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The Treatment of Late Relapse in Prostatic Carcinoma by Cortisone
THE JOURNAL OF UROLOGY
Vol. 69, No. 1, January 1953
Printed in U .S .A.
THE TREATMENT OF LATE RELAPSE IN PROSTATIC CARCINOMA BY CORTISONE W. GIFFORD HAYWARD
Following the monumental work of Huggins which he reported in 1941, untold numbers of men, the victims of prostatic carcinoma, have had a prolongation of life and have had their last days made easier with hormone therapy, and of course castration is a big part of hormone therapy. Huggins 1 states that "androgens cause both normal and neoplastic prostatic tissue to grow and secrete. The urinary 17-ketosteroids average about the same level in prostatic cancer as in other men of that age but enough androgen is produced to make a tumor grow vigorously if untreated. In certain cases following orchiectomy the adrenal continues to produce androgens which can be controlled to some extent by estrogens. In other cases death ensues with the primary tumor greatly inhibited but metastatic areas grow vigorously and in still others the growth is too primitive to be influenced by hormones. It is now known definitely that the adrenal is the sole agency producing androgen in castrated men." Frame and Jewett 2 state "that there is abundant evidence to indicate that the testis is not the sole source of the urinary 17-ketosteroid and that the adrenal cortex is the one, if not the only extra testicular source, that the testes do not contribute to the 17-ketosteroid output in the older age group or the removal of the testes results in an increased contribution by the adrenal cortex. Estrogenic substances while combating the effect of this androgenic hormone still stimulate its production in the adrenal through the luteinizing hormone of the pituitary. The time then arises, if the patient has not already succumbed to some intercurrent disease, that a relapse occurs and from that time on there is a rapid decline." Recent reports have appeared in the literature of bilateral adrenalectomy and still later hypophysectomy followed promptly by great improvement in these carcinomatous patients who were on the decline. Although of experimental interest, these operations seem too radical to be adopted by the average urologist. These few reports formed the background of my awakened interest in hormonal therapy and the opinions that I have formed are the subject of the following discussion. Briefly I should like to review with you the physiology of the endocrine glands that are pertinent to the subject of prostatic carcinoma; namely, the testes, pituitary and adrenals. vVe must accept from work that has been done before that the anterior pituitary is the only regulating center of most of the endocrine glands. It exerts its influence on the other glands by means of trophic hormones. In response to this, these target glands produce tissue affecting hormones (Reifenstein). 3 Accepted for publication June 6, 1952. Read at annual meeting, Northeastern Section, American Urological Association, on cruise to Bermuda, October 4-10, 1952. 1 Huggins, C. and Scott, W.W.: Ann. Surg., 122: 1031-1041, 1945. 2 Frame, E. and Jewett, H.J.: J. Ural., 52: 330-333, 1944. 3 Reifenstein, E. C.: Pathologic Physiology, Wm. A. Sodeman; Philadelphia: W. B. Saunders Co., pp. 513-555. 152
CORTISONE THERAPY IN PROSTATIC CANCER
153
The anterior pituitary contains three types of cells; acidophilic, basophilic and chromophobe. Only the first two interest us. The acidophilic cells produce the growth hormone, the thyrotrophic hormone, adrenocorticotrophic (ACTH) and perhaps gonadotrophic hormone. The basophilic cells are all gonadotrophic: a. Follicle stimulating hormone. b. Luteinizing hormone. c. Luteotrophic hormone (but this is a hypothetical hormone which is supposed to maintain the corpus luteum. It is identical with the gonadotrophic hormone previously mentioned but may be produced by the acidophilic cells). Of the hormones produced by the acidophilic cells the adrenocorticotrophic hormone is the one that interests us in this discussion. This stimulates the adrenal cortex to produce the sugar hormone or (S) hormone. The adrenal cortex produces desoxycorticosterone and an androgenic hormonB. Present investigation has not definitely determined whether ACTH has stimulated their production, whether they are due to stimulation by other or luteinizing hormones or whether their production is independent of pituitary control. The trophic hormones of the basophilic group are qualitatively identical in both sexes. Both the follicle stimulating hormone and the luteinizing hormone are of interest to us because in the female the former stimulates the production of estrogen and in the male the production of spermatozoa. In the male the luteinizing hormone stimulates the Leydig cells to produce androgenic hormone. There is fairly convincing evidence that the luteinizing hormone or the luteotrophic hormone stimulates the adrenal cortex to produce in both sexes an androgenic hormone similar to the androgen produced by the testes which has protein anabolic properties and which leads to the excretion of 17-ketosteroids in the urine. It is apparently axiomatic that there is a governing control over the production of hormones. For example, after the luteinizing hormone of the pituitary has stimulated Leydig cells to produce androgenic hormone and a sufficient quantity has been produced, the Leydig cells in some way retard further action by the pituitary to prevent over production. Now, if the testicles are removed by castration, not only is the testicular source of androgen removed but also the retarding power is removed. Hotchkiss4 states "that the pituitary gland of castrated animals exercises a greater stimulation of the sex glands when implanted into normal animals thereby suggesting that the pituitary activates and is restrained by the sex gland hormones." Greep and J ones 5 state "that the pituitary of the castrate has a rich content of gonadotropine and an increased output of these hormones. The adrenal gland may in turn form a retarding substance to prevent overstimulation but the fact remains that the adrenal is producing androgenic hormones that are the bane of prostatic carcinoma." Hotchkiss, R. S.: Fertility in Men. Philadelphia: Lippincott, 1944. Greep, R. 0. and Jones, I. C.: Symposium on Steroid Hormones, E. S. Gordon: Madison: University of Wisconsin Press, p. 551. 4
5
154
W. GIFFORD HAYWARD
The object in view then is to minimize or abolish the adrenal production of androgenic hormone. Reifenstein in his reference to Selye's adaptation syndrome makes the statement that recent evidence suggests that the sugar hormone (cortisone) inhibits the production of nitrogen hormone or androgenic hormone. It has also been shown by vVilkins and his associates 6 and by Bartter and his colleagues7 that the elevated 17-ketosteroid excretion in the adrenogenital syndrome can be reduced practically to zero by the administration of cortisone. And again it has been shown that the continuous administration of an excess of any hormone (trophic or tissue affecting) may result in atrophy of the gland that i3 the endogenous source of the hormone. Sprague et al. 8 have made the following points: 1. Cortisone causes a depression of the endogenous production of adrenal cortical hormone. 2. Experimentally, cortisone causes atrophy of adrenal cortices in rats. 3. A depression of urinary 17-ketosteroids occurs during and subsequent to administration of cortisone. 4. In general, the effects of cortisone or adrenal cortical structure and function are the opposite of those of pituitary adrenocorticotrophic hormone. Greep and Jones are of the opinion that "histologically and functionally the adrenal cortex is divided into three zones, the outer zona glomerulosa, middle zona fasciculata and the inner zona reticularis. Experimental work on rats tends to show that the outer zone produces desoxycorticosterone independent of pituitary influence, the middle zone produces the S hormone dependent on pituitary stimulation and the inner zone produces androgenic hormones dependent on the pituitary. There has been little experimental opportunity to study the adrenal histologically in the human but they report one woman who had marked pituitary atrophy, with normal zona glomerulosa of the adrenal and atrophic zona fasciculata." Cortisone or the sugar hormone is produced by the adrenal following stimula tion by ACTH. Although urine of children under eight contains corticosteroids there is no 17-ketosteroid. Yet, stimulation with androgens before that age will cause 17-ketosteroids to appear. It is therefore improbable that the pituitary does stimulate the adrenal cortex with this hormone before that age. This is the basis for the belief that the pituitary produces two kinds of ACTH, one for the sugar hormone and the other for the N hormone or androgenic hormone. It would seem unwise then in prostatic carcinoma to try to obtain the cortisone action by using ACTH. Rather, cortisone should be used for its replacement effect to produce partial adrenal atrophy. Now in addition to this all important effect, cortisone has side effects which are in the main, beneficial. There is an increase in appetite which in turn causes a gain in weight. Its effect is euphoristic and increases mental capacity and activity. Although cortisone causes some fluid retention, its effect on electrolytes is only about 3 per cent of the desoxycorticosterone effect. Patients taking it should have Wilkins, Lawson, et al.: J. Clin. Endocrinol. and Metab., 12: 3, 1952. Barrter, F. C. et al: Pathologic Physiology, Wm. A. Sodeman; page 551. 8 Sprague, R. G., Power, l\f. H., and Mason, H. L.: Physiological effects of cortisone and pituitary adrcnocotrophic hormone (ACTH) in man. J.A.M.A., 144: 1341-1347, 1950. 6
7
COR'l'ISONE THERAPY IN PROSTATIC CANCER
J.55
a restricted sodium intake. Even then they may have to be given diuretics occasionally. If there is too much loss of potassimn as evidenced by loss of energy and muscular weakness it may be detected by electrocardiographic changes and potassium then administered to make up the loss. Its contra-indications are: 1) congestive heart failure, 2) psychotic tendencies, 3) tuberculosis, ..Jc) active ulcer, 5) diabetes and G) renal insufficiency. During treatment it is ·well to do a weekly urinalysis; blood sugar detenni11a.t10n if the patient is glycosuric and a glucose tolerance if the patient is hyperglycemic. CASE REPORT
W. S. B aged 81 ·was referred to me in 1942 because of slight dy,mria. A preop0rative diagnosis of carcinoma of the prostate was made and an endoscopic resection was done. Bilateral orchiectomy immediately follmrnd and stilbe:-ltrol was faithfully taken, }fo; progress was satisfactory until the summer of 1951, ·when he again had dysuria. Rectal examination shmrnd no induration alld very little prostate but cystoscopic examination shmYed carcinomatous tissue in the prostatic urethra ,Yhich ·was again resected. His decline became very rapid characterized by loss of weight and strength and severe perineal pain, This became so severe that it was necessary to institute around the clock nursing and the administration of narcotics both orally and by hypodermic every few hours. The patienL ,Yas an intelligent man and knmY the reason for his pam and asked only that his last days he made as comfortable as possible. At about this time the reports of bilateral adrenalectomy came ro my attcn tio11, and although 1 kneYv the patient ,vas in no condition to undergo such a radical procedure, the thought occurred to me that some atrophy of the adrenals might be obtained by using replacement therapy. This ,ms talked on:r at great length with the patient and he consented to give it a triaL Treatment begaH in September 1951, ,,·ith 100 mg. of rortisone a day reducing it rapidly to 25 mg. per day. For the first f-i days practically no change ,ms evidenced. Thell almost, immediately the 1·esults became drama.tic. Appetite and strength returned amazingly, and although metapon was continued it became apparent that other narcotics by hypodnrmic could he abandoned. Instead of resigning himself to die he made plans to move to his ·winter home in Florida, ,vhieh he did, 'flw follo\\'ing excerpt from a letter ,vas received December 11, 1951: "R.eporting for myself, as you suggested, I fully underntand that you are dealing in terms of relief and comfort, and not of cure. J,~evertheless I have been able to move dmrn here without a jolt and that of itself was impossible until you began the present treatment But more than that, my increased vigor and strength seem an amazing change. ·whereas a few tmm, about the room ,va.s formerly all I was good for, I nmY ,rn1h. around town without tiring and spend hours tinkering i11 my shop, I still haYe some pain at timef:l, but nothing to compare ,Yith the rough going of last snmmer." Since that time, his nurse has reported at weekly intervals. He a.na.ngecl and conducted a town meeting in Florida; ,Yorked in his shop every day and wa8 able to drive his car ,Yhere eyer he wished to go. It was necessary on t-1Yo occasions to administer diuretirs. The patient is st.i 11 comfortable, active and happy (November 6, 1952).
156
W. GIFFORD HAYWARD DISCUSSION
Although the value of reporting the results of 1 case may be open to question, the complete absence of mention of this type of therapy in the literature to date and the excellent results, though temporary, make it seem not presumptuous and not premature. Its trial in a large number of cases will determine its value or futility. ADDENDUM
Since the paper was prepared, two other personal cases and one other case treated by a colleague have all responded favorably to this treatment, J. E., aged 62, had an anaplastic growth. He is now in relapse. No benefit was derived from cortisone therapy (November 6, 1952).
319 Pine St., Jamestown, N. Y.
Vol. 69, No. 1, January 1953
Printed in U .S .A.
THE TREATMENT OF LATE RELAPSE IN PROSTATIC CARCINOMA BY CORTISONE W. GIFFORD HAYWARD
Following the monumental work of Huggins which he reported in 1941, untold numbers of men, the victims of prostatic carcinoma, have had a prolongation of life and have had their last days made easier with hormone therapy, and of course castration is a big part of hormone therapy. Huggins 1 states that "androgens cause both normal and neoplastic prostatic tissue to grow and secrete. The urinary 17-ketosteroids average about the same level in prostatic cancer as in other men of that age but enough androgen is produced to make a tumor grow vigorously if untreated. In certain cases following orchiectomy the adrenal continues to produce androgens which can be controlled to some extent by estrogens. In other cases death ensues with the primary tumor greatly inhibited but metastatic areas grow vigorously and in still others the growth is too primitive to be influenced by hormones. It is now known definitely that the adrenal is the sole agency producing androgen in castrated men." Frame and Jewett 2 state "that there is abundant evidence to indicate that the testis is not the sole source of the urinary 17-ketosteroid and that the adrenal cortex is the one, if not the only extra testicular source, that the testes do not contribute to the 17-ketosteroid output in the older age group or the removal of the testes results in an increased contribution by the adrenal cortex. Estrogenic substances while combating the effect of this androgenic hormone still stimulate its production in the adrenal through the luteinizing hormone of the pituitary. The time then arises, if the patient has not already succumbed to some intercurrent disease, that a relapse occurs and from that time on there is a rapid decline." Recent reports have appeared in the literature of bilateral adrenalectomy and still later hypophysectomy followed promptly by great improvement in these carcinomatous patients who were on the decline. Although of experimental interest, these operations seem too radical to be adopted by the average urologist. These few reports formed the background of my awakened interest in hormonal therapy and the opinions that I have formed are the subject of the following discussion. Briefly I should like to review with you the physiology of the endocrine glands that are pertinent to the subject of prostatic carcinoma; namely, the testes, pituitary and adrenals. vVe must accept from work that has been done before that the anterior pituitary is the only regulating center of most of the endocrine glands. It exerts its influence on the other glands by means of trophic hormones. In response to this, these target glands produce tissue affecting hormones (Reifenstein). 3 Accepted for publication June 6, 1952. Read at annual meeting, Northeastern Section, American Urological Association, on cruise to Bermuda, October 4-10, 1952. 1 Huggins, C. and Scott, W.W.: Ann. Surg., 122: 1031-1041, 1945. 2 Frame, E. and Jewett, H.J.: J. Ural., 52: 330-333, 1944. 3 Reifenstein, E. C.: Pathologic Physiology, Wm. A. Sodeman; Philadelphia: W. B. Saunders Co., pp. 513-555. 152
CORTISONE THERAPY IN PROSTATIC CANCER
153
The anterior pituitary contains three types of cells; acidophilic, basophilic and chromophobe. Only the first two interest us. The acidophilic cells produce the growth hormone, the thyrotrophic hormone, adrenocorticotrophic (ACTH) and perhaps gonadotrophic hormone. The basophilic cells are all gonadotrophic: a. Follicle stimulating hormone. b. Luteinizing hormone. c. Luteotrophic hormone (but this is a hypothetical hormone which is supposed to maintain the corpus luteum. It is identical with the gonadotrophic hormone previously mentioned but may be produced by the acidophilic cells). Of the hormones produced by the acidophilic cells the adrenocorticotrophic hormone is the one that interests us in this discussion. This stimulates the adrenal cortex to produce the sugar hormone or (S) hormone. The adrenal cortex produces desoxycorticosterone and an androgenic hormonB. Present investigation has not definitely determined whether ACTH has stimulated their production, whether they are due to stimulation by other or luteinizing hormones or whether their production is independent of pituitary control. The trophic hormones of the basophilic group are qualitatively identical in both sexes. Both the follicle stimulating hormone and the luteinizing hormone are of interest to us because in the female the former stimulates the production of estrogen and in the male the production of spermatozoa. In the male the luteinizing hormone stimulates the Leydig cells to produce androgenic hormone. There is fairly convincing evidence that the luteinizing hormone or the luteotrophic hormone stimulates the adrenal cortex to produce in both sexes an androgenic hormone similar to the androgen produced by the testes which has protein anabolic properties and which leads to the excretion of 17-ketosteroids in the urine. It is apparently axiomatic that there is a governing control over the production of hormones. For example, after the luteinizing hormone of the pituitary has stimulated Leydig cells to produce androgenic hormone and a sufficient quantity has been produced, the Leydig cells in some way retard further action by the pituitary to prevent over production. Now, if the testicles are removed by castration, not only is the testicular source of androgen removed but also the retarding power is removed. Hotchkiss4 states "that the pituitary gland of castrated animals exercises a greater stimulation of the sex glands when implanted into normal animals thereby suggesting that the pituitary activates and is restrained by the sex gland hormones." Greep and J ones 5 state "that the pituitary of the castrate has a rich content of gonadotropine and an increased output of these hormones. The adrenal gland may in turn form a retarding substance to prevent overstimulation but the fact remains that the adrenal is producing androgenic hormones that are the bane of prostatic carcinoma." Hotchkiss, R. S.: Fertility in Men. Philadelphia: Lippincott, 1944. Greep, R. 0. and Jones, I. C.: Symposium on Steroid Hormones, E. S. Gordon: Madison: University of Wisconsin Press, p. 551. 4
5
154
W. GIFFORD HAYWARD
The object in view then is to minimize or abolish the adrenal production of androgenic hormone. Reifenstein in his reference to Selye's adaptation syndrome makes the statement that recent evidence suggests that the sugar hormone (cortisone) inhibits the production of nitrogen hormone or androgenic hormone. It has also been shown by vVilkins and his associates 6 and by Bartter and his colleagues7 that the elevated 17-ketosteroid excretion in the adrenogenital syndrome can be reduced practically to zero by the administration of cortisone. And again it has been shown that the continuous administration of an excess of any hormone (trophic or tissue affecting) may result in atrophy of the gland that i3 the endogenous source of the hormone. Sprague et al. 8 have made the following points: 1. Cortisone causes a depression of the endogenous production of adrenal cortical hormone. 2. Experimentally, cortisone causes atrophy of adrenal cortices in rats. 3. A depression of urinary 17-ketosteroids occurs during and subsequent to administration of cortisone. 4. In general, the effects of cortisone or adrenal cortical structure and function are the opposite of those of pituitary adrenocorticotrophic hormone. Greep and Jones are of the opinion that "histologically and functionally the adrenal cortex is divided into three zones, the outer zona glomerulosa, middle zona fasciculata and the inner zona reticularis. Experimental work on rats tends to show that the outer zone produces desoxycorticosterone independent of pituitary influence, the middle zone produces the S hormone dependent on pituitary stimulation and the inner zone produces androgenic hormones dependent on the pituitary. There has been little experimental opportunity to study the adrenal histologically in the human but they report one woman who had marked pituitary atrophy, with normal zona glomerulosa of the adrenal and atrophic zona fasciculata." Cortisone or the sugar hormone is produced by the adrenal following stimula tion by ACTH. Although urine of children under eight contains corticosteroids there is no 17-ketosteroid. Yet, stimulation with androgens before that age will cause 17-ketosteroids to appear. It is therefore improbable that the pituitary does stimulate the adrenal cortex with this hormone before that age. This is the basis for the belief that the pituitary produces two kinds of ACTH, one for the sugar hormone and the other for the N hormone or androgenic hormone. It would seem unwise then in prostatic carcinoma to try to obtain the cortisone action by using ACTH. Rather, cortisone should be used for its replacement effect to produce partial adrenal atrophy. Now in addition to this all important effect, cortisone has side effects which are in the main, beneficial. There is an increase in appetite which in turn causes a gain in weight. Its effect is euphoristic and increases mental capacity and activity. Although cortisone causes some fluid retention, its effect on electrolytes is only about 3 per cent of the desoxycorticosterone effect. Patients taking it should have Wilkins, Lawson, et al.: J. Clin. Endocrinol. and Metab., 12: 3, 1952. Barrter, F. C. et al: Pathologic Physiology, Wm. A. Sodeman; page 551. 8 Sprague, R. G., Power, l\f. H., and Mason, H. L.: Physiological effects of cortisone and pituitary adrcnocotrophic hormone (ACTH) in man. J.A.M.A., 144: 1341-1347, 1950. 6
7
COR'l'ISONE THERAPY IN PROSTATIC CANCER
J.55
a restricted sodium intake. Even then they may have to be given diuretics occasionally. If there is too much loss of potassimn as evidenced by loss of energy and muscular weakness it may be detected by electrocardiographic changes and potassium then administered to make up the loss. Its contra-indications are: 1) congestive heart failure, 2) psychotic tendencies, 3) tuberculosis, ..Jc) active ulcer, 5) diabetes and G) renal insufficiency. During treatment it is ·well to do a weekly urinalysis; blood sugar detenni11a.t10n if the patient is glycosuric and a glucose tolerance if the patient is hyperglycemic. CASE REPORT
W. S. B aged 81 ·was referred to me in 1942 because of slight dy,mria. A preop0rative diagnosis of carcinoma of the prostate was made and an endoscopic resection was done. Bilateral orchiectomy immediately follmrnd and stilbe:-ltrol was faithfully taken, }fo; progress was satisfactory until the summer of 1951, ·when he again had dysuria. Rectal examination shmrnd no induration alld very little prostate but cystoscopic examination shmYed carcinomatous tissue in the prostatic urethra ,Yhich ·was again resected. His decline became very rapid characterized by loss of weight and strength and severe perineal pain, This became so severe that it was necessary to institute around the clock nursing and the administration of narcotics both orally and by hypodermic every few hours. The patienL ,Yas an intelligent man and knmY the reason for his pam and asked only that his last days he made as comfortable as possible. At about this time the reports of bilateral adrenalectomy came ro my attcn tio11, and although 1 kneYv the patient ,vas in no condition to undergo such a radical procedure, the thought occurred to me that some atrophy of the adrenals might be obtained by using replacement therapy. This ,ms talked on:r at great length with the patient and he consented to give it a triaL Treatment begaH in September 1951, ,,·ith 100 mg. of rortisone a day reducing it rapidly to 25 mg. per day. For the first f-i days practically no change ,ms evidenced. Thell almost, immediately the 1·esults became drama.tic. Appetite and strength returned amazingly, and although metapon was continued it became apparent that other narcotics by hypodnrmic could he abandoned. Instead of resigning himself to die he made plans to move to his ·winter home in Florida, ,vhieh he did, 'flw follo\\'ing excerpt from a letter ,vas received December 11, 1951: "R.eporting for myself, as you suggested, I fully underntand that you are dealing in terms of relief and comfort, and not of cure. J,~evertheless I have been able to move dmrn here without a jolt and that of itself was impossible until you began the present treatment But more than that, my increased vigor and strength seem an amazing change. ·whereas a few tmm, about the room ,va.s formerly all I was good for, I nmY ,rn1h. around town without tiring and spend hours tinkering i11 my shop, I still haYe some pain at timef:l, but nothing to compare ,Yith the rough going of last snmmer." Since that time, his nurse has reported at weekly intervals. He a.na.ngecl and conducted a town meeting in Florida; ,Yorked in his shop every day and wa8 able to drive his car ,Yhere eyer he wished to go. It was necessary on t-1Yo occasions to administer diuretirs. The patient is st.i 11 comfortable, active and happy (November 6, 1952).
156
W. GIFFORD HAYWARD DISCUSSION
Although the value of reporting the results of 1 case may be open to question, the complete absence of mention of this type of therapy in the literature to date and the excellent results, though temporary, make it seem not presumptuous and not premature. Its trial in a large number of cases will determine its value or futility. ADDENDUM
Since the paper was prepared, two other personal cases and one other case treated by a colleague have all responded favorably to this treatment, J. E., aged 62, had an anaplastic growth. He is now in relapse. No benefit was derived from cortisone therapy (November 6, 1952).
319 Pine St., Jamestown, N. Y.