- Email: [email protected]
Reply of Dr. Merrin
LETTERS TO THE EDITOR CIS-PLATINUM AND HORMONES IN CANCER OF PROSTATE I wish to comment on the article by Dr. C. E. Merrin entitled “Treatment of Previously Untreated (by hormonal manipulation) Stage D Adenocarcinoma of Prostate with Combined Orchiectomy, Estrogen, and Cisdiaminedichloroplatinum,” published in the February issue (vol. 15, page 123) of UROLOGY. As a medical oncologist experienced in the use of hormonal and chemotherapeutic treatment of carcinoma of the prostate, I find the conclusions in this article to be misleading and potentially damaging to patients. He reports that 22 of 34 patients (65 per cent) had a partial objective response to the treatment with an average duration of nine months. Partial objective response was based on bone scans and x-ray films of bone, and it was purported that a 50 per cent decrease in size of lesion could be judged from these radiographs and scans. I find this unconvincing, although the high subjective response rate is expected because all of the patients were receiving their first hormonal therTO the Editor:
“PY. It is claimed that the combination of cis-platinum and hormone treatment is synergistic. This conclusion is based on the fallacious assumption that one can add previously reported objective response rates for cis-platinum alone and for hormonal manipulation alone and derive an expected response rate for the combination. However, even if two different treatments did not interact, and one were comparing series of patients that were in all ways similar, the expected objective response rate to combined treatment would be greater than the objective response rate to each treatment alone. This is because each treatment independently will cause some patients to have minimal responses that would be converted into objective partial responses by the additional therapy. It has already been shown by the extensive VA studies that the combination of orchiectomy and estrogen adds no benefit compared with either treatment alone in a large series of patients. That hormones appear to produce a high subjective response rate but a lower objective response rate as judged from bone scans and radiographs is also known, but what is important to the patient is how he feels and not what his bone scan looks like. Since many patients with
UROLOGY
/ SEPTEMBER1980
/ VOLUMEXVI,
NUMBER3
carcinoma of the prostate can receive effective palliation with minimal side effects from lowdose estrogens or from orchiectomy, it seems untenable to me that one should add such a highly toxic treatment as cis-platinum at this stage of disease and claim that a median response of nine months conveys benefit. Cisplatinum should remain an experimental drug for treatment of carcinoma of the prostate; it should be used only in younger patients who have failed less toxic treatment and who are able to withstand the considerable toxicity and have a possibility of deriving the minimal benefit that has been observed in other studies. IanTannock, Departments
M.D., Ph.D., F.R.C.P.(C) of Medicine and Biophysics The Ontario Cancer Institute Toronto, Canada
Reply of Dr. Merrin In the past forty years, dissemiTo the Editor: nated cancer of the prostate has been treated in the palliative fashion advocated by Dr. Tannock. It has now become evident that a better treatment was necessary to improve survival. As a result several cooperative groups (National Prostatic Cancer Project, Uro-oncology Veteran’s Group, ECOG, CALGB Southwest Group) and individual investigators have tested different programs of chemotherapy. Single drugs or combinations have been used. The fundings for most of these studies have come from the National Cancer Institute, These efforts express the general interest in the matter and the need to improve therapeutic results. Our study is a phase II trial, testing in a rational fashion the combination of hormonal therapy to a single drug, cis-platinum. The results of our trial appears to be better than any combination tested until the present. I, therefore, do not see how such a study can be misleading and potentially damaging to patients. Platinum toxicity has now improved significantly since the early trials. Platinum now can be administered in a way to produce a minimal (acute and chronic) toxicity. Toxicity in the patients in our study has been reviewed, analyzed, and presented by an independent party (ASCO, vol. 21, p. 355, #C 142). This toxicity has been
331
to be low and tolerable by the patients. possible synergy between hormonal manipulation and nonhormonal chemotherapy has been observed in other hormonal dependent tumors (Richards Cooper, Breast Ca). Our clinical observation seems to indicate that such synergy occurs in carcinoma of the prostate. In addition there is experimental evidence of synergy in the Nb rat prostatic adenocarcinoma treated by the combination of castration and cyclophosphamide (Joseph Drago, Hershey, Pa.). This of course will have to be confirmed by future clinical observations. The records pertaining to these patients were independently reviewed as well as the bone scans, laboratory results, and x-ray films. The patients have continued to respond in the manner described in our article, and some have achieved lasting complete clinical remissions. The therapeutic program tested in this study is certainly not the definitive answer to the treatment of disseminated carcinoma of the prostate, but it is certainly a progress. If Dr. Tannock had tested the therapeutic program as described in this article, I am sure his comments would have been more positive. found
The
Claude E. Merrin, M.D., F.A.C.S. Chicago, Illinois 60625
SEMEN CRYOPRESERVATION TESTICULAR CANCER To the Editor:
AND
The data of R. Bruce Bracken, M.D., and Keith D. Smith, M.D., in their article, Is Semen Cryopreservation Helpful in Testicular Cancer?, published in the June issue (vol. 15:581, 1980) of UROLOGY do not support their conclusion that, “cryopreservation constitutes an unrealistic solution for the potential infertility of patients treated for testicular cancer.” The conclusion is drawn from analysis of fresh semen obtained from 25 men, three of whom were fathers, with Stage I or II germinal testicular tumor confined to one gonad. In each case semen was obtained after the time of unilateral orchiectomy and prior to cancer treatment. The authors did not freeze the semen. A major factor in the conclusion drawn by the authors is that only one of the 25 patients had semen which met minimum criteria “to insure an optimum chance for pregnancy” when semen is cryopreserved. Many people including Stein-
332
berger and Smith’ and Keel and Karow’ have noted that thawed semen has fewer motile sperm than the semen prior to freezing and that this effect is exacerbated when the concentration of sperm is marginal. But the “freezability” of human semen is highly variable. Even though the number of motile sperm may be decreased by 50 per cent as a consequence of freezing, this is certainly not the case in all patients. The lower limit of the normal range for sperm concentration is now thought to be 20 million/ml.3 In reality the only test of the fertilizing capacity of thawed semen is pregnancy itself. Therefore the decision of whether or not sperm should be kept frozen must be made by the patient based on the value he places on sperm storage. The principal conclusion which can be drawn from the study is the authors’ observation that patients who have undergone a unilateral orchiectomy and have been found to have testicular cancer are likely to have a sperm count of less than 40 million/ml. We believe that patients with sperm counts of 20 to 40 million/ml. are candidates for cryopreservation of semen. Because of this we believe that these patients should be presented with the option of cryopreservation. A commercial kit enables physicians to freeze semen and to ship it frozen to a specialized clinical laboratory for maintenance and evaluations.4 Analysis of a sample from the frozen ejaculate rather than from the prefreeze ejaculate is more likely to be predictive of the utility of the semen in AIH. J. J. Carswell, M.D. University Urology Associates 820 Saint Sabastian Way Augusta, Georgia 30901 A. M. Karow, Ph.D. Department of Surgery Medical College of Georgia Augusta, Georgia 30912 References 1. SmithKD, and Steinberger E: Survival of spermatozoa in a human sperm bank, JAMA 223: 774 (1973). 2. Keel BA, and Karow AM: Motility characteristics of human sperm, nonfrozen and cryopreserved, Arch. Androl. 4: 205 (1980). 3. MacLeod J, and Wang Y: Male fertility potential in terms of semen quality: a review of the past, a study of the present, Fertil. Steril. 31: 103 (1979). 4. Bergman S, Howards S, and Sanger W: Practical aspects of banking patients semen for future artificial insemination, Urology 13: 408 (1979).
UROLOGY
/
SEITEMBER
1980
i
VOLUME
XVI,
NUMBER
3
“PY. It is claimed that the combination of cis-platinum and hormone treatment is synergistic. This conclusion is based on the fallacious assumption that one can add previously reported objective response rates for cis-platinum alone and for hormonal manipulation alone and derive an expected response rate for the combination. However, even if two different treatments did not interact, and one were comparing series of patients that were in all ways similar, the expected objective response rate to combined treatment would be greater than the objective response rate to each treatment alone. This is because each treatment independently will cause some patients to have minimal responses that would be converted into objective partial responses by the additional therapy. It has already been shown by the extensive VA studies that the combination of orchiectomy and estrogen adds no benefit compared with either treatment alone in a large series of patients. That hormones appear to produce a high subjective response rate but a lower objective response rate as judged from bone scans and radiographs is also known, but what is important to the patient is how he feels and not what his bone scan looks like. Since many patients with
UROLOGY
/ SEPTEMBER1980
/ VOLUMEXVI,
NUMBER3
carcinoma of the prostate can receive effective palliation with minimal side effects from lowdose estrogens or from orchiectomy, it seems untenable to me that one should add such a highly toxic treatment as cis-platinum at this stage of disease and claim that a median response of nine months conveys benefit. Cisplatinum should remain an experimental drug for treatment of carcinoma of the prostate; it should be used only in younger patients who have failed less toxic treatment and who are able to withstand the considerable toxicity and have a possibility of deriving the minimal benefit that has been observed in other studies. IanTannock, Departments
M.D., Ph.D., F.R.C.P.(C) of Medicine and Biophysics The Ontario Cancer Institute Toronto, Canada
Reply of Dr. Merrin In the past forty years, dissemiTo the Editor: nated cancer of the prostate has been treated in the palliative fashion advocated by Dr. Tannock. It has now become evident that a better treatment was necessary to improve survival. As a result several cooperative groups (National Prostatic Cancer Project, Uro-oncology Veteran’s Group, ECOG, CALGB Southwest Group) and individual investigators have tested different programs of chemotherapy. Single drugs or combinations have been used. The fundings for most of these studies have come from the National Cancer Institute, These efforts express the general interest in the matter and the need to improve therapeutic results. Our study is a phase II trial, testing in a rational fashion the combination of hormonal therapy to a single drug, cis-platinum. The results of our trial appears to be better than any combination tested until the present. I, therefore, do not see how such a study can be misleading and potentially damaging to patients. Platinum toxicity has now improved significantly since the early trials. Platinum now can be administered in a way to produce a minimal (acute and chronic) toxicity. Toxicity in the patients in our study has been reviewed, analyzed, and presented by an independent party (ASCO, vol. 21, p. 355, #C 142). This toxicity has been
331
to be low and tolerable by the patients. possible synergy between hormonal manipulation and nonhormonal chemotherapy has been observed in other hormonal dependent tumors (Richards Cooper, Breast Ca). Our clinical observation seems to indicate that such synergy occurs in carcinoma of the prostate. In addition there is experimental evidence of synergy in the Nb rat prostatic adenocarcinoma treated by the combination of castration and cyclophosphamide (Joseph Drago, Hershey, Pa.). This of course will have to be confirmed by future clinical observations. The records pertaining to these patients were independently reviewed as well as the bone scans, laboratory results, and x-ray films. The patients have continued to respond in the manner described in our article, and some have achieved lasting complete clinical remissions. The therapeutic program tested in this study is certainly not the definitive answer to the treatment of disseminated carcinoma of the prostate, but it is certainly a progress. If Dr. Tannock had tested the therapeutic program as described in this article, I am sure his comments would have been more positive. found
The
Claude E. Merrin, M.D., F.A.C.S. Chicago, Illinois 60625
SEMEN CRYOPRESERVATION TESTICULAR CANCER To the Editor:
AND
The data of R. Bruce Bracken, M.D., and Keith D. Smith, M.D., in their article, Is Semen Cryopreservation Helpful in Testicular Cancer?, published in the June issue (vol. 15:581, 1980) of UROLOGY do not support their conclusion that, “cryopreservation constitutes an unrealistic solution for the potential infertility of patients treated for testicular cancer.” The conclusion is drawn from analysis of fresh semen obtained from 25 men, three of whom were fathers, with Stage I or II germinal testicular tumor confined to one gonad. In each case semen was obtained after the time of unilateral orchiectomy and prior to cancer treatment. The authors did not freeze the semen. A major factor in the conclusion drawn by the authors is that only one of the 25 patients had semen which met minimum criteria “to insure an optimum chance for pregnancy” when semen is cryopreserved. Many people including Stein-
332
berger and Smith’ and Keel and Karow’ have noted that thawed semen has fewer motile sperm than the semen prior to freezing and that this effect is exacerbated when the concentration of sperm is marginal. But the “freezability” of human semen is highly variable. Even though the number of motile sperm may be decreased by 50 per cent as a consequence of freezing, this is certainly not the case in all patients. The lower limit of the normal range for sperm concentration is now thought to be 20 million/ml.3 In reality the only test of the fertilizing capacity of thawed semen is pregnancy itself. Therefore the decision of whether or not sperm should be kept frozen must be made by the patient based on the value he places on sperm storage. The principal conclusion which can be drawn from the study is the authors’ observation that patients who have undergone a unilateral orchiectomy and have been found to have testicular cancer are likely to have a sperm count of less than 40 million/ml. We believe that patients with sperm counts of 20 to 40 million/ml. are candidates for cryopreservation of semen. Because of this we believe that these patients should be presented with the option of cryopreservation. A commercial kit enables physicians to freeze semen and to ship it frozen to a specialized clinical laboratory for maintenance and evaluations.4 Analysis of a sample from the frozen ejaculate rather than from the prefreeze ejaculate is more likely to be predictive of the utility of the semen in AIH. J. J. Carswell, M.D. University Urology Associates 820 Saint Sabastian Way Augusta, Georgia 30901 A. M. Karow, Ph.D. Department of Surgery Medical College of Georgia Augusta, Georgia 30912 References 1. SmithKD, and Steinberger E: Survival of spermatozoa in a human sperm bank, JAMA 223: 774 (1973). 2. Keel BA, and Karow AM: Motility characteristics of human sperm, nonfrozen and cryopreserved, Arch. Androl. 4: 205 (1980). 3. MacLeod J, and Wang Y: Male fertility potential in terms of semen quality: a review of the past, a study of the present, Fertil. Steril. 31: 103 (1979). 4. Bergman S, Howards S, and Sanger W: Practical aspects of banking patients semen for future artificial insemination, Urology 13: 408 (1979).
UROLOGY
/
SEITEMBER
1980
i
VOLUME
XVI,
NUMBER
3