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Experiences in the Treatment of Carcinoma of the Prostate with Stilbestrol and with Castration by the Technique of Intra-capsular Orchidectomy12
EXPERIENCES IN THE TREATMENT OF CARCINOMA OF THE PROSTATE WITH STILBESTROL AND WITH CASTRATION BY THE TECHNIQUE OF INTRA-CAPSULAR ORCHIDECTOMY1 •2 RICHARD CHUTE
AND
ARTHUR T. WILLETTS
AND
JOHN P. GENS
(by invitation) From the Urological Service of the Massachusetts General Hospital, Boston
It was a year ago that Huggins by the presentation of his brilliant pioneer work with castration and also estrogen, and Herbst by the report of his favorable experiences with estrogen gave tremendous new hope and impetus to the difficult problem of the treatment of inoperable carcinoma of the prostate. Great improvement in these patients, both subjectively and objectively, had been brought about by reducing the physiological action of the androgens in the body. This had been accomplished either by curtailing the production of androgens through surgical castration, or by biochemically inactivating or neutralizing the existing androgens by the administration of estrogen. The remarkably fine results reported in these inoperable cases, far better than any previous results, fired us, as well as many others, with excitement and hope, and this report deals with our experiences in treating 27 cases of inoperable carcinoma of the prostate with castration, with estrogen, or, in most cases, with a combination of the 2 over the course of the last 10 months. This is, of course, too short a time in which to be able to appraise the final value of the treatment, but since our results have been so favorable, and since some of the successful results reported by Huggins have lasted for more than 2 years, it seems suitable to present a preliminary report of our experiences at this time. As a preamble we hasten to say that we are in favor of performing radical perineal prostatectomy in those few early cases of carcinoma of the prostate that can be entirely removedsurgically and are without demonstrable metastases, but unfortunately such cases compose only a small proportion of the total. All but 4 of our 27 cases were proven to be carcinoma of the prostate by microscopic examination of tissue, and there was convincing clinical evidence in the other 4, as 2 cases had hard prostates with x-ray findings of typical bone met~stases, and the other 2 cases had obstruction to urination by enlarged, hard and irregular prostates which became much smaller and softer within a few months after castration. Therefore we are sure ·that all these were cases of carcinoma of the prostate. We have recently been using the Silverman biopsy needle through the perineum with some success in establishing the diagnosis of carcinoma of the prostate in debatable cases, and in the future there should be no cases in which tissue is not obtained for pathological examination. Four of our 27 cases were simply treated by the administration of the potent synthetic estrogen, diethylstilbestrol, or, more frequently, the closely related 1 Read at the Annual Meeting American Urological Association, New York, N. Y., June 2, 1942. 2 The authors wish to thank the Department of Medical Research, Winthrop Chemical Company, for kindly supplying the stilbestrol used in this work.
682
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diethylstilbestrol dipropionate, hereinafter referred to simply as stilbestrol, 2 cases were treated with castration alone, while the majority of 21 cases (77 per cent) were treated with a combination of castration and stilbestrol. We chose the synthetic estrogen stilbestrol partly because others had reported success with its use, partly because it was less expensive than the natural estrogens, and partly because in addition to being highly effective when injected, it is also much more potent when taken by mouth than an equal amount of any oral preparation of a natural estrogen, it being considered that only twice the dose must be taken orally to produce the same effect as by injection. We were unable to detect any significant difference in effect between diethylstilbestrol and diethylstilbestrol dipropionate, and used the dipropionate almost entirely in the second half of our series. From the clinical point of view there was only 1 case out of the 27 that was not benefited by the treatment. In all the other cases, while the amount of improvement varied, the average amount was marked, and in a few cases the improvement was so marked as to almost suggest cure. Our original plan had been to use castration only, unless that were refused by the patient, but then we found that stilbestrol increased the castration effect markedly giving a much more rapid and marked effect than castration alone. For instance, 2 of our early patients, 2 months and 3 months respectively after castration, had improved considerably in general condition, but had not shown a great deal of reduction in the size of their prostates. However, after 10 days of intensive therapy with injections of stilbestrol their glands became markedly smaller and softer. In view of this we have used a combination of castration and stilbestrol in all but our early cases. We also found that, in every way, the results when stilbestrol alone without castration was used were the equal of those when stilbestrol and castration were used. However, the effect of castration, even if slower, is permanent, while if stilbestrol alone is used, the effect lasts only during its administration, and symptoms return soon if it is discontinued, and therefore patients have to be carried on a small oral maintenance dose indefinitely. Perhaps the most immediate and striking result of treatment was the rapid relief from the severe pain due to metastases. In 9 of our cases (33 per cent), all but one of which had metastases to the bones of the pelvis or spine demonstrable by x-ray, pain was a prominent feature, and in 8 out of these 9 cases the pain was quickly and practically completely relieved, in 1 case by castration alone, in 3 cases by stilbestrol alone and 4 by castration and stilbestrol. Sometimes the rapidity of the relief from pain was astonishing. One man got complete relief from his pain within 24 hours after castration, another experienced the same thing within 3 days, while the severe pains of a third vanished after the injection of a total of 10 mg. of stilbestrol in 5 days. Another old man of 84, who had been bedridden on account of agonizing pain in his spine and his legs, got up out of bed for the first time in four months a:fter 100 mg. of stilbestrol had been injected in 10 days. Another patient with metastases to the spine and pelvis had a pathological fracture of the first lumbar vertebra which kept
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him miserable and in constant pain. After castration followed by 135 mg. of stilbestrol in 17 days, his pain, which was rather slow to subside, was gone completely. When he was seen 1 month later he had discarded the brace which he had been wearing for the pathological fracture, had a good appetite and had gained weight, and said he was "a different man." Five months later the improvement had been maintained. This man originally had a very high acid phosphatase: 39.5 Gutman units per cent (normal 4 G units per cent). This fell to 26.3 units 2 days after castration, and at the end of his stilbestrol injections it had diminished to 7.5 units. After the relief of pain, the next most noticeable effect of this treatment was the almost immediate improvement in appetite, weight, and feeling of wellbeing of these patients, many of whom were miserable and had become cachectic with anorexia, sometimes nausea, and often great loss of weight. Within a few days they started to feel better and their appetite improved. This improvement in appetite occurred with such complete regularity that it seemed almost like a physiological response. More than half of our cases before therapy had disturbances of gastric function, ranging from anorexia to nausea, and in all but the one failure this condition was definitely benefited by the treatment. In response to the improved appetite, there was a noticeable gain in weight. The effect of the treatment on__ the prostate itself was marked, the gland becoming smaller and softer in almost all the cases. Although the gland became definitely softer in all these cases, the amount of softening varied and, while in some cases the gland became so much softer that the diagnosis of carcinoma could no longer be made from rectal examination, a number of these prostates, while softer have still remained fairly firm during the period of our observations. The effect on the size was more marked, as the prostate became definitely smaller in practically all these cases. Again, while the amount of reduction varied, most cases showed marked reduction, and some almost complete disappearance. In a number of these cases the size of the prostate was measured before and after the treatment by the method described by Peirson and Wilson and the reduction in size shown graphically by x-ray. As to the effect on bony metastases, we have not been able to detect any favorable effect. In 5 patients followed for more than 6 months, 4 of whom have had castration plus stilbestrol, and the fifth stilbestrol therapy alone, xrays have shown the bony metastases apparently progressing as usual. Determinations of the acid phosphatase were made on 17 patients before and after castration, and our findings confirmed those of Huggins that in every case where this determination was definitely elevated above normal (7 cases), the level fell very rapidly to or towards normal following castration, and was still further reduced following intensive injection therapy with stilbestrol. Our findings also agreed in general with those of Robinson, Gutman and Gutman and those of Huggins in that most (5 out of 7) of the cases with elevated acid phosphatase had roentgenologically demonstrable metastases to bone. All of the patients had x-ray examinations for bony metastases which were found in 13 cases (48 per cent).
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There seemed to be no definite correlation between the elevation of the acid phosphatase and pain. Only 4 of the 9 cases where pain was a prominent feature had determinations of the acid phosphatase before treatment, and this determination was elevated in only one of these four. In this case, following castration and estrogenic therapy the level came down to nearly normal within 1 week- 10 days before the pain was fully relieved. Furthermore, the patient who had the highest acid phsophatase level of any of our series (44.8 G units per cent) with widespread metastases to his -pelvis and spine, had absolutely no pain. His acid phosphatase decreased to 10 G units per cent within 6 days after castration. Estimations of the alkaline phosphatase were made before and after castration on 19 cases, elevated values being found in 8 of these cases, all but 2 of which had metastases demonstrable by x-ray, and our experience agreed with that of Huggins that there was usually a rise in the a~kaline phosphatase shortly following castration with or without stilbestrol. Estimations of the 17 ketosteroids were made before and after castration in 18 cases, and as was to be expected this value fell immediately after castration in all but 4 cases. In those 4 cases where the 17 ketosteroids did not decrease, the acid phosphatase had decreased, and the patients were doing well clinically. Conversely, our 2 patients who did worst (1 of whom died) had 17 ketosteroids that became low after castration and remained low for several months afterwards during which time their metastases were increasing and their general condition was worsening. Therefore our general impression is that the measurement of the 17 ketosteroids does not give information of value as to the progress of the disease in cases of carcinoma of the prostate. These results just summarized, with the exception of the 17 ketosteroid findings, have been confirmatory of similar results already reported by Huggins, Herbst and others. However the authors of this paper have two propositions which they would like to submit as being possibly worth-while new contributions to this subject. The first is the use of large amounts of stilbestrol in conjunction with castration, and the second is a technique of intracapsular orchidectomy which they have devised and have been using for 10 months. Having found out how markedly and rapidly stilbestrol reinforced and augmented the castration effect and reduced the size of the prostate, we have carried out the following procedures in 13 cases of inoperable carcinoma with retention of urine. The patient is put on constant catheter drainage, and after preliminary laboratory studies and x-rays, bilateral surgical castration is carried out by the intracapsular technique. Shortly after this, a series of injections of stilbestrol is started, 10 mg. being injected intramuscularly every day for from 5 to 10 days. By that time favorable effects have usually commenced, including relief of pain, shrinkage in the size of the prostate, and improvement in ability to urinate. This treatment was so effective in reducing the size of the prostate and relieving obstruction to urination that of these 13 patients who entered with moderate or marked inability to urinate and were treated in this way, 9 were improved so that they could void freely, did not have much residual urine, and
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therefore escaped a prostatic operation. However, if the patient is still unable to void satisfactorily after receiving 100 mg. in 10 days or 2 weeks, it seems economically extravagant to prolong his hospital stay to have further injection therapy, and he is subjected to transurethral resection. When the patient goes home, whether his obstruction was relived by the stilbestrol injections or whether he had to have a transurethral resection, in either case he is put on a small daily maintenance dose of oral stilbestrol, usually 1 mg. 3 times per day, for a month or 2 to re-inforce the castration effect and thus to accelerate the shrinking of the prostate. As regards the advisability of intensive or prolonged administration of stilbestrol, there have been reports in the literature, based largely on experimentation with small animals as rats, suggesting the possibility that such administration might be dangerous. Since it has been shown that stilbestrol is normally detoxified in the liver,' attention has been focussed on this organ as the one most likely to show toxic changes, and huge amounts of stilbestrol, sometimes several thousand times the physiological estrinizing dose, have been administered to experimental animals in efforts to find the answer to this question. While not unanimous, the trend of recent opinion on this matter is that even very large doses of stilbestrol are relatively harmless to the liver. Other harmful effects which have been reported in laboratory animals following adininistration of temendous doses are anaemia and neutropenia, changes in the pituitary and adrenals, and the occurrence of pituitary, mammary or testicular tumors in cancer strain rats and mice. However, these changes have mostly been produced by the administration of truly huge amounts of stilbestrol, hundreds of times the physiological dose, and r~cent papers by Grauer and Nugent, Morrell and Hart, and Russell and his co-workers tend to substantiate the growing clinical opinion that, in the doses commonly given to man, stilbestrol does not have harmful effects. Certainly no dangerous or harmful effects were noted in any of our cases, a number of whom had well over 100 mg. stilbestrol injected during the course of 2 weeks, and others of whom have taken orally 1- 3 mg. stilbestrol per day for many months. The 1 patient in our series who was not benefited at all by castration and stilbestrol therapy, and who died with widespread metastases to bones and viscera, showed absolutely no evidence of toxic liver damage although, in addition to castration, he had had 100 mg. of stilbestrol intramuscularly, and 200 mg. orally during the six weeks preceding his death. (See figures 1, 2 and 3.) There were the usual well-known unpleasant side-effects of stilbestrol therapy, although none of them was serious. The majority of those taking the drug lost their libido and power of erection. Also most of those taking stilbestrol, especially those taking the small oral maintenance dose over a period of time, had tenderness, hypertrophy and sometimes pigmentation of the nipples and frequently also some hypertrophy of the whole breast . This was not usually bothersome, but could be lessened by cutting down the dose, and disappeared when the drug was discontinued. Another effect was that the testes, if present, became definitely smaller. Two cases, while receiving intensive injection
Fra. 1. A, Cystoproctogram to show size of carcinomatous prostate before treatment . Prostate greatly enlarged (3X), hard and irregular. Acute retention of urine. B, Cystoproctogram showing reduction in depth and length of prostate after receiving injection of 63 mg. stilbestrol in 11 days. Patient still could not void, and transurethral resection was done . At resection only a very small amount of prostatic tissue was found to resect . Pathological report showed adenocarcinoma (grade 3) with considerable fibrosis . Since then (November 1941 ) patient has been on a daily oral dose of 2 to 3 mg. stilbestrol, and is getting along nicely. There is still some hard and irregular tissue to be felt in region of prostate. Castration was refused .
Frn. 2. A, Cystoproctogram to show size of carcinomatous prostate before treatment . Prostate somew hat enlarged and hard . Biopsy showed adenocarcinoma . Voiding was difficult . Residual urine 6 oz. Metastases to spine and pelvic bones. Acid phosphatase 44 .8 Gutman units per cent. Alkaline phosphatase 23 Bodansky units . B, Cystoproctogram showing reduction in depth and length of prostate 19 days postorchidectomy and after injection of 115 mg . stilbestrol. Prostate felt much softer as well as smaller. Voiding was normal with negligible residual urine . Acid phosphatase 4.2 Gutman units per cent . Alkaline phosphatase 33.3 Bodansky units . 687
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R. CHU'l'E, A. T. WILLETTS AND J . P. G E NS
FIG. 3. A, Cystoproctogram to show size of carcinomatous prostate before t reatmen t. Prostate greatly enlarged and stony ha rd . Biopsy showed adenocarcinoma . Voiding was difficult. Residua l urine 500 cc. Metastases to pelvic bones and spine with pathologica l fra cture of first lumbar vertebra . P atient could not move about in bed without agony . Acid phosphatase 39.5 Gutman units per cent. Alkaline phospha tase 13.5 Bodansky units. B, Cystoproetogram showing reduction in depth and length of prostate 21 days after orchidectomy a nd the injection of 135 mg. stilbestrol. Voiding was normal with no residual urine. Prostate not only much sma ller but m arkedly softer and no longer fel t like carcinoma . Pain was a great deal better and patient was up ou t of bed. Acid phosphat ase 7.5 Gutman units per cent. Alka line phosphatase 32.6 Bodansky units .
FIG. 4. 1, Horizontal incision in skin of scrotum which has been made taut over t he testes . 2, Tunica vaginalis squeezed taut a nd incised, exposing testis.
Incision in Tunica Albugi nea--------.. exposing :rest icular Subs ta nee
3.
Gauze dissection of Testicular
~
.~~l
4.
--~ - : ; , -
FIG. 5. 3, Incision in tunica albuginea, exposing testicular substance. 4, Testicular substance being freed from inside of tunica albuginea with gauze dissection. Mediastinum of Testis
FIG. 6. 5, Mediastinum of testis, containing blood vessels, clamped and ligated, preparatory to cutting testicular substance away. 6, Testicular substance has been cut away. Incision in tunica albuginea being sutured . 7, Incision in tunica albuginea sutured.
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therapy, had bilateral edema of the ankles and lower legs. This edema disappeared when the dose was descreased. Surprisingly few cases complained of anorexia and nausea, although this did occur in a few cases, necessitating temporarily discontinuing or reducing the dose of the drug. No other bad effects were noted. In view of the evidence therefore, we favor supplementing castration with stilbestrol therapy. The second subject we wish to present is intracapsular orchidectomy. In order to lessen the likelihood of any mental distress or depression, either conscious or sub-conscious, being occasioned in patients by the feeling that by castration they had been deprived of their manhood, bilateral orchidectomy in most of Tunica Voginolis
8
9 Frn. 7. 8, Tunica vaginalis sutured. 9, Scrotum sutured after bilateral intra-capsular orchidectomy.
these cases was performed with a special technique, which we have called intracapsular orchidectomy. We started using this technique in July 1941, and have now used it in 18 cases, having done all our orchidectomies in this manner for the last 6 months. After the testis has been expm,led surgically, a generous incision is made in the tunica albuginea, and the soft, stringy, tan-colored testicular substance is easily separated with gauze dissection from the inside of the tunica down to the mediastinum of the testis. Here the blood vessels which form a sort of pedicle are clamped and ligated en masse, and the testicular substance cut away. After this is done, the incision in the tunica is sutured together again. In this way the functioning substance of the testis is removed, but there remain the spermatic cord, the epididymis, and the oval mass formed
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by the sutured tunica albuginea, and the patient is not left with an empty and shrunken scrotum as is the case following the usual type of bilateral orchidectomy. Physical examination after this type of intracapsular bilateral orchidectomy usually gives the impression that the testes are present although very small, but in some instances the remnants feel surprisingly like normal testes to the casual examination. In this way, although the patient knows that the essential part of the testes has been removed, he does not feel that he has been completely castrated and thus deprived of the traditional badge of his manhood to the extent that he feels with an absolutely empty scrotum. This may seem like a minor point, but we feel that it might be a consideration of considerable psychological importance in the avoidance of depression in certain morbidly introspective patients. We found no harmful effect of castration on mind or body, except the loss of libido and the power of erection in almost all cases. To blame this entirely on castration is perhaps not scientifically fair, as many of these sick, elderly men had not been sexually active for a long time before castration, and very probably age, the presence of bladder discomfort or pain, etc., played a part. SUMMARY
Reducing the action of androgens in the body, either by surgical castration, or by biochemical neutralization by the administration of the synthetic estrogen stilbestrol, or by a combination _of the two, which was used in a majority of the cases (77 per cent), benefited 26 out of 27 cases of inoperable carcinoma of the prostate. Beneficial effects in these cases included rapid relief from the pain of metastases, if present, great improvement in appetite and general health with gain in weight, and reduction in the size and induration of the prostate with improvement in ability to urinate in most cases. The injection of 10 mg. of stilbestrol per day for 5 to 10 days augmented the beneficial effects of castration markedly and rapidly. Similar injections of stilbestrol without castration gave equally marked and rapid effects, but these disappeared when its administration was discontinued, whereas the effects of castration, while slower to appear, were permanent. If stilbestrol alone is used, patients have to be carried on a small oral maintenance dose indefinitely (1-3 mg. per day). The authors feel that the quickest and most satisfactory results in this series were obtained by castration followed by the injection of 10 mg. of stilbestrol per day for 5 to 10 days. In 13 patients who were suffering from moderate or marked inability to urinate and were treated in this way, the size of the obstructing prostate was so reduced in 9 cases that they could void freely, did not have much residual urine, and escaped having to undergo an operation for the relief of prostatic obstruction, and the authors recommend this type of treatment. No serious harmful effects were noted from the injection of 10 mg. stilbestrol per day for 5 to 10 days, or from the oral ingestion of 2 to 3 mg. of stilbestrol per day over a period of 9 months. Unpleasant side-effects of stilbestrol therapy were loss of libido and power of
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erection, tenderness and hypertrophy of the nipples and breasts, atrophy of the testes, and anorexia or occasionally nausea. After castration, libido and power of erection usually disappeared, but there were no other harmful effects. No beneficial effect was noted on bony metastases. X -rays taken over a period of more than 6 months showed them apparently progressing ~s usual. As found by other authors, the acid phosphatase, if elevated, fell rapidly towards normal following castration or stilbestrol therapy, whereas the alkaline phosphatase usually rose. Estimations of the 17 ketosteroids were made in 18 cases before and after castration, and from this the authors have gained the impression that the level of the 17 ketosteroids does not give information of value as to the progress of t he disease in cases of carcinoma of the prostate. The authors present a new type of cosmetic intra-capsular orchidectomy. 352 Marlborough St., Boston, Mass. REFERENCES GRAUER, R . C. AND NUGENT, E. : Surg., Gynec. and Obst., 74: 686, 1942. HERBST, W . P . : Trans. Amer. Assoc. Genito-Urin. Surg., 34: 195, 1941. H UGGINS, C., ScoTT, W.W., AND HoDGES, C . V.: J. U rol., 46 : 997, 1941. HUGGINS, C., STEVENS, R. E ., JR. , AND HODGES, C. V . : Arch. Surg., 43: 209, 1941. MORRELL, J. A. AND HART, G. W.: Endocrinol., 29: 796, 1941. PEIRSON, E. L. AND WILSON, S. A.: J. Urol., 46: 82, 1941. ROBINSON, J. N., GUTMAN, E. B., AND GUTMAN, A. B.: J. Urol., 42: 602, 1939. RussELL, H.K., PAGE, R . C ., MATTHEWS, C . S., SCHWABE, E. L., AND EMERY, F. E. : Endocrinol., 28: 897, 1941.
AND
ARTHUR T. WILLETTS
AND
JOHN P. GENS
(by invitation) From the Urological Service of the Massachusetts General Hospital, Boston
It was a year ago that Huggins by the presentation of his brilliant pioneer work with castration and also estrogen, and Herbst by the report of his favorable experiences with estrogen gave tremendous new hope and impetus to the difficult problem of the treatment of inoperable carcinoma of the prostate. Great improvement in these patients, both subjectively and objectively, had been brought about by reducing the physiological action of the androgens in the body. This had been accomplished either by curtailing the production of androgens through surgical castration, or by biochemically inactivating or neutralizing the existing androgens by the administration of estrogen. The remarkably fine results reported in these inoperable cases, far better than any previous results, fired us, as well as many others, with excitement and hope, and this report deals with our experiences in treating 27 cases of inoperable carcinoma of the prostate with castration, with estrogen, or, in most cases, with a combination of the 2 over the course of the last 10 months. This is, of course, too short a time in which to be able to appraise the final value of the treatment, but since our results have been so favorable, and since some of the successful results reported by Huggins have lasted for more than 2 years, it seems suitable to present a preliminary report of our experiences at this time. As a preamble we hasten to say that we are in favor of performing radical perineal prostatectomy in those few early cases of carcinoma of the prostate that can be entirely removedsurgically and are without demonstrable metastases, but unfortunately such cases compose only a small proportion of the total. All but 4 of our 27 cases were proven to be carcinoma of the prostate by microscopic examination of tissue, and there was convincing clinical evidence in the other 4, as 2 cases had hard prostates with x-ray findings of typical bone met~stases, and the other 2 cases had obstruction to urination by enlarged, hard and irregular prostates which became much smaller and softer within a few months after castration. Therefore we are sure ·that all these were cases of carcinoma of the prostate. We have recently been using the Silverman biopsy needle through the perineum with some success in establishing the diagnosis of carcinoma of the prostate in debatable cases, and in the future there should be no cases in which tissue is not obtained for pathological examination. Four of our 27 cases were simply treated by the administration of the potent synthetic estrogen, diethylstilbestrol, or, more frequently, the closely related 1 Read at the Annual Meeting American Urological Association, New York, N. Y., June 2, 1942. 2 The authors wish to thank the Department of Medical Research, Winthrop Chemical Company, for kindly supplying the stilbestrol used in this work.
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diethylstilbestrol dipropionate, hereinafter referred to simply as stilbestrol, 2 cases were treated with castration alone, while the majority of 21 cases (77 per cent) were treated with a combination of castration and stilbestrol. We chose the synthetic estrogen stilbestrol partly because others had reported success with its use, partly because it was less expensive than the natural estrogens, and partly because in addition to being highly effective when injected, it is also much more potent when taken by mouth than an equal amount of any oral preparation of a natural estrogen, it being considered that only twice the dose must be taken orally to produce the same effect as by injection. We were unable to detect any significant difference in effect between diethylstilbestrol and diethylstilbestrol dipropionate, and used the dipropionate almost entirely in the second half of our series. From the clinical point of view there was only 1 case out of the 27 that was not benefited by the treatment. In all the other cases, while the amount of improvement varied, the average amount was marked, and in a few cases the improvement was so marked as to almost suggest cure. Our original plan had been to use castration only, unless that were refused by the patient, but then we found that stilbestrol increased the castration effect markedly giving a much more rapid and marked effect than castration alone. For instance, 2 of our early patients, 2 months and 3 months respectively after castration, had improved considerably in general condition, but had not shown a great deal of reduction in the size of their prostates. However, after 10 days of intensive therapy with injections of stilbestrol their glands became markedly smaller and softer. In view of this we have used a combination of castration and stilbestrol in all but our early cases. We also found that, in every way, the results when stilbestrol alone without castration was used were the equal of those when stilbestrol and castration were used. However, the effect of castration, even if slower, is permanent, while if stilbestrol alone is used, the effect lasts only during its administration, and symptoms return soon if it is discontinued, and therefore patients have to be carried on a small oral maintenance dose indefinitely. Perhaps the most immediate and striking result of treatment was the rapid relief from the severe pain due to metastases. In 9 of our cases (33 per cent), all but one of which had metastases to the bones of the pelvis or spine demonstrable by x-ray, pain was a prominent feature, and in 8 out of these 9 cases the pain was quickly and practically completely relieved, in 1 case by castration alone, in 3 cases by stilbestrol alone and 4 by castration and stilbestrol. Sometimes the rapidity of the relief from pain was astonishing. One man got complete relief from his pain within 24 hours after castration, another experienced the same thing within 3 days, while the severe pains of a third vanished after the injection of a total of 10 mg. of stilbestrol in 5 days. Another old man of 84, who had been bedridden on account of agonizing pain in his spine and his legs, got up out of bed for the first time in four months a:fter 100 mg. of stilbestrol had been injected in 10 days. Another patient with metastases to the spine and pelvis had a pathological fracture of the first lumbar vertebra which kept
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him miserable and in constant pain. After castration followed by 135 mg. of stilbestrol in 17 days, his pain, which was rather slow to subside, was gone completely. When he was seen 1 month later he had discarded the brace which he had been wearing for the pathological fracture, had a good appetite and had gained weight, and said he was "a different man." Five months later the improvement had been maintained. This man originally had a very high acid phosphatase: 39.5 Gutman units per cent (normal 4 G units per cent). This fell to 26.3 units 2 days after castration, and at the end of his stilbestrol injections it had diminished to 7.5 units. After the relief of pain, the next most noticeable effect of this treatment was the almost immediate improvement in appetite, weight, and feeling of wellbeing of these patients, many of whom were miserable and had become cachectic with anorexia, sometimes nausea, and often great loss of weight. Within a few days they started to feel better and their appetite improved. This improvement in appetite occurred with such complete regularity that it seemed almost like a physiological response. More than half of our cases before therapy had disturbances of gastric function, ranging from anorexia to nausea, and in all but the one failure this condition was definitely benefited by the treatment. In response to the improved appetite, there was a noticeable gain in weight. The effect of the treatment on__ the prostate itself was marked, the gland becoming smaller and softer in almost all the cases. Although the gland became definitely softer in all these cases, the amount of softening varied and, while in some cases the gland became so much softer that the diagnosis of carcinoma could no longer be made from rectal examination, a number of these prostates, while softer have still remained fairly firm during the period of our observations. The effect on the size was more marked, as the prostate became definitely smaller in practically all these cases. Again, while the amount of reduction varied, most cases showed marked reduction, and some almost complete disappearance. In a number of these cases the size of the prostate was measured before and after the treatment by the method described by Peirson and Wilson and the reduction in size shown graphically by x-ray. As to the effect on bony metastases, we have not been able to detect any favorable effect. In 5 patients followed for more than 6 months, 4 of whom have had castration plus stilbestrol, and the fifth stilbestrol therapy alone, xrays have shown the bony metastases apparently progressing as usual. Determinations of the acid phosphatase were made on 17 patients before and after castration, and our findings confirmed those of Huggins that in every case where this determination was definitely elevated above normal (7 cases), the level fell very rapidly to or towards normal following castration, and was still further reduced following intensive injection therapy with stilbestrol. Our findings also agreed in general with those of Robinson, Gutman and Gutman and those of Huggins in that most (5 out of 7) of the cases with elevated acid phosphatase had roentgenologically demonstrable metastases to bone. All of the patients had x-ray examinations for bony metastases which were found in 13 cases (48 per cent).
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There seemed to be no definite correlation between the elevation of the acid phosphatase and pain. Only 4 of the 9 cases where pain was a prominent feature had determinations of the acid phosphatase before treatment, and this determination was elevated in only one of these four. In this case, following castration and estrogenic therapy the level came down to nearly normal within 1 week- 10 days before the pain was fully relieved. Furthermore, the patient who had the highest acid phsophatase level of any of our series (44.8 G units per cent) with widespread metastases to his -pelvis and spine, had absolutely no pain. His acid phosphatase decreased to 10 G units per cent within 6 days after castration. Estimations of the alkaline phosphatase were made before and after castration on 19 cases, elevated values being found in 8 of these cases, all but 2 of which had metastases demonstrable by x-ray, and our experience agreed with that of Huggins that there was usually a rise in the a~kaline phosphatase shortly following castration with or without stilbestrol. Estimations of the 17 ketosteroids were made before and after castration in 18 cases, and as was to be expected this value fell immediately after castration in all but 4 cases. In those 4 cases where the 17 ketosteroids did not decrease, the acid phosphatase had decreased, and the patients were doing well clinically. Conversely, our 2 patients who did worst (1 of whom died) had 17 ketosteroids that became low after castration and remained low for several months afterwards during which time their metastases were increasing and their general condition was worsening. Therefore our general impression is that the measurement of the 17 ketosteroids does not give information of value as to the progress of the disease in cases of carcinoma of the prostate. These results just summarized, with the exception of the 17 ketosteroid findings, have been confirmatory of similar results already reported by Huggins, Herbst and others. However the authors of this paper have two propositions which they would like to submit as being possibly worth-while new contributions to this subject. The first is the use of large amounts of stilbestrol in conjunction with castration, and the second is a technique of intracapsular orchidectomy which they have devised and have been using for 10 months. Having found out how markedly and rapidly stilbestrol reinforced and augmented the castration effect and reduced the size of the prostate, we have carried out the following procedures in 13 cases of inoperable carcinoma with retention of urine. The patient is put on constant catheter drainage, and after preliminary laboratory studies and x-rays, bilateral surgical castration is carried out by the intracapsular technique. Shortly after this, a series of injections of stilbestrol is started, 10 mg. being injected intramuscularly every day for from 5 to 10 days. By that time favorable effects have usually commenced, including relief of pain, shrinkage in the size of the prostate, and improvement in ability to urinate. This treatment was so effective in reducing the size of the prostate and relieving obstruction to urination that of these 13 patients who entered with moderate or marked inability to urinate and were treated in this way, 9 were improved so that they could void freely, did not have much residual urine, and
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therefore escaped a prostatic operation. However, if the patient is still unable to void satisfactorily after receiving 100 mg. in 10 days or 2 weeks, it seems economically extravagant to prolong his hospital stay to have further injection therapy, and he is subjected to transurethral resection. When the patient goes home, whether his obstruction was relived by the stilbestrol injections or whether he had to have a transurethral resection, in either case he is put on a small daily maintenance dose of oral stilbestrol, usually 1 mg. 3 times per day, for a month or 2 to re-inforce the castration effect and thus to accelerate the shrinking of the prostate. As regards the advisability of intensive or prolonged administration of stilbestrol, there have been reports in the literature, based largely on experimentation with small animals as rats, suggesting the possibility that such administration might be dangerous. Since it has been shown that stilbestrol is normally detoxified in the liver,' attention has been focussed on this organ as the one most likely to show toxic changes, and huge amounts of stilbestrol, sometimes several thousand times the physiological estrinizing dose, have been administered to experimental animals in efforts to find the answer to this question. While not unanimous, the trend of recent opinion on this matter is that even very large doses of stilbestrol are relatively harmless to the liver. Other harmful effects which have been reported in laboratory animals following adininistration of temendous doses are anaemia and neutropenia, changes in the pituitary and adrenals, and the occurrence of pituitary, mammary or testicular tumors in cancer strain rats and mice. However, these changes have mostly been produced by the administration of truly huge amounts of stilbestrol, hundreds of times the physiological dose, and r~cent papers by Grauer and Nugent, Morrell and Hart, and Russell and his co-workers tend to substantiate the growing clinical opinion that, in the doses commonly given to man, stilbestrol does not have harmful effects. Certainly no dangerous or harmful effects were noted in any of our cases, a number of whom had well over 100 mg. stilbestrol injected during the course of 2 weeks, and others of whom have taken orally 1- 3 mg. stilbestrol per day for many months. The 1 patient in our series who was not benefited at all by castration and stilbestrol therapy, and who died with widespread metastases to bones and viscera, showed absolutely no evidence of toxic liver damage although, in addition to castration, he had had 100 mg. of stilbestrol intramuscularly, and 200 mg. orally during the six weeks preceding his death. (See figures 1, 2 and 3.) There were the usual well-known unpleasant side-effects of stilbestrol therapy, although none of them was serious. The majority of those taking the drug lost their libido and power of erection. Also most of those taking stilbestrol, especially those taking the small oral maintenance dose over a period of time, had tenderness, hypertrophy and sometimes pigmentation of the nipples and frequently also some hypertrophy of the whole breast . This was not usually bothersome, but could be lessened by cutting down the dose, and disappeared when the drug was discontinued. Another effect was that the testes, if present, became definitely smaller. Two cases, while receiving intensive injection
Fra. 1. A, Cystoproctogram to show size of carcinomatous prostate before treatment . Prostate greatly enlarged (3X), hard and irregular. Acute retention of urine. B, Cystoproctogram showing reduction in depth and length of prostate after receiving injection of 63 mg. stilbestrol in 11 days. Patient still could not void, and transurethral resection was done . At resection only a very small amount of prostatic tissue was found to resect . Pathological report showed adenocarcinoma (grade 3) with considerable fibrosis . Since then (November 1941 ) patient has been on a daily oral dose of 2 to 3 mg. stilbestrol, and is getting along nicely. There is still some hard and irregular tissue to be felt in region of prostate. Castration was refused .
Frn. 2. A, Cystoproctogram to show size of carcinomatous prostate before treatment . Prostate somew hat enlarged and hard . Biopsy showed adenocarcinoma . Voiding was difficult . Residual urine 6 oz. Metastases to spine and pelvic bones. Acid phosphatase 44 .8 Gutman units per cent. Alkaline phosphatase 23 Bodansky units . B, Cystoproctogram showing reduction in depth and length of prostate 19 days postorchidectomy and after injection of 115 mg . stilbestrol. Prostate felt much softer as well as smaller. Voiding was normal with negligible residual urine . Acid phosphatase 4.2 Gutman units per cent . Alkaline phosphatase 33.3 Bodansky units . 687
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FIG. 3. A, Cystoproctogram to show size of carcinomatous prostate before t reatmen t. Prostate greatly enlarged and stony ha rd . Biopsy showed adenocarcinoma . Voiding was difficult. Residua l urine 500 cc. Metastases to pelvic bones and spine with pathologica l fra cture of first lumbar vertebra . P atient could not move about in bed without agony . Acid phosphatase 39.5 Gutman units per cent. Alkaline phospha tase 13.5 Bodansky units. B, Cystoproetogram showing reduction in depth and length of prostate 21 days after orchidectomy a nd the injection of 135 mg. stilbestrol. Voiding was normal with no residual urine. Prostate not only much sma ller but m arkedly softer and no longer fel t like carcinoma . Pain was a great deal better and patient was up ou t of bed. Acid phosphat ase 7.5 Gutman units per cent. Alka line phosphatase 32.6 Bodansky units .
FIG. 4. 1, Horizontal incision in skin of scrotum which has been made taut over t he testes . 2, Tunica vaginalis squeezed taut a nd incised, exposing testis.
Incision in Tunica Albugi nea--------.. exposing :rest icular Subs ta nee
3.
Gauze dissection of Testicular
~
.~~l
4.
--~ - : ; , -
FIG. 5. 3, Incision in tunica albuginea, exposing testicular substance. 4, Testicular substance being freed from inside of tunica albuginea with gauze dissection. Mediastinum of Testis
FIG. 6. 5, Mediastinum of testis, containing blood vessels, clamped and ligated, preparatory to cutting testicular substance away. 6, Testicular substance has been cut away. Incision in tunica albuginea being sutured . 7, Incision in tunica albuginea sutured.
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therapy, had bilateral edema of the ankles and lower legs. This edema disappeared when the dose was descreased. Surprisingly few cases complained of anorexia and nausea, although this did occur in a few cases, necessitating temporarily discontinuing or reducing the dose of the drug. No other bad effects were noted. In view of the evidence therefore, we favor supplementing castration with stilbestrol therapy. The second subject we wish to present is intracapsular orchidectomy. In order to lessen the likelihood of any mental distress or depression, either conscious or sub-conscious, being occasioned in patients by the feeling that by castration they had been deprived of their manhood, bilateral orchidectomy in most of Tunica Voginolis
8
9 Frn. 7. 8, Tunica vaginalis sutured. 9, Scrotum sutured after bilateral intra-capsular orchidectomy.
these cases was performed with a special technique, which we have called intracapsular orchidectomy. We started using this technique in July 1941, and have now used it in 18 cases, having done all our orchidectomies in this manner for the last 6 months. After the testis has been expm,led surgically, a generous incision is made in the tunica albuginea, and the soft, stringy, tan-colored testicular substance is easily separated with gauze dissection from the inside of the tunica down to the mediastinum of the testis. Here the blood vessels which form a sort of pedicle are clamped and ligated en masse, and the testicular substance cut away. After this is done, the incision in the tunica is sutured together again. In this way the functioning substance of the testis is removed, but there remain the spermatic cord, the epididymis, and the oval mass formed
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by the sutured tunica albuginea, and the patient is not left with an empty and shrunken scrotum as is the case following the usual type of bilateral orchidectomy. Physical examination after this type of intracapsular bilateral orchidectomy usually gives the impression that the testes are present although very small, but in some instances the remnants feel surprisingly like normal testes to the casual examination. In this way, although the patient knows that the essential part of the testes has been removed, he does not feel that he has been completely castrated and thus deprived of the traditional badge of his manhood to the extent that he feels with an absolutely empty scrotum. This may seem like a minor point, but we feel that it might be a consideration of considerable psychological importance in the avoidance of depression in certain morbidly introspective patients. We found no harmful effect of castration on mind or body, except the loss of libido and the power of erection in almost all cases. To blame this entirely on castration is perhaps not scientifically fair, as many of these sick, elderly men had not been sexually active for a long time before castration, and very probably age, the presence of bladder discomfort or pain, etc., played a part. SUMMARY
Reducing the action of androgens in the body, either by surgical castration, or by biochemical neutralization by the administration of the synthetic estrogen stilbestrol, or by a combination _of the two, which was used in a majority of the cases (77 per cent), benefited 26 out of 27 cases of inoperable carcinoma of the prostate. Beneficial effects in these cases included rapid relief from the pain of metastases, if present, great improvement in appetite and general health with gain in weight, and reduction in the size and induration of the prostate with improvement in ability to urinate in most cases. The injection of 10 mg. of stilbestrol per day for 5 to 10 days augmented the beneficial effects of castration markedly and rapidly. Similar injections of stilbestrol without castration gave equally marked and rapid effects, but these disappeared when its administration was discontinued, whereas the effects of castration, while slower to appear, were permanent. If stilbestrol alone is used, patients have to be carried on a small oral maintenance dose indefinitely (1-3 mg. per day). The authors feel that the quickest and most satisfactory results in this series were obtained by castration followed by the injection of 10 mg. of stilbestrol per day for 5 to 10 days. In 13 patients who were suffering from moderate or marked inability to urinate and were treated in this way, the size of the obstructing prostate was so reduced in 9 cases that they could void freely, did not have much residual urine, and escaped having to undergo an operation for the relief of prostatic obstruction, and the authors recommend this type of treatment. No serious harmful effects were noted from the injection of 10 mg. stilbestrol per day for 5 to 10 days, or from the oral ingestion of 2 to 3 mg. of stilbestrol per day over a period of 9 months. Unpleasant side-effects of stilbestrol therapy were loss of libido and power of
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erection, tenderness and hypertrophy of the nipples and breasts, atrophy of the testes, and anorexia or occasionally nausea. After castration, libido and power of erection usually disappeared, but there were no other harmful effects. No beneficial effect was noted on bony metastases. X -rays taken over a period of more than 6 months showed them apparently progressing ~s usual. As found by other authors, the acid phosphatase, if elevated, fell rapidly towards normal following castration or stilbestrol therapy, whereas the alkaline phosphatase usually rose. Estimations of the 17 ketosteroids were made in 18 cases before and after castration, and from this the authors have gained the impression that the level of the 17 ketosteroids does not give information of value as to the progress of t he disease in cases of carcinoma of the prostate. The authors present a new type of cosmetic intra-capsular orchidectomy. 352 Marlborough St., Boston, Mass. REFERENCES GRAUER, R . C. AND NUGENT, E. : Surg., Gynec. and Obst., 74: 686, 1942. HERBST, W . P . : Trans. Amer. Assoc. Genito-Urin. Surg., 34: 195, 1941. H UGGINS, C., ScoTT, W.W., AND HoDGES, C . V.: J. U rol., 46 : 997, 1941. HUGGINS, C., STEVENS, R. E ., JR. , AND HODGES, C. V . : Arch. Surg., 43: 209, 1941. MORRELL, J. A. AND HART, G. W.: Endocrinol., 29: 796, 1941. PEIRSON, E. L. AND WILSON, S. A.: J. Urol., 46: 82, 1941. ROBINSON, J. N., GUTMAN, E. B., AND GUTMAN, A. B.: J. Urol., 42: 602, 1939. RussELL, H.K., PAGE, R . C ., MATTHEWS, C . S., SCHWABE, E. L., AND EMERY, F. E. : Endocrinol., 28: 897, 1941.