal therapy remain stable for a mean interval of eleven months. Nilsson and Jonsson l5 found no qualitative difference in their results from conventional hormones although they believe “regression was more constant and results faster and more reliable than with conventional treatment.” Others report no advantage over conventional hormones. 5,26 Patients who had failed previous hormonal manipulation have a reported objective response rate of 13 to 44 per cent and a partial objective response rate of 10 to 26 per cent with disease stabilization in 30 to 59 per cent. Overall, objective and subjective responses of up to 73 per cent are quoted in the literature.13~14~‘7-27 The median duration of response reported in the literature is between twenty to forty-five weeks and is said to be better than with conventional therapy. 20,23We had only 2 patients in this category who exhibited disease stabilization for a mean duration of thirty months. The remaining patients progressed and did so at an average interval of 3.4 months. Others have documented few subjective or objective responses in patients with hormone-refractory tumors and have equated both mode of action and efficacy of EP to that of conventional estrogens.20.24.26,27 This again raises the issue of how one defines subjective and objective responses. Prior to the efforts by the National Prostatic Cancer Project to induce objectivity, many reports included parameters which have little or no proved correlation with disease progression or remission. Pain relief, weight gain, decreased morbidity, discontinuation of catheter drainage, decreased ureteral stasis, and decreased residual urine have questionable validity as objective parameters of response. 13.15.27~2g Even the seemingly more objective parameter of decrease in tumor size is known not to be accurate as assessed by digital rectal examination. Most authors would include a decreased prostatic acid phosphatase as objective evidence of regression. Yet as noted by Hurst and Byar30 this can be achieved in at least 50 per cent of patients who have become resistant to hormonal therapy simply by using another type of estrogen. It is thus apparent that only by universal adherence to strict criteria such as those proposed by the National Pros-
UROLOGY
/ JULY 1984
i
VOLUME
XXIV, NUMBER 1
tatic Cancer Project can meaningful reporting and comparison of different agents be achieved. A lack of disease progression on bone scan may be far from an ideal tumor marker, yet it is the best parameter currently available. Side effects of EP include gastrointestinal toxicity. Others have noted leukopenia, thrombocytopenia, perineal pain, thrombophlebitis, diarrhea, and urticaria.20.21x25Despite claims of low estrogen side effects, congestive heart failure, pulmonary emboli, salt and water retention, gynecomastia, and impotence also have been reported. 5.g,18,24.31Low levels of serum testosterone, dihydrotestosterone, and gonadotropins as well as high plasma estradiol have been documented.4.‘7,20 This would account for a rate of cardiovascular complications similar to that of conventional estrogens reported by others. 31 Toxicity in this study was confined to frequent nausea and vomiting, thrombocytopenia, and increased bilirubin in 1 patient. Only 1 patient had to discontinue therapy because of side effects. Androgen evaluation was not routinely performed. The small numbers in this series prohibit definitive conclusions, yet our results agree with those in the literature. Patients who received EP as primary therapy or who never previously received hormonal manipulation did well with disease stabilization rates of 62.5 per cent in both groups. Those who previously failed hormonal manipulation did not fair as well with a disease stabilization rate of 12.5 per cent. Both Stage C patients in this series responded. Fifty per cent of Dl and 28 per cent of D2 patients remained stable. There is no statistically significant correlation between tumor differentiation and response. Only 50 per cent of patients whose originally elevated acid phosphatase decreased showed disease stabilization with the remainder progressing. Eighty-two per cent of patients who did not show a decrease in their prostatic acid phosphatase after commencement of therapy either progressed or died. This would suggest that response of prostatic acid phosphatase is a weak indicator of effective therapy yet that a lack of decline is ominous. There is no correlation between clinical response and response of alkaline phosphatase. We conclude that estramustine phosphate works well in patients who have never previously undergone hormonal manipulation. In patients refractory to hormones, the prognosis is poor. Data exist, however, to support the superiority of EP over conventional therapy in
57
this situation.20,23 Furthermore, isolated reports of complete disappearance of bone32 and soft tissue metastases15.25 and revision of prostatic histology to negative 13,25do exist. We therefore believe that continued evaluation in the use of this agent is justified although one should beware of generating undue enthusiasm as to its efficacy as other than an alternative form of hormonal manipulation. 956 Court, Box 10 Memphis, Tennessee 38163 (DR. SOLOWAY) References 1. Alfthan DS, and Rusk J: Estracyt in advanced prostatic carcinoma, Ann Chir Cynecologine Fennial 58: 234 (1969). 2. Schmidt JD, et al: Chemotherapy of advanced prostatic cancer, evaluations or response parameters, Urology 7: 602 (1976). 3. Murphy GP, and Slack NH: Response criteria for the prostate, U.S.A. National Prostatic Cancer Project. The Prostate, 1: 375 (1980). 4. Scott WW, et al: The continued evaluation of the effects of chemotherapy in patients with advanced carcinoma of the prostate, J Urol 116: 211 (1976). 5. Kuss R, et al: Estramustine phosphate in the treatment of advanced prostatic cancer, Br J Urol 52: 29 (1980). 6. Kane RD, Stocks LH, and Paulson DF: Multiple drug chemotherapy regimen for patients with hormonally-unresponsive carcinoma of the prostate: a preliminary report, J Urol 117: 467 (1977). 7. Merrin C: Preliminary report on combination therapy for advanced prostate cancer, Cancer Treat Rep 61: 313 (1977). 8. Kirdani RY, Karr JP, Murphy GP, and Sandberg AA: Prostate cancer; plasma concentrationsof estramustine phosphate and its metabolites. NY State T Med 80: 1390 (1980). 9. Sandberg AA, Rosenthal H, Mittelman A,‘and Murphy GP: Prostatic cancer transcortin levels during treatment with estramustine phosphate, Urology 6: 17 (1975). 10. Nilsson I, Liskowski L, and Nilsson T: Inhibition by estramustine phosphate on estradiol and androgen binding in benign and malignant prostate in humans, ibid 8:- 118 (1976). 11. Kirdana RY, et al: Estramustine binding in rat, baboon and human prostate measured by high pressure liquid chromatography, Steroids 37: 471 (1981). 12. Karr Il? et al: Effects of diethvlstilbestrol and estramustine phosphate dn’serum sex hormone binding globulin and testosterone levels in prostate cancer patients, J Urol 124: 239 (1980). 13. J&son G, Hogherg B, and Nilsson T: Treatment of advanced prostatic carcinoma with estramustine phosphate (Estracyt), Stand J Urol Nephrol 11: 231 (1977).
58
14. Nilsson T: Estracyt-clinical experiences, ibid (Suppl) 55: 135 (1980). 15. Nilsson T, and Jbnsson G: Primary treatment of prostatic carcinoma with estramustine phosphate: preliminary report, J Urol 115: 168 (1976). 16. Slack NH, et al: Relationship of prior hormonal therapy to subsequent estramustine phosphate treatment in advanced prostatic cancer, Urology 14: 549 (1979). 17. Mittelman A, Shukla SK, and Murphy GP: Extended therapy of stage D carcinoma of the prostate with oral estramustine phosphate, J Urol 115: 409 (1976). 18. Fossi SD, Fossi J, and Aakvaag A: Hormone changes in patients with prostatic carcinoma during treatment with estramustine phosphate, ibid 118: 1013 (1977). 19. Benson RC, Wear JB, and Gill GM: Treatment of stage D hormone-resistant carcinoma of the prostate with estramustine phosphate, ibid 121: 452 (1979). 20. Soloway MS, et al: Comparison of estramustine phosphate and vincristine alone or in combination for patients with advanced hormone-refractory, previously irradiated carcinoma of the prostate, ibid 125: 664 (1983). 21. Murphy GP, et al: The use of estramustine and prednimustine versus prednimustine alone in advanced metastatic prostatic cancer patients who have received prior irradiation, ibid 121: 763 (1979). 22. Miintzing J, et al: Pharmacoclinical study of oral estramustine phosphate (Estracyt) in advanced carcinoma of the prostate, Invest Urol 12: 65 (1974). 23. Murphy GP, et al: A comparison of estramustine phosphate and streptozotocin in patients with advanced prostatic carcinoma who have had extensive radiation, J Urol 118: 288 (1977). 24. Foss& SD, and Miller A: Treatment of advanced carcinoma of the prostate with estramustine phosphate, ibid 115: 406 (1976). 25. Edsmyr F, Esposti PL, and Anderson L: Estramustine phosphate therapy in poorly differentiated carcinoma of the prostate, Stand J Urol Nephrol (Suppl) 55: 139 (1980). 26. Andersson L, et al: Estramustine versus conventional estrogenie hormones in the initial treatment of highly or moderately differentiated prostatic carcinoma: a randomized study, ibid (Suppl) 55: 143 (1980). 27. Chisholm GD, O’Donoghue EPN, and Kennedy CL: The treatment of estrogen-escaped carcinoma of the prostate with estramustine phosphate, Br J Uro149: 717 (1977). 28. Hagel R, and Kblln CP: Treatment of advanced carcinoma of the prostate with estramustine phosphate, ibid 49: 73 (1977). 29. Lindberg B: Treatment of rapidly progressing prostatic carcinoma with Estracyt, J Urol 108:-303 (1972). _ 30. Hurst KS, and Bvar DP: An analvsis of the effect of changes from the assigned treatment in a clinical trial or treatment-for prostatic cancer, J Chron Dis 26: 311 (1973). 31. Hedlund PO. Gustafson H. and Siberen S: Cardiovascular complications to treatment of prostate cancer with estramustine phosphate (Estracyt) or conventional estrogen, Stand J Urol Nephrol (Suppl) 55: 103 (1980). 32. Catane R, Kaufman J, Mittelman A, and Murphy GP: Disappearance of osteoblastic metastases in prostatic carcinoma following estramustine therapy, JAMA 237: 2471 (1977). I
UROLOGY
I
JULY 1984
v
/ VOLUME XXIV, NUMBER 1
PHOSPHATE-HORMONE,
CHEMOTHERAPEUTIC YAIR WALZER,
AGENT, OR BOTH?*
M.D.
JOYE OSWALT, R.N. MARK S. SOLOWAY M.D. From the Department of Urology, University of Tennessee Center for the Health Sciences, and the Memphis Veterans Administration Hospital, Memphis, Tennessee
ABSTRACT-Estramustine phosphate, a combination steroid and alkylating agent, has been used for treatment of cancer of the prostate since 1969. We treated 32 patients with Stages C and D prostate cancer with this compound. Using the National Prostatic Cancer Project criteria of response, no patient achieved complete or partial objective response. Sixty-two per cent of the patients without prior hormonal manipulation and 12 per cent of those who were progressingfollowing hormonal therapy met the criteria for a stable response. Both Stage C patients, 50 per cent of Dl and 28 per cent of 02 patients achieved disease stabilization for a mean duration of 14.8 months. There was no correlation between tumor grade and response to treatment. Fifty per cent of the patients whose elevated acid phosphatase declined remain stable, whereas 80 per cent in whom the acid phosphatase did not decline have progressed. Estramustine is effective in patients without prior hormonal manipulation. In those refractory to hormones, the prognosis is poor yet data exist to support the superiority of estramustine phosphate over conventional therapy.
Estramustine phosphate (EP), a conju,gate of 17-beta estradiol and nitrogen mustard, is a synthetic agent first manufactured in Sweden and introduced into clinical use in 1969.’ It is one of a series of synthesized agents linking steroids and alkylating moieties evaluated for initial therapy of metastatic and hormonerefractory prostate cancer. Despite extensive clinical trials and laboratory investigations over the last decade, there are conflicing views regarding its mode of action and effectiveness. Since 1979 we have treated 32 patients as part of ongoing protocols of the National Prostatic Cancer Project (NPCP). These patients form the basis of this report. *Supported by PHS Grant CA20618 awarded by The National Prostatic Cancer Project.
UROLOGY
i
JULY 1984
i
VOLUME
XXIV, NUMBER
1
Material and Methods Thirty-two patients with Stage C-D histologically confirmed cancer of the prostate were entered into NPCP protocols. Their ages ranged from fifty-five to eighty-two. Patients were admitted to the study between February, 1979, and August, 1982. Patients received EP either as initial therapy or as a crossover at progression of other modes of therapy as per Protocols 1000, 1300, or 1500 of the NPCP. Table I lists the patients according to prior therapy. Eight patients received EP as initial treatment. All patients were expected to survive ninety days on entry into the study. All had a minimal white blood count of 3,OOO/cu mm and a platelet count greater than 1OO,OOO/cumm. Pretreatment studies included an SMA-12, prostatic acid phosphatase, and alkaline phosphatase. A bone
53
TABLE I.
Initial therapy
Treatment
No. of Patients 8 7
Estracyt Radiation Radiation + orchiectomy Orchiectomy + TUR Orchiectomy + stilbestrol Orchiectomy Radical prostatectomy Radical prostatectomy + orchiectomy + radiation
5
5 3 2 1 1
TOTAL
32
TABLE II. Group I II III IV TOTAL
Response to estracyt Category
No. of Pts.
Stable Progressed Died Off protocol
12 5 12 3 32
scan and appropriate x-ray films were performed prior to entry into a protocol. Blood studies and pertinent physical findings were assessed every three weeks. The bone scan was repeated every three months. At the twelveweek interval, response was determined. If there was objective tumor regression or stabilization, EP was continued. At progression, patients received other antitumor agents as per protocol. Criteria of response have been previously reported.2 Complete objective regression, all of thefollowing: 1. Absence of any clinically detectable soft tissue tumor mass which must include the primary tumor. 2. Return of elevated acid phosphatase to normal. of osteolytic lesions, if 3. Recalcification present. 4. No evidence of progression of osteoblastic lesions, if any. 5. If hepatomegaly is present, there must be complete reduction in liver size and normalization of all pretreatment abnormalities of liver function. Partial objective regression, all of the following: 1. A 50-per cent reduction in measurable or palpable soft tissue tumor mass when present.
54
2. Return of an elevated acid phosphatase to normal. 3. Recalcification of some osteolytic lesions, if present. 4. If hepatomegaly is a significant indicator, there must be reduction in liver size and at least a 30-per cent improvement of all pretreatment abnormalities of liver function 5. There may be no increase in any other lesion and no new areas of malignant disease. * 6. No significant deterioration in weight (> 10 % ), symptoms, or performance status (one score level). * Objectively stable, all of the following: 1. Insufficient regression of indicator lesion to meet aforementioned criteria. 2. Less than 25-per cent increase in any measurable lesion. 3. No significant deterioration in weight (> 10 % ), symptoms, or performance status (one score level). Objective progression, any of following: deterioration in symptoms, 1. Significant decrease in weight or performance status. 2. Appearance of new areas of malignant disease. 3. Increase in any previously measurable lesion (soft tissue and lung, exclude bone) by greater than 50 per cent in two perpendicular diameters. 4. Increase in acid phosphatase alone is not considered an indication of progression; these should be used in conjunction with other criteria. Two patients in this study cannot be fully evaluated. One patient moved away and a second refused treatment at one and thirty-one months, respectively. An additional patient was removed because of toxicity (severe nausea and vomiting). Results No patient had a complete or partial objective response (Table II). Twelve patients have remained stable after initiation of treatment from one to forty months with a mean of 14.8 months and a median duration of thirteen months. Five patients progressed from one to eighteen months following EP These patients continue to be followed and are receiving other *Criteria sion.
applicable
to complete and partial objective
regres-
UROLOGY / JULY 1984 / VOLUMEXXIV, NUMBER1
TABLE III.
No. of Pts. 8
No previous therapy
16
No previous hormonal therapy Hormonal manipulation f anything else
16
Results related to previous therapy
Stage
Stable*
8 Dz 2c 4 D, 10 Dz 16 De
62.5%/11
Lost to F/U
Progressedt 37.5%/2.7 (3) 31% 17.4 (5) 75 % 13.4 (12)
62 *0. 5?7?4 1 (IO) 12.5% 130 (2)
. *
*Mean interval on therapy in months. fMean interval to progression in months.
therapy. Twelve patients died of carcinoma of the prostate from one to five months after beginning EP. Three patients were removed from the protocol at one, six, and thirty-one months for reasons already mentioned. Subjective response was evaluated primarily in terms of decreased bone pain and need for analgesics and was found in 7 patients, 5 in the stable category and 2 in those with objective progression. Since any prior therapy (e.g., radiation, hormonal) may affect response to subsequent EP, response was correlated with types of prior therapy (Table III). Eight patients qualify as both having had no previous therapy and no previous hormonal manipulation and thus appear twice. Eight patients with Stage D2 prostate cancer received EP as initial therapy. Five (62.5%) remain stable for a mean duration of eleven months. Three progressed at a mean of 2.7 months. Sixteen patients received either no treatment, radiation, or radical prostatectomy. Thus, this group did not have prior hormonal manipulation. Two patients in this group were Stage C; four, Dl; and 10, D2 when EP was initiated. Ten (62.5%) patients in this group remain stable for between one and forty-one months with a mean duration of 14.1 months. The remaining six progressed after an average of 7.4 months. Sixteen patients received some form of hormonal manipulation as part of their primary therapy and were placed on EP after documented progression. All patients were D2. Two patients (12.5%) in this group were stable on EP for a mean of thirty months. The remaining 14 patients progressed despite EI? The mean interval to progression was 3.4 months. Table IV reviews patient response according to tumor stage when patients began receiving EI! Two, 4, and 25 patients were Stages C, Dl, D2, respectively. Both Stage C patients have re-
UROLOGY
/ JULY 1984
/
VOLUME XXIV, NUMBER 1
TABLE IV.
Stage c
D, D, ?
No. of
Pts.
2 (6)
4 (12) 25 (78) I (3)
TABLE V.
Stable (%) 2 (100) 2 (50) 7 (28) I
to stage
Progression (%)
Lost to F/U (%)
l’(25) 16 (64)
l(25) 2 (8)
. .
. .
Response according to dijferentiation of primary tumor
Degree of Differentiation Well Moderately well Poor TOTALS
Response according
No. of
Pts. (%)
Stable (%)
Progression (%)
5 (19) 12 (44) 10
I (26) 5 (42) 5 (56)
4 (86) 7 (58) 5 (56)
27
11
16
mained stable. Two of 4 (50%) Stage Dl patients remain stable. Seven of 25 (28%) Stage D2 patients have remained stable. Table V presents patient response according to differentiation of the primary tumor. Five were welldifferentiated tumors, 12 were moderately well differentiated, and 10 were poorly differentiated. Twenty per cent of patients with well differentiated tumors, 42 per cent with moderately well differentiated tumors, and 50 per cent of patients with poorly differentiated tumors have remained stable. In 29 patients the effect of therapy on prostatic acid phosphatase and alkaline phosphatase could be evaluated. Figure 1 presents the data in the 23 patients (79 per cent) who had an elevated prostatic acid phosphatase at initiation of therapy. In 12, the prostatic acid phosphatase level decreased, and one half of these patients have remained stable for a mean duration of
55
5 4 (23%)
l’-”
6 STABLE (50%) MEAN :
18.8
‘~~%~RESSED
MONTHS
(50%) 6.8
MONTHS
2 STABLE “~)PRcIGRESSED (18%) (82%) 4.5
FIGURE 1. Patient with originally tatic acid phosphatase.
MONTHS
2.1
elevated
MONTHS
2 STABLE ’ (40%) MEAN :
17
MONTHS
\
17-/t (77%)
3 PROGRESSED (60%) 7.7
MONTHS
5 STABLE’ (29%) 16
MONTHS
’
12 PROGRESSED (71%) 3.6
MONTHS
pros-
FIGURE 2. Patients with originally elevated alkaline phosphatase.
18.8 months. The remaining patients progressed after a mean interval of 6.8 months. In 11 patients the prostatic acid phosphatase remained stable or continued to increase and only 2 of these patients remained stable for a mean duration of 4.5 months. The remainder progressed after a mean interval of 2.1 months. Figure 2 presents the data in the 22 patients who had an elevated alkaline phosphatase at initiation of therapy. In 5 patients the alkaline phosphatase decreased, and 2 of these remained stable for a mean duration of seventeen months. The remainder have progressed at a mean interval of 7.7 months. In 17 patients the alkaline phosphatases remained the same or increased, and 5 of these remained stable for a mean duration of sixteen months. The remainder have progressed at a mean of 3.6 months. Toxicity was noted in 18 of 32 patients and consisted of mild to severe nausea and vomiting, 1 transient decrease in platelets, 1 increase in bilirubin (2.4) which reversed with temporary discontinuation of therapy. Only 1 patient had therapy discontinued because of toxicity.
peutic regimens do show some promise yet often at the expense of toxicity in this elderly group of patients who frequently have little bone marrow reserve.4,e*7 In an effort to improve on this, estramustine phosphate was designed and manufactured in the hope of carrying the cytotoxic agent directly to hormone-dependent cells. The metabolism of EP involves initial dephosphorylation to estramustine which is then oxidized to estromustine. Estromustine is then hydrolyzed to 17-beta estradiol and the nitrogen mustard moiety. * It is believed that the prostate as well as the liver is capable of hydrolyzing EP thus releasing the alkylating agent inside the cancer cell9 The major circulating metabolite is estromustine, followed by estramustine phosphate, estramustine, estrone, and 17-beta estradiol. The considerable amount of parent compound and its immediate metabolites present in the plasma explains the reportedly low levels of clinical feminization, In vitro, EP was localized originally to both estradiol and dihydrotestosterone receptor sites. lo More recent work has revealed a protein localized in the human, baboon, and rat prostate with a high affinity for estramustine phosphate. This has been named estramustine binding protein (EBP) and is likely similar to other previously described prostatic proteins such as alpha protein, prostatic binding protein, and prostatein. r1 Intracellular binding to such a high-affinity specific protein and hydrolysis with release of the nitrogen mustard directly in the tumor cell could result in a clinical effect after failure of conventional estrogens. An additional theoretical advantage of EP is that the estrogenic component of the compound results in both a depressed serum testosterone as well as a markedly elevated level of testosterone estradiol binding globulin and consequently less available free testosterone than is seen following orchiectomy.12 Several studies have been done using EP as primary therapy. It might be expected that the
Comment The inaccuracies in monitoring tumor status in patients with carcinoma of the prostate make it difficult to assess the results of any currently available therapy. Most patients with Stage D2 disease have bone metastases as the indicator lesion, and thus it is often difficult objectively to monitor response to therapy. The fact remains, however, that this is the primary and usually the only available site of metastases in patients with metastatic prostate cancer. Thus lack of progression, i, e., stable disease and survival, are important parameters for evaluation of therapy.3 The mean survival of patients with metastatic cancer of the prostate resistant to hormonal therapy is approximately twelve months.4.5 Single and multi-agent chemothera.. 56
UROLOGY
i ~u~yi984 / v~LuMEXXIV,N~MBER~
results would be better than with conventional hormones because of theoretical effectiveness against a hormone-resistant tumor cell population. Objective response rates of 60 to 94 per cent have been reported.4x13-1s In our experience, 62 per cent of the patients who received EP as primary hormonal therapy remain stable for a mean interval of eleven months. Nilsson and Jonsson l5 found no qualitative difference in their results from conventional hormones although they believe “regression was more constant and results faster and more reliable than with conventional treatment.” Others report no advantage over conventional hormones. 5,26 Patients who had failed previous hormonal manipulation have a reported objective response rate of 13 to 44 per cent and a partial objective response rate of 10 to 26 per cent with disease stabilization in 30 to 59 per cent. Overall, objective and subjective responses of up to 73 per cent are quoted in the literature.13~14~‘7-27 The median duration of response reported in the literature is between twenty to forty-five weeks and is said to be better than with conventional therapy. 20,23We had only 2 patients in this category who exhibited disease stabilization for a mean duration of thirty months. The remaining patients progressed and did so at an average interval of 3.4 months. Others have documented few subjective or objective responses in patients with hormone-refractory tumors and have equated both mode of action and efficacy of EP to that of conventional estrogens.20.24.26,27 This again raises the issue of how one defines subjective and objective responses. Prior to the efforts by the National Prostatic Cancer Project to induce objectivity, many reports included parameters which have little or no proved correlation with disease progression or remission. Pain relief, weight gain, decreased morbidity, discontinuation of catheter drainage, decreased ureteral stasis, and decreased residual urine have questionable validity as objective parameters of response. 13.15.27~2g Even the seemingly more objective parameter of decrease in tumor size is known not to be accurate as assessed by digital rectal examination. Most authors would include a decreased prostatic acid phosphatase as objective evidence of regression. Yet as noted by Hurst and Byar30 this can be achieved in at least 50 per cent of patients who have become resistant to hormonal therapy simply by using another type of estrogen. It is thus apparent that only by universal adherence to strict criteria such as those proposed by the National Pros-
UROLOGY
/ JULY 1984
i
VOLUME
XXIV, NUMBER 1
tatic Cancer Project can meaningful reporting and comparison of different agents be achieved. A lack of disease progression on bone scan may be far from an ideal tumor marker, yet it is the best parameter currently available. Side effects of EP include gastrointestinal toxicity. Others have noted leukopenia, thrombocytopenia, perineal pain, thrombophlebitis, diarrhea, and urticaria.20.21x25Despite claims of low estrogen side effects, congestive heart failure, pulmonary emboli, salt and water retention, gynecomastia, and impotence also have been reported. 5.g,18,24.31Low levels of serum testosterone, dihydrotestosterone, and gonadotropins as well as high plasma estradiol have been documented.4.‘7,20 This would account for a rate of cardiovascular complications similar to that of conventional estrogens reported by others. 31 Toxicity in this study was confined to frequent nausea and vomiting, thrombocytopenia, and increased bilirubin in 1 patient. Only 1 patient had to discontinue therapy because of side effects. Androgen evaluation was not routinely performed. The small numbers in this series prohibit definitive conclusions, yet our results agree with those in the literature. Patients who received EP as primary therapy or who never previously received hormonal manipulation did well with disease stabilization rates of 62.5 per cent in both groups. Those who previously failed hormonal manipulation did not fair as well with a disease stabilization rate of 12.5 per cent. Both Stage C patients in this series responded. Fifty per cent of Dl and 28 per cent of D2 patients remained stable. There is no statistically significant correlation between tumor differentiation and response. Only 50 per cent of patients whose originally elevated acid phosphatase decreased showed disease stabilization with the remainder progressing. Eighty-two per cent of patients who did not show a decrease in their prostatic acid phosphatase after commencement of therapy either progressed or died. This would suggest that response of prostatic acid phosphatase is a weak indicator of effective therapy yet that a lack of decline is ominous. There is no correlation between clinical response and response of alkaline phosphatase. We conclude that estramustine phosphate works well in patients who have never previously undergone hormonal manipulation. In patients refractory to hormones, the prognosis is poor. Data exist, however, to support the superiority of EP over conventional therapy in
57
this situation.20,23 Furthermore, isolated reports of complete disappearance of bone32 and soft tissue metastases15.25 and revision of prostatic histology to negative 13,25do exist. We therefore believe that continued evaluation in the use of this agent is justified although one should beware of generating undue enthusiasm as to its efficacy as other than an alternative form of hormonal manipulation. 956 Court, Box 10 Memphis, Tennessee 38163 (DR. SOLOWAY) References 1. Alfthan DS, and Rusk J: Estracyt in advanced prostatic carcinoma, Ann Chir Cynecologine Fennial 58: 234 (1969). 2. Schmidt JD, et al: Chemotherapy of advanced prostatic cancer, evaluations or response parameters, Urology 7: 602 (1976). 3. Murphy GP, and Slack NH: Response criteria for the prostate, U.S.A. National Prostatic Cancer Project. The Prostate, 1: 375 (1980). 4. Scott WW, et al: The continued evaluation of the effects of chemotherapy in patients with advanced carcinoma of the prostate, J Urol 116: 211 (1976). 5. Kuss R, et al: Estramustine phosphate in the treatment of advanced prostatic cancer, Br J Urol 52: 29 (1980). 6. Kane RD, Stocks LH, and Paulson DF: Multiple drug chemotherapy regimen for patients with hormonally-unresponsive carcinoma of the prostate: a preliminary report, J Urol 117: 467 (1977). 7. Merrin C: Preliminary report on combination therapy for advanced prostate cancer, Cancer Treat Rep 61: 313 (1977). 8. Kirdani RY, Karr JP, Murphy GP, and Sandberg AA: Prostate cancer; plasma concentrationsof estramustine phosphate and its metabolites. NY State T Med 80: 1390 (1980). 9. Sandberg AA, Rosenthal H, Mittelman A,‘and Murphy GP: Prostatic cancer transcortin levels during treatment with estramustine phosphate, Urology 6: 17 (1975). 10. Nilsson I, Liskowski L, and Nilsson T: Inhibition by estramustine phosphate on estradiol and androgen binding in benign and malignant prostate in humans, ibid 8:- 118 (1976). 11. Kirdana RY, et al: Estramustine binding in rat, baboon and human prostate measured by high pressure liquid chromatography, Steroids 37: 471 (1981). 12. Karr Il? et al: Effects of diethvlstilbestrol and estramustine phosphate dn’serum sex hormone binding globulin and testosterone levels in prostate cancer patients, J Urol 124: 239 (1980). 13. J&son G, Hogherg B, and Nilsson T: Treatment of advanced prostatic carcinoma with estramustine phosphate (Estracyt), Stand J Urol Nephrol 11: 231 (1977).
58
14. Nilsson T: Estracyt-clinical experiences, ibid (Suppl) 55: 135 (1980). 15. Nilsson T, and Jbnsson G: Primary treatment of prostatic carcinoma with estramustine phosphate: preliminary report, J Urol 115: 168 (1976). 16. Slack NH, et al: Relationship of prior hormonal therapy to subsequent estramustine phosphate treatment in advanced prostatic cancer, Urology 14: 549 (1979). 17. Mittelman A, Shukla SK, and Murphy GP: Extended therapy of stage D carcinoma of the prostate with oral estramustine phosphate, J Urol 115: 409 (1976). 18. Fossi SD, Fossi J, and Aakvaag A: Hormone changes in patients with prostatic carcinoma during treatment with estramustine phosphate, ibid 118: 1013 (1977). 19. Benson RC, Wear JB, and Gill GM: Treatment of stage D hormone-resistant carcinoma of the prostate with estramustine phosphate, ibid 121: 452 (1979). 20. Soloway MS, et al: Comparison of estramustine phosphate and vincristine alone or in combination for patients with advanced hormone-refractory, previously irradiated carcinoma of the prostate, ibid 125: 664 (1983). 21. Murphy GP, et al: The use of estramustine and prednimustine versus prednimustine alone in advanced metastatic prostatic cancer patients who have received prior irradiation, ibid 121: 763 (1979). 22. Miintzing J, et al: Pharmacoclinical study of oral estramustine phosphate (Estracyt) in advanced carcinoma of the prostate, Invest Urol 12: 65 (1974). 23. Murphy GP, et al: A comparison of estramustine phosphate and streptozotocin in patients with advanced prostatic carcinoma who have had extensive radiation, J Urol 118: 288 (1977). 24. Foss& SD, and Miller A: Treatment of advanced carcinoma of the prostate with estramustine phosphate, ibid 115: 406 (1976). 25. Edsmyr F, Esposti PL, and Anderson L: Estramustine phosphate therapy in poorly differentiated carcinoma of the prostate, Stand J Urol Nephrol (Suppl) 55: 139 (1980). 26. Andersson L, et al: Estramustine versus conventional estrogenie hormones in the initial treatment of highly or moderately differentiated prostatic carcinoma: a randomized study, ibid (Suppl) 55: 143 (1980). 27. Chisholm GD, O’Donoghue EPN, and Kennedy CL: The treatment of estrogen-escaped carcinoma of the prostate with estramustine phosphate, Br J Uro149: 717 (1977). 28. Hagel R, and Kblln CP: Treatment of advanced carcinoma of the prostate with estramustine phosphate, ibid 49: 73 (1977). 29. Lindberg B: Treatment of rapidly progressing prostatic carcinoma with Estracyt, J Urol 108:-303 (1972). _ 30. Hurst KS, and Bvar DP: An analvsis of the effect of changes from the assigned treatment in a clinical trial or treatment-for prostatic cancer, J Chron Dis 26: 311 (1973). 31. Hedlund PO. Gustafson H. and Siberen S: Cardiovascular complications to treatment of prostate cancer with estramustine phosphate (Estracyt) or conventional estrogen, Stand J Urol Nephrol (Suppl) 55: 103 (1980). 32. Catane R, Kaufman J, Mittelman A, and Murphy GP: Disappearance of osteoblastic metastases in prostatic carcinoma following estramustine therapy, JAMA 237: 2471 (1977). I
UROLOGY
I
JULY 1984
v
/ VOLUME XXIV, NUMBER 1