The Effect of Diethylstilbestrol and Diethylstilbestrol Dipropionate on Carcinoma of the Prostate Gland. I. Clinical Observations

THE

EFFECT OF DIETHYLSTILBESTROL AND DIETHYLSTILBESTROL DIPROPIONATE O::\f CARCINOMA OF THE 1"ROSTATE GLAND. I. CLINICAL OBSERVATIONS PIERRE JORDA KAHLE, HILAIRE D. OGDEN, .JR., PAUL LIONEL GETZOFF

AND

From the Department of Urology, School of 11:Iedicine, Louisiana State University, New Orleans

In 1940 one of us (P ..T. K, with Maltry) reported the treatment of 14 cases of prostatic hyperplasia by means of diethylstilbestrol and diethylstilbeRtrol dipropionate, combined in 7 cases with various drainage operations. In all 14 cases there was a marked improvement in or complete relief of the symptoms associated with the obstruction and residual urine. As treatment progressed, changes in the size and consistency of the gland were observed in all cases, and were confirmed at autopsy in 3 patients who died from causes unconnected with the therapy employed. Histologic study of specimens obtained by biopsy after treatment showed deviations from the usual findings in hyperplasia of the prostate, chiefly manifested as a reduction in the number of papillary infoldings, a reduction in the height of the epithelium, vacuolization of the cytoplasm of the epithelium, decrease in the size of the acini, and stratification of the epithelium, with and without vacuolization. The successful results of this method of therapy, even though the number of cases was small, suggested that possibly the use of the same estrogenic substances might be beneficial in carcinoma of the prostate; this type of malignancy develops in the epithelium, in which changes produced by therapy had been most constant and most notable. ..While the plan was still under discussion, unexpected support was provided for it by the accidental finding that one of the patients under treatment for hyperplasia of the prostate actually had adenocarcinoma also, as proved by biopsy, and that the malignant cells showed FmggeRtivc evidence of regression, presumably as the result of estrogen therapy employed in the treatment of the hyperplasia (Case 1). CASE REPORTS

The 7 patients with carcinoma of the prostate gland whose histories follow include 2 patient8 treated in private practice and 5 treated on the GenitoUrinary Services of Charity Hospital of Louisiana at New Orleans. Two were negroes, 70 and 71 years old respectively, and 5 were white, with an age range from 64 to 76 years. The diagnosis of carcinoma of the prostate was confirmed by biopsy in 6 ca8eR. In the remaining case (CaRe 2) the combination of an abnormally small urethra and a urethral stricture made biop8y mechanically imposRible, aside from the fact that the patient's critical condition when he was first seen would not have justified even this procedure. Diagnosis was made by rectal palpation, and was confirmed by the presence of metastases to the inguinal and abdominal 83

84

P. J. KAHLE, H. D. OGDEN, JR. AND P. L. GETZOFF

lymph nodes, as well as to the bones. The osseous metastases were studied by serial roentgenography (figs. 1, A-3, B). In 5 of the 6 cases in ·which biopsy was done, a second biopsy was done at intervals varying from 25 to 67 days after the institution of treatment. In the remaining case (Case 7) it was not possible to obtain a second specimen of prostatic tissue, but biopsies of the inguinal glands, to which metastases had occurred, were secured before and after treatment. Six of the 7 patients were treated with diethylstilbestrol (1 mg. of which is equivalent to 25,000 i.u.). The remaining patient (Case 1) was treated with diethylstilbestrol dipropionate (1 mg. of which is equivalent to 20,000 i.u.). Both preparations were dissolved in oil, and administration was always by the intramuscular route. Generally speaking, regressive changes were observed after treatment in the neoplastic cells in each case, the changes consisting fundamentally of nuclear pyknosis and cytoplasmic vacuolization. These changes are discussed in detail in a subsequent paper, and only abbreviated reports are attached to the clinical histories. Case 1. S. Q., a 70 year old negro male, was admitted to the New Orleans Charity Hospital March 28, 1940. For the past 2½ years he had suffered from a progressive diminution of the urinary stream, dribbling and frequency, especially at night (index 12). The negro, although not acutely ill, was poorly nourished. The blood pressure was 180/100. Positive findings included bilateral arcus senilis, marked dental caries, and slight tenderness over the left lumbar region. On rectal examination the prostate gland was found to be firm, slightly tender, and about 7.5 cm. in diameter. Slight difficulty was experienced in passing a No. 18 F. catheter. The residual urine amounted to 360 cc. Examination of the blood revealed 2,000,000 red cells per cu. mm., and 60 per cent hemoglobin (Sahli). Blood chemical studies were within the normal range. Phenolsulphonphthalein excretion amounted to 15 per cent the first hour, 10 per cent the second, and 25 per cent for 2 hours. Roentgenologic examination of the pelvis and long bones showed no abnormalities. Drainage by means of an indwelling catheter was established March 28. Between J\/[arch 28 and April 10 the patient was given 15.5 mg. (310,000 i.u.) of diethylstilbestrol dipropionate. April 25 suprapubic cystostomy and biopsy were performed under spinal analgesia. At this time the prostate was approximately two-thirds smaller than on the first examination. Although the patient's condition had been diagnosed as benign prostatic hypertrophy, examination of the tissue removed by biopsy revealed adenocarcinoma, with changes in the neoplastic cells suggestive of regression. Between April 26 and May 22, 1940, the patient was given an additional 63 mg. of diethylstilbestrol dipropionate (1,260,000 i.u.), making a total of 78.5 mg. A second biopsy was performed June 4, and examination of the tissue revealed marked regressive changes in the neoplastic cells. When the patient was discharged June 20, 1940, he was completely reli~ved of the complaints

Frc. 1, A. Antero-posterior projection of the lumb[Lr spine rmd pelvis (J[LnU[Lry 29, 1\)40) showing fairly complete replacement of the norm[Ll bone structure of the vertebrae by metast[\tic lesions and small, scattered osteobl[\stic foci in the trnnsverse processes, ns well as extensive metastatic involvement of the sacrum, innominate bone and upper femurs. B. An tern-posterior projection of the lumbar spine and pelvis (:'-! ovember 30, Hl40) showing complete eburnation of the vertebral bodies and much more extensive involvement of the transverse processes th[Ln was observed in figure 1, A. The spinous proccssr;s now appear to be affected [Llso. The metastatic process in the pelvis observed in figure 1, A has also advanced consider[Lbly. The sacrum is almost completely replaced by metastatic lesions, as are the contiguous portions of the ilia, the anterolatcral portion of the crest of the right ilium, the bodies of the ilia, and the bodies and rnmi of the pubic bones. Note also the large coalescent lesions in the proximal femurs. C. Antcro-posterior projection of the lumbar spine and pelvis (February 23, ID-12). Examination of the lumbar spine shows comparatively little alteration in th0- ebunrnted bodies [LS compared with figun,s A, "1 [Incl B, but only a few small, faint, residual lesions are now observed in the transverse prncesses, and the spinous processes have apparently returned to normal. There is also a striking regression in the metastatic processes in the pelvic bones observed in figures A, A and B. Note the diminution in intensity of tlw diffusely involved bone, in which some semblance of normal trnbecnlar architecture can now be made out, and the diminution in size and density of the large confluent foci in the femurs. The bodies and superior rnmi of the pubic bones have returned almost to normal, and the involvement of the ischiatic portions of the conjoined rnmi, although still cousider-able, is distinctly less than on the previous examinations. 85

86

P. J. KAHLE, H. D. OGDEN, JR. AND P. L. GETZOFF

with which he had entered, and examination of the prostate gland per rectum revealed it to be normal in size and consistency. This patient does not live in New Orleans, and attempts to induce him to return for examination have been unsuccessful. Case 2. B. P., a 70 year old white machinist, was first seen in private practice in September 1940. In the spring of 1939 he had first observed a diminution in the size of the urinary stream but he had no other symptoms until several months later, when he began to suffer from frequency and occasional dysuria. In January 1940, he became acutely ill with chills, fever, malaise, muscular aches and pains, lumbar pain and tenderness, and suprapubic discomfort, in addition to the frequency and dysuria already mentioned. Carcinoma of the prostate gland was diagnosed by his family physician and by the urologist who saw him in consultation. The patient's condition became progressively worse. His appetite almost disappeared, he lost a great deal of weight, his sleep was so disturbed by pain that he sometimes paced his room all night, and eventually he became bedridden and required huge doses of morphine, which, however, gave him only temporary relief. When he was first seen by one of us (H. D. 0.) in September 1940, he looked at least 10 years older than his stated age. He was emaciated, toxic and cachectic, and evidently was in great pain. Examination was difficult because he could not relax and constantly tossed about the bed. The skin was dry, loose, and somewhat furfuraceous. Other positive findings not related to the urinary tract included bilateral arcus senilis, dental caries, tachycardia, and a functional systolic murmur heard over the entire precordium. Examination of the abdomen revealed a mass about 7 .5 cm. in diameter, which partially overlay the pubis and was slightly lateral to it; this mass was ovoid, ligneous, nodular and fixed. On deep palpation numerous enlarged, indurated lymph nodes could be felt in the lower abdomen. The lower extremities were edematous and apparently twice their normal size. The prostate gland (per rectum) was fixed and was stony-hard in some areas and somewhat softer in others, so that it had a definitely nodular feel; it was 7.5 cm. in diameter. The urine was foul and infected; it contained a trace of albumin, many pus cells, a few red blood cells, casts and cylindroids, and many mixed bacterial flora. Roentgenologic examination in January 1940, had revealed extensive osteoblastic and osteoclastic metastases to the heads of both femurs, all the pelvic bones, and the vertebral column (fig. 1, A) and to the ribs and possibly the lungs (fig. 2, A). The urethra was congenitally small, and a No. 20 F. sound fitted snugly. A filiform stricture encountered at the bulbomembranous junction was subsequently dilated to accommodate a No. 20 F sound. As the patient was almost incoherent from suffering, he was at once given a unilateral subarachnoid injection of 1 cc of absolute alcohol at the level of the second lumbar interspace. A week later the same procedure was carried out on the other side. Two or 3 days after the second injection the patient's gen-

DIETHYLSTILBESTROL AND DIETHYLSTILBESTROL DIPROPIONATE

87

eralized pains disappeared almost entirely and his only discomfort consisted of transitory aches in the shoulders and upper extremities, which were not relieved by bi-weekly injections of cobra venom. Intramuscular injections of diethylstilbestrol were begun in October 1940, and to date (March 1942) the patient has received a total of 503 mg. (12,575,000 i.u.) administered in 70 intramuscular injections of 5 mg. each and 153 injections of 1 mg. each. The only side effect of the therapy has been a slight enlargement and soreness of the breasts, more pronounced when the larger (5 mg.) doses were employed. Within a month after the injections had been begun the patient was gaining in weight and strength, he slept well, his appetite had returned, and he was able to leave the house when he desired. A second series of roentgenologic studies taken· at this time showed a distinct increase in the number and extent of the metastases previously observed (figs. 1, B, 2, B). In March 1941, the patient again began to complain of agonizing pain in the pelvis and lower limbs, and it was evident that the effect of the subarachnoid injections of alcohol given the previous fall had worn off. They were repeated bilaterally, with complete relief of the pain. Soon afterward the patient developed paralysis of the bladder, with chronic retention of urine, and catheterization has been a routine necessity ever since. Aside from the inconvenience of this mode of life the patient is in excellent condition at this time (March 1942). He has gained 30 pounds. He is free from pain and requires no opiates. His appetite is good, he sleeps well, and he is strong enough to drive his car and attend his place of business daily. The suprapubic mass and the abdominal lymph nodes observed on the first examination are no longer palpable. The edema of the lower extremities, probably as a result of the relief of extrinsic pressure from these nodes, has completely disappeared. The consistency of the prostate gland (examined per rectum) is somewhat softer than normal, and the nodules felt on the first examination have completely disappeared. It would be difficult, indeed, to differentiate the gland at this time from a gland of normal structure. Roentgenologic examination in February 1942, showed a marked diminution in the number and extent of the metastatic lesions as compared with previous examination (figs. 1, C, 2, C, 3, B). Histologic examination was not possible in this case. The urethra was too small to accommodate a resectoscope, and biopsy via the perinea! route, although considered, was not carried out because of the patient's critical condition when he was first seen. When he had recovered sufficiently to permit it, he would not consent to it. Case 3. R.R., a 71 year old colored male, was admitted to the New Orleans Charity Hospital March 12, 1941. For the past 3 years he had suffered from a marked diminution in the size of the urinary stream, increasing frequency, especially at night, and dysuria. Recently there had been some burning on urination. In the course of his illness he had lost 15 pounds. The patient had had antisyphilitic treatment many years before, and for the last several years had had occasional attacks of dyspnea, orthopnea and chest pain. Physical

88

P. J. KAHLE, H. D. OGDEN, JR. A;';D P. L. GETZOFF

examination was essentially negative except for the prostate gland, which was examined per rectum. It was hard, smooth and non-tender, and was approximately 5 times normal size. The residual urine amounted to 1200 cc.

Fm. 2, A. Antero-posterior projection of the chest (January 27, 1940), showing osteoblastic metastatic costal lesions. Note the discrete foci in all the ribs and the diffuse segmental involvement in the posterior portion of the right sixth rib. B. Antero-posterior projection of the chest (November 30, 1940), showing definite increases in the metastatic cost al lesions observed in figure 2, A. C. Antero-posterior projection of the chest (February 23, 1942), showing a diminution in the number and size of the cost al lesions observed in figures S, A and B. N otc the disappearance of many of the smaller lesions, the diminution in density and extent of thc1 intermediate lesions, and the regression of the diffuse segmental involvement previously observed in the right sixth rib posteriorly.

DIETHYLSTILBESTIWL AND DU;THYLSTILBl~STROL DIPROPIONATE

89

The urine contained a trace of albumin and a few red and ,vhite blood cells and gram-positive cocci. Examination of the blood revealed 2,500,000 reel cells and 9,000 white cells per cu. mm.; there was 50 per cent of hemoglobin (Sahli). The phenolsulphonphthalein excretion was 15 per cent the first hour, 5 per cent the second, and 20 per cent for 2 hourR. Roentgenologic examination of the kidneys, urcterH and bladder showed no evidence of stones. Examination of the chest showed a moderate enlargement of the cardiac shadow, especially on the left. Electrocardiographic findings were compatible with cardiac disease but presented no evidence of myocardial infarction.

FJG. ;3, A. Antero-posterior projection of the shoulder (August 6, 1941), showing osteoblastic metastatic lesions in the humeri similar to those observed in the other lon1s h01ws. B. Ant.ero-posterior project.ion of the shoulder (February 23, 1D42), showing a definite diminu(.ion in the size and number of the ost.cobla.stic metastatic lesions observed in the humeral neck and the proximal third of the shaft in figure 3, A. Note that the axillary bonler of the scapula, which was formerly irregularly increr1sed in density, has returned nearly to normal.

The patient waR treated by blood trarmfnsions and other supportive therapy until his general condition was Hufficiently improved to permit suprapubic cyHtostomy, which was performed March 24. Fifty-four days later he was discharged, with the suprapubic tube in situ. He was re-admitted June 16, 1941. The suprapubic tube was draining well, and his general condition vvas much improved. The red blood cells had increased by almost 2,000,000, the hemoglobin by 25 per cent, and the phenolsulphonphthalein excretion by 45 per cent. Examination of a biopsied section of the prostate gland June 28, 1941, revealed adenocarcinoma. Intramuscular injections of diethylstilbestrol in 5 mg. closes were begun June 30, 1941, and between that date ancl Augm,t 4 the patient received a total of 76 mg. (1,900,000 i.u.). Examination of a second

90

P. J. KAHLE, H. D. OGDEN, JR. AND P. L. GETZOFF

biopsied specimen August 6, 1941, revealed regressive changes in the neoplastic cells. When the patient was discharged from the hospital August 22, 1941, the suprapubic fistula had closed, there were no symptoms of urinary obstruction, and his general condition was excellent. He lives out of town and it has not been possible to induce him to return for further observation. Case 4. H. H., a 74 year old white male, was admitted to the New Orleans Charity Hospital October 24, 1940, complaining that for the past 2 years he had suffered from a progressive diminution in the size of the urinary stream and from frequency, especially at night. Gross hematuria had been observed on 1 occasion shortly before admission. Stones had been removed from the bladder by the suprapubic route in 1930. The patient, although not acutely ill, was poorly developed. The blood pressure was 160/110. Positive physical findings included marked dental caries, chronic hypertrophic tonsillitis, a systolic apical murmur, and bilateral inguinal hernias. The prostate, examined per rectum, was found to be stony-hard, nodular, and 4 times normal size. The residual urine amounted to 1100 cc. The urine contained a trace of albumin and gross blood. Gram-negative bacilli were observed in a smear of the sediment. Examination of the blood revealed 3,400,000 red blood cells per cu. mm. and 70 per cent hemoglobin. Blood chemical studies were within normal limits. The phenolsulphonphthalein excretion was 5 per cent for the first hour, 20 per cent for the second, and 25 per cent for 2 hours. Roentgenologic examination of the chest revealed a slight enlargement of the heart; electrocardiographic study revealed no evidence of myocardial disease. Examination of the pelvis, lumbar spine and long bones showed no evidence of metastases, but at least 10 calculi were noted in the bladder. Suprapubic cystotomy was performed under spinal analgesia November 6, 1940, and the stones mentioned above were removed. Biopsy of the prostate gland was performed November 27, 1940, and the specimen was reported as showing hyperplasia and adenocarcinoma. The patient's recovery was without incident and he refused further treatment at this time. He returned to the hospital August 1.5, 1941, complaining of persistent drainage of urine from the suprapubic wound, and of pain in the lower portion of the chest and back. Laboratory examinations revealed substantially the same findings as on the first admission, except that culture of the urine now showed B. coli, streptococcus fecalis, and salmonella morgagni. The patient improved considerably under supportive treatment, and was discharged with the suprapubic wound well healed. He returned to the hospital November 26, 1941, complaining of a recurrence of the suprapubic fistula and of difficulty in voiding. Laboratory findings were substantially the same as on previous admissions except that the urea nitrogen of the blood was now 30.7 mg. per cent and the total excretion of phenolsulphonphthalein was 35 per cent. The residual urine amounted to 360 cc. The prostate, although of about the same consistency as on previous examinations, was appreciably larger.

DIETHYLSTILBESTROL AND DIETHYLSTILBESTROL DIPROPIONATE

91

Secondary closure of the suprapubic wound was performed under spinal anesthesia December 1. Between November 27, 1941, and January 5, 1942, the patient received a total of 75 mg. (1,875,000 i.u.) of diethylstilbestrol. Examination of the prostate gland per rectum at the termination of therapy showed it to be markedly decreased in size. The stony-hardness had disappeared, and the consistency now suggested that of a bag of small seeds. Examination of a biopsied specimen January 7, 1942, revealed marked regressive changes in the neoplastic cells. At this time (March, 1942) the patient is receiving semi-weekly injections of diethylstilbestrol in 5 mg. doses (125,000 i.u.). He is free from symptoms, has gained weight and strength, and his urinary function is perfectly normal. Additional biopsies will be carried out at later dates. Case 5. P. P., a 75 year old white male, was admitted to the New Orleans Charity Hospital May 15, 1941, in acute retention, which had lasted for 48 hours. For the past 4 months there had been progressively greater difficulty in starting the urinary stream, and for the past week there had been considerable retching and vomiting. For some years the patient had suffered from occasional dyspnea on exertion. The temperature was 102.4°F., the pulse rate 94 per minute, and the blood pressure 150/90. The patient was apparently acutely ill. The abdomen was greatly distended and there was considerable tenderness in the left suprapubic region. Peristalsis and borborygmi were audible. The bladder was distended and could easily be outlined. There was a small hydrocele on the left side. The reflexes were sluggish. The prostate was felt per rectum to be firm, nodular, and twice normal size. The residual urine amounted to 1050 cc. The urine contained a large number of white blood cells. Examination of a smear of the sediment revealed bacilli which were identified on culture as Aerobacter. Blood chemical studies revealed 40 mg. of nonprotein nitrogen and 597 mg. of chlorides per 100 cc; the carbon dioxide combining power was 48 volumes per cent. The excretion of phenolsulphonphthalein was 25 per cent the first hour, 15 per cent the second, and 40 per cent for 2 hours. Roentgenologic study of the long bones and the chest revealed no evidence of metastases. Cystography revealed no evidence of projection of the prostate gland into the bladder. Drainage of the bladder was instituted by means of an indwelling catheter and supportive measures were employed. A biopsied specimen of the prostate gland was reported June 7, 1941, as showing adenocarcinoma. Between June 28 and July 23, 1941, the patient was given a total of 52 mg. (1,300,000 i.u.) of diethylstilbestrol. A second biopsy of the prostate gland August 4, 1941, was reported as showing marked regressive changes in the neoplastic cells. The patient was discharged from the genito-urinary service of the hospital August 7, 1941, and was re-admitted to the surgical service 10 days later, with acute abdominal symptoms, for which emergency appendectomy was performed. ,Examination per rectum at this time showed the prostate gland to be entirely normal except for slight tenderness on palpation. At the present time (March, 1942) the patient, according to a recent letter,

92

P. J. KAHLE, H. D. OGDEN, JR. AND P. L. GETZOFF

is in excellent condition and free from symptoms. Since he lives out of town, there has been no opportunity to examine him in the last few months. Case 6. D. L., a 64 year old white male, was admitted to the New Orleans Charity Hospital January 11, 1941, in acute retention. For the past 3 weeks there had been progressive difficulty in starting the urinary stream, a progressive diminution in its size, and hematuria. He thought he had lost about 35 pounds during the past year. Physical examination was essentially negative except for the rectal examination, which revealed the prostate to be stony-hard, studded with nodules, partially fixed, and 4 times normal size. The urine was grossly bloody. Blood chemical studies were within normal range. The phenolsulphonphthalein test was 45 per cent for the first hour, 15 per cent for the second, and 60 per cent for the 2 hours. Electrocardiographic examination was reported as showing a slight left axis deviation, with some slurring of the QRS complex. Roentgenologic examination of the chest and of the kidneys, ureters and bladder revealed no abnormalities. A biopsied specimen of the prostate gland November 15, 1941, showed adenocarcinoma. Between November 15 and December 30, 1941, the patient received 95 mg. (2,375,000 i.u.) of diethylstilbestrol. January 7, 1942, the prostate was considerably smaller and softer than on the first examination, and examination of a biopsied specimen revealed carcinomatous changes only in the middle lobe. At the present time (March, 1942) the patient is receiving injections of diethylstilbestrol in 5 mg. doses (125,000 i.u.) 3 times a week. He is free from symptoms and the prostate is small, soft and atrophic. Additional biopsies will be carried out at later dates. Case 7. L. C. B., a 65 year old white male, was admitted to the private services of Touro Infirmary March 13, 1940. For the past 8 months he had suffered from frequency (diurnal index 3-10, nocturnal 1-3) and dysuria. The urinary stream lacked force. The condition had been diagnosed as prostatitis and had not been improved by periodic massage. The blood pressure was 188/100. Physical examination was essentially negative except for the prostate gland, in which a small, firm nodule, suggestive of cancer, was palpated on the left lobe near the apex. The residual urine amounted to 180 cc. Pan-endoscopic examination showed a median bar and some obstruction of the prostatic urethra by intra-urethral encroachment of the lateral lobes. Chemical examination of the blood revealed 48 mg. of nonprotein nitrogen and 80 mg. of dextrose per 100 cc. The excretion of phenolsulphonphthalein was 30 per cent the first hour, 15 per cent the second hour, and 45 per cent for the 2 hours. Transurethral prostatic resection was carried out March 25, 1940, and the specimen was reported as showing hyperplasia with some areas of carcinoma (Broders' classification No. 2). Postoperative roentgenologic examination of the pelvis and long bones revealed some increase in the density of the pubic rami but the roentgenologist did not consider deep roentgen ray therapy indicated at the time. The patient was discharged in good condition April 1, 1940. When he was examined July 10, 1940, he had no symptoms and no positive

DIETHYLSTILBESTROL AND DIETHYLSTILBESTROL DIPROPIONATE

93

physical findings except for the nodule previously described in the prostate. March 5, 1941, he returned complaining of frequency of urination and diminution in the size of the stream. The residual urine amounted to 60 cc. On rectal examination the prostate was found to be about normal size but indurated and diffusely nodular. The roentgenologist again advised against deep ray therapy. When the patient was seen May 25, 1941, his urinary difficulties were persistent, he had lost about 10 pounds, and the inguinaUymph nodes were enlarged and tender, especially on the right side. The prostate gland presented an increase in the nodular areas and was now of ligneous consistency. A biopsied right inguinal lymph node was reported as showing metastatic adenocarcinoma. August 12, 1941, the patient reported that he had lost 17 pounds, was constantly nauseated, and could not force himself to eat. He had begun to show signs of cachexia. He had persistent, progressively more severe pain in the back and upper aspects of the thighs, for which opiates gave only temporary relief. The inguinal lymph nodes had increased in size and were very tender. Rectal examination showed the prostate to be diffusely nodular, stony-hard, and much larger than on the previous examination. The patient became progressively worse. Cobra venom was advised for the relief of pain but was without effect. By January, 1942, he could not leave his bed, and his local physician considered him doomed. He was given 5 consecutive daily injections of diethylstilbestrol in 5 mg. doses January 13-17, and the same dosage was administered on alternate days until February 6. In all, he received 74 mg. of diethylstilbestrol (1,850,000 i.u.) during this period, and no other medication except 30 mg. of thiamin chloride by the intramuscular route every second day. A biopsied left inguinal lymph node was reported February 6, 1942, as showing adenocarcinoma, with marked regressive changes in the neoplastic cells. On February 24, 1942, Dr. F. H. Davis of Lafayette, Louisiana, under whose direction treatment had been administered, stated that the patient had begun to improve with the institution of estrogen therapy, and that improvement had been steady and consistent. At the present time (March, 1942), he is still receiving 15 mg. of diethylstilbestrol (375,000 i.u.) weekly in 3 doses. He is free from pain and does not require sedation. His nausea has disappeared and his appetite has returned. His strength has so increased that he is able to drive his own car, and he attends daily to his routine business affairs. COMMENT AND DISCUSSION

Clinical results. In all 7 patients reported ~n this paper as treated by diethylstilbestrol and diethylstilbestrol dipropionate clinical improvement was observed following therapy, as evidenced by gains in body weight, improved color, increased energy, and a definite sense of well-being. Two bedridden patients (Cases 2 and 7), who were formerly kept constantly under narcotics for the relief of pain, now require no sedation at all. Within 4 weeks and 6 weeks, respectively, after the beginning of treatment they were able to leave their homes, and now both drive their cars and attend to their business affairs. In 6 of the 7 cases bladder function is completely restored to normal, there

94

P. J. KAHLE, H. D. OGDEN, JR. AND P. L. GETZOFF

being no complaint of frequency, urgency, or dysuria. In the remaining case (Case 2) subarachnoid alcoholic injections produced a neurogenic bladder, and the patient now leads a catheter life. His prostate, however, is normal in size and consistency on rectal examination, and it is fair to assume that under different circumstances there would have been no impairment of urinary function. There seems no reason to believe that the biopsies carried out in Cases 1, 3, 4, 5, and 6 could have produced the improvement observed in urinary function. They were too small to bring about such results, the total amount of gland removed exceeding 1 gm. only in 1 case. In Case 7, although prostatic resection was carried out, it was not until 11 months after the operation that obstructive symptoms recurred. Then they were considerably more severe than before the operation, and were associated with enlargement and induration of the remnant of the gland and with coincident extension of the neoplasm to adjacent structures. Further biopsies were limited to the regional lymph nodes, and the return of bladder function to normal can be attributed only to treatment by diethylstilbestrol. Regardless of the original state of the prostate gland, whether it was large or small, nodular or without nodules, of variable consistency or stony-hardness, or completely or partially fixed to adjacent structures, softening was observed after the first few injections of the synthetic substance. Decreases in size followed promptly and in time all the glands either regressed to normal size, or (in 2 instances) became somewhat atrophic. In all 7 cases at the time of the last examinations the glands had lost all the characteristics of malignancy, and it would have been impossible to make a diagnosis of carcinoma by rectal palpation. The effect of estrogen therapy on metastases to regional lymph nodes was equally marked. In Case 2 a mass 7.5 cm. in diameter was observed lateral to and partially overlying the pubis on the first examination, and deep palpation revealed the presence of many enlarged, indurated lymph nodes in the lower abdomen as well as in the inguinal regions. In Case 7 enlarged and painful lymph nodes were first observed 8 months before treatment was begun and continued to grow during this period; biopsy revealed them to be caused by metastatic malignancy. In both these cases regression of the glands and relief of pain were observed shortly after treatment was begun. In Case 7 a second biopsy during the course of treatment revealed regressive changes in the neoplastic cells. At present neither patient presents enlarged or tender glands. Side effects. The only notable side effect observed in the patients treated with diethylstilbestrol or. diethylstilbestrol dipropionate occurred in Case 2, in which the patient complained of moderate enlargement of the breasts and some soreness of the nipples. These symptoms were observed only when intensive therapy was employed, and subsided rapidly when it was withdrawn. It was not possible to demonstrate damage to any organ or system by clinical examination or laboratory tests during or after estrogen therapy. The gonads were studied with special care, but no evidence of atrophy was observed, nor has this change been observed in patients with hyperplasia, some of whom have

DIETHYLSTILBESTROL AND DIETHYLSTILBESTROL DIPROPIONATE

95

been receiving diethylstilbestrol therapy for a period of 2 years or more. In 3 of the 14 patients with benign hyperplasia treated by this method an examination of the ejaculate after a few treatments showed an absence of spermatozoa. Several patients who had been virile before treatment complained of impotence and lack of libido, but their symptoms disappeared when the dosage was reduced to a maintenance level; others were not affected. It has not been possible to study our cancer cases from this standpoint, but if these conditions develop, they would be trivial in comparison with the clinical relief and apparent control of the pathologic process (as demonstrated by regressive histologic changes) achieved by this mode of therapy in an inevitably fatal disease. Roentgenologic studies. Roentgenologic studies of the bones were carried out in all 7 cases in this series, and metastases were observed in 2, in 1 of which treatment was not continued over a long enough time to permit evaluation of its effect in this regard. The effect of estrogenic therapy on osseous metastases, however, as well as on pulmonary metastases, is clearly illustrated in Case 2, in which serial studies were carried out over a period of 16 months. This patient, who was bedridden when first seen, has made a striking clinical recovery. He has received to date 12,575,000 i.u. (503 mg.) of diethylstilbestrol. Examination of the chest (fig. 2, A), and the lower dorsal and lumbar spine and the pelvis (fig. 1, A) January 27, 1940, before estrogen therapy was begun, revealed a widely disseminated osteoblastic type of metastatic malignancy. Examination of the same areas (figs. 2, B, 1, B) November 30, 1940, one month after estrogen therapy was begun, revealed considerable advance in the disease. A greater number of individual foci involved previously unaffected bones, and there was also a confluence of many of the lesions, in such a fashion that complete replacement of anatomic segments by tumor tissue had occurred. Examination of the shoulders in July, 1941, also revealed metastases to the bones (fig. 3, A). Examination of the same areas February 23, 1942, after estrogen therapy had been administered for approximately 15 months, indicated a marked regression affecting both the size and the number of metastases (figs. 1, C, 2, C, 3, B). A final comparative study of the serial films suggested that although not all of the metastatic lesions which developed in the interim between the first and second examinations had disappeared at the time of the third examination, the degree of regression had been so great that the patient's status was definitely improved over his status at the time of the initial examination. Further details of the comparative changes observed in the serial studies of the various areas will be found in the legends attached to the illustrations. Discussion. The ideal treatment of carcinoma of the prostate gland is surgical extirpation, but actually this is seldom possible because the patient is seen too late to permit it. Suprapubic cystostomy, transurethral resection and irradiation are employed as palliative measures in advanced cases, but even from the standpoint of palliation their results leave much to be desired. In short, the situation in this disease is so very discouraging that a constant search for new methods of treatment is always under way.

96

P. J. KAHLE, H. D. OGDEN, JR. AND P. L. GETZOFF

Our studies up to this time provide no evidence at all that carcinoma of the prostate can be cured by the use of diethylstilbestrol or diethylstilbestrol dipropionate. On the other hand, although the number of our cases is still very small, the results in every one of them show that under this form of therapy original lesions in the prostate as well as metastatic lesions will regress and apparently remain latent, that life can be prolonged in comfort, and that rehabilitation to useful occupations can be achieved even in some apparently hopeless cases. Such results do not indicate that the disease is cured, but they do indicate that it has been arrested and, from the patient's standpoint, they are not unimportant. Freedom from pain and restoration to normal activity, even though as yet we do not know how long the improvement will last, are benefits which cannot and should not be ignored. How to explain the effects secured by the administration of estrogenic substances in carcinoma of the prostate we still cannot undertake to say. In our earlier paper on the use of these agents in hyperplasia of the prostate we wrote that we would leave it to those more competent than ourselves to determine "whether they act through the hypophysis, directly on the elaboration of androgenic substances by the gonads, by changing the androgen-estrogen balance in relation to hyperplasia, or directly on cell proliferation and cell changes.'' The same problems present themselves in the use of estrogenic substances in prostatic cancer. The rapid and undoubted changes in the consistency and size of the hyperplastic prostate gland which we had observed following their administration had led us to speculate whether there were not possibilities of direct action, at least in part, on cell proliferation in this benign neoplastic condition. The rapid changes in the consistency of the carcinomatous gland, sometimes observable as early as 48 hours after the first injection, again suggested direct and possibly even selective action on the epithelial cells. This hypothesis, of course, does not exclude the possible influence of the anterior lobe of the pituitary gland on the androgens elaborated by the interstitial cells of the testes, or the possible effects of inactivation of the androgens by a change in the androgen-estrogen balance, or perhaps the operation of both mechanisms, in patients with carcinoma of the prostate. The work carried out by Huggins and his associates during the last 2 years is of interest in this connection. It concerns the effects of castration and of the injection of estrogens on normal and hyperplastic prostate glands in experimental animals, and the effect of castration on carcinomatous glands in clinical subjects. The results of these studies are further proof of the role of the hormones elaborated by the testes in the course of hyperplasia and carcinoma of the prostate gland, and the authors recommend castration as a direct and sure method of eliminating the gonadal androgens. At the meeting of the American Urological Association in May, 1941, Munger, in another demonstration of the influence of the hormones elaborated by the testes on the progress of prostatic malignancy, proposed irradiation of these organs. Lowsley, in discussing the proposal, suggested that perhaps castration

DIETHYLSTILBESTROL AND DIETHYLSTILBESTROL DIPROPIONATE

97

by irradiation had already been inadvertently employed by urologists who did not protect the testes while employing irradiation for this type of cancer. He believed this point to be of considerable importance. Practically, although surgical excision of the testes is a relatively simple operation, it is often more than a seriously ill patient can tolerate in safety. Furthermore, neither excision nor irradiation of the testes necessarily eradicates all the sources of androgen elaboration. In fact, the possibility of an extragonadal source is implied by Huggins and his associates in their suggestion that patients who do not respond to castration should be treated supplementally with stilbestrol. In a discussion of Munger's paper, Herrold reported that stilbestrol had been given orally to 12 patients with prostatic cancer at the University of Illinois. He observed the same improvement in their general condition which we had observed in our patients, as well as changes in the consistency of the gland, and believed that in some instances, at least, there had been stabilization or regression of the malignant growth. The oral route is believed to be only 50 per cent as effective as the intramuscular route, by which all our patients were treated. SUMMARY

Seven cases of adenocarcinoma of the prostate, six of which were proved by biopsy, have been treated during the past 2 years with diethylstilbestrol or diethylstilbestrol dipropionate. In all the cases treated, this method of therapy brought about prompt relief of pain and urinary symptoms and a general improvement in health. Two bedridden patients were restored to activity in 4 and 6 weeks, respectively, after the institution of treatment. The clinical improvement was associated in all instances with a regression of the malignant lesion. At the time of the last examination all the glands had lost their malignant characteristics, and it would have been impossible to make a diagnosis of carcinoma by rectal palpation. The clinical improvement was also associated with a regression of metastatic lesions to the bones in the only case in which serial roentgenologic observations were possible, and with a regression of metastases to the lymph nodes in the 2 patients who exhibited such lesions. Gynecomastia was observed in 1 case, but was only transient. No other side effects were observed. The reduction in the size and the alteration of the consistency of the primary neoplastic growths, as well as the regression in the metastatic lesions, could readily be correlated with the marked regressive tissue changes observed in the histologic study of specimens secured by biopsy after treatment. Note.-Further studies with diethylstilbestrol and diethylstilbestrol dipropionate are now being carried out in carcinoma of the bladder on our urological service, and in gastric, rectal and esophageal carcinoma and fibrosarcoma by Dr. H. Reichard Kahle, in co-operation with Dr. Paul L. Getzoff. Our thanks are due to Dr. M. D. Teitelbaum of Touro Infirmary, who made

98

P, J. KAHLE, H. D. OGDEN, JR . AND P. L. GETZOFF

the comparative x-ray studies in Case 2; to Drs. George Vickery and John Paul Burton of the Charity Hospital resident staff, who cooperated with us throughout this study; and to the Medical Research Department of the Winthrop Chemical Company, which supplied the estrogenic substances used. 812 Pere Marquette Bldg ., New Orleans, La. REFERENCES HERROLD, R . D . : Discussion of Huggins and of Munger's article . J. Urol., 46: 1016-1017, 1941. HUGGINS, CHARLES, ScoTT, W.W., AND HODGES, C. V. : Studies on prostatic cancer . III. The effects of fever, of desoxycorticosterone and of estrogen on clinical patients with metastatic carcinoma of the prostate. J. Urol., 46: 997-1006, 1941. KAHLE, P . J ., AND MALTRY, EMILE: Treatment of hyperplasia of the prostate with diethylstilbestrol and diethylstilbestrol dipropionate . New Orleans Med. & Surg. J ., 93: 121-131, 1940. LowsLEY, 0. S.: Discussion of Huggins and of Munger's Article . J . Urol., 46: 1015-1016, 1941. MUNGER, A. D.: Experiences in the treatment of carcinoma of the prostate with irradiation of the testicles . J . Urol., 46: 1007-1011, 1941.