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Hypophysectomy and Adrenalectomy for Disseminated Prostatic Carcinoma
Vol. 105, June Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright© 1971 by The Williams & Wilkins Co.
HYPOPHYSECTOMY AND ADRENALECTOMY FOR DISSE.;.\IINATED PROSTATIC CARCINOMA G. P. MURPHY, G. REYNOSO, R. SCHOONEES, S. GAILANI, R. BOURKE, G. M. KENNY, E. A. MIRAND AND D. S. SCHALCH From the Roswell Park il/Iemorial Institute, New York State Department of Health, Buffalo and the University of Rochester School of Medicine and Strong Memorial Hospital, Rochester, New York
Scott and associates studied the effects of open hypophysectomy as a form of endocrine palliation in patients with disseminated prostatic carcinoma.1-4 They established the available criteria for judgment of objective and subjective signs of improvement in these patients. 4 A significant number of patients were benefited. 4 Concurrent clinical studies on hypophysectomized patients were made by other investigators. 5- 12 Objective and subjective signs of benefit were noted in more Accepted for publication September 1, 1970. Read at annual meeting of American Urological Association, Philadelphia, Pennsylvania, May 10-14, 1970. Supported in part by United States Public Health Service grants 5 SOl RR05648 and C-5834. 1 Scott, W. W.: Endocrine management of disseminated prostatic cancer, including bilateral adrenalectomy and hypophysectomy. Trans. Amer. Ass. Genitourin. Surg., 44: 101, 1952. 2 Scott, W.W.: Appraisal of present methods of treatment of advanced prostatic cancer. J. Urol., 72: 530, 1954. 3 Scott, W.W.: Role of pituitary in normal and abnormal proslatic growth. Trans. Amer. Ass. Genitourin. Surg., 46: 33, 1954. 4 Scott, W.W. and Schirmer, H. K. A.: Hypophysectomy for disseminated prostatic cancer. In: On Cancer and Hormones. Chicago: University of Chicago Press, p. 175, 1962. 5 Whitmore, W. F.: Hormone therapy in prostatic cancer. Amer. J. Med., 21: 697, 1956. 6 Ray, B. S.: Some inferences from hypophysectomy on four hundred fifty human patients. Arch. Neurol., 3: 121, 1960. 7 Pearson, 0. H., Ray, B. S., Harrold, C. C., West, C. D., Li, M. C., Maclean, J. P. and Lipsett, M. B.: Hypophysectomy in treatment of advanced cancer. J.A.M.A., 161: 17, 1956. 8 Ray, B. S.: The neurosurgeon's new interest in the pituitary. J. Neurosurg., 17: 1, 1960. 9 Luft, R. and Olivecrona, H.: Hypophysectomy in the treatment of malignant tumors. Cancer, 10: 789, 1957. 10 Pearson, 0. H. and Ray, B. S.: Hypophysectomy in the treatment of metastatic mammary cancer. Amer. J. Surg., 99: 544, 1960. 11 Smith, E. J. R., Gurling, K. J. and Baron, D. N.: The effect of hypophysectomy in advanced carcinoma of the prostate. Brit. J. Urol., 31: 181, 1959. 12 Murphy, G. P., Boctor, Z. N., Gailani, S. and Belmusto, L.: Hypophysectomy for disseminated prostatic carcinoma. J. Surg. Oncology, 1: 81, 1969.
than 40 per cent of the ]latients described. 1· 12 Heretofore, however, assessment of the degree of pituitary ablation was based on general clinical responses and postmortem anatomical studies. The series of observations presented herein describes new methods and results of correlation of functional ablation of the anterior pituitary with the objective and subjective signs of improvement in patients with disseminated prostatic carcinoma. These studies were further correlated with additional techniques for measurement of urinary androgen fractions. Other studies were also completed on adrenalectomized patients before and after hypophysectomy for progressive disseminated prostatic carcinoma. MATERIALS A:'sfD l\IETHODS
Adult male patients with disseminated prostatic carcinoma were selected for study. Patients were admitted randomly to protocol when they demonstrated clinical signs of progression or dissemination of histologically proved prostatic carcinoma. Progression was judged on the results of biochemical (for example acid phosphatase), radiological, symptomatic and physical examinations. Patients were treated with open or cryosurgical hypophysectomy after completion of preoperative evaluation. l)ossible bias was present to the extent that some patients underwent closed cryohypophysectomy rather than the open operation on the basis of personal selection, for example extremely poor general medical condition. Additional patients also were selected at random initially for treatment by bilateral adrenalectomy. Others underwent this form of therapy following relapse post-hypophysectomy. Evaluation studies were completed in all patients at 14 days and at 1, 3, 6 and 9 months postoperatively. Patients who were well at this time were then evaluated every 3 to 6 months. Other patients who had relapsed were evaluated earlier and at variable periods. All patients were studied while in a basal state on the urology service. The studies that were 817
818 TABLE
MURPHY AND ASSOCIATES
1. Patients treated with hypophysectomy for disseminated prostatic carcinoma Open Operation
No. patients Immediate mortality Satisfactory remission Mean age (yrs.) Previous response (mos.)
11
2 (18.2%) 7 (63.3%) 58.09 (±1.30) 43.3 (±11.29)
Cryosurgery 23 0
5 (21. 7%) 64. 91 (±1. 47) 29.00 (±6. 71)
completed preoperatively and postoperatively included human growth hormone (HGH) ,1 2 luteinizing hormone (LH), 13 follicle stimulating hormone (FSH), 13 plasma testosterone, 12 acid phosphatase, alkaline phosphatase, hematocrit, body weight and blood urea nitrogen (BUN). Total 24-hour urinary 17-ketosteroids were determined by the standard chemical procedure and by gas liquid chromatography. Total 24-hour urinary androgenic fractions were determined by the gas liquid chromatographic procedure of Haahti and associates14 following enzymatic hydrolysis and conversion of the free steroids to trimethyl sylil ethers. The procedure in our laboratory has an over-all coefficient of variation of 15 per cent (± standard deviation of the difference between replicate samples). In all cases total 17-ketosteroids, whether determined by the routine Zimmerman reaction or by the gas-chromatography procedure, were within normal limits for the age group. However, individual fractions showed significant deviations from normality. Growth hormone levels were determined in all patients during insulin-induced hypoglycemia. 12 Continuous monitoring and physician attendance are necessary during the test. Details of the technique are described in part elsewhere.12 The test represents a potential hazard in the post-hypophysectomy or adrenalectomy patient. However, despite occasional symptoms of hypoglycemia, all tests were completed without incident in this series. The criteria of clinical response in this series were those enumerated by Scott. 4 Subjective remission describes a patient who has: I) pain re13 Schalch, D. 8., Parlow, A. F., Boon, R. C. and Reichlin, S.: Measurement of human luteinizing hormone in plasma by radioimmunoassay. J. Clin. Invest., 47: 665, 1968. "Haahti, E. 0., Vandenheuvel, W. J. and Horning, E. C.: Separation of urinary 17-ketosteroids by gas chromatography. Anal. Biochem., 2: 182, 1961.
lief, 2) sensation of well-being and 3) improved appetite. Objective remission includes: 1) decrease in serum acid phosphatase, 2) delayed decrease of serum alkaline phosphatase, 3) weight gain, 4) improved radiological appearance of osseous metastases and 5) improvement of anemia. Even in terms of objective criteria obvious clinical judgment must be made in interpreting the clinical signs. In the present report we judged a patient to have had a satisfactory clinical response if remission of the previously described symptoms and/or signs occurred for more than 6 months. All patients were followed up to the present time or until death. This series was closed for purposes of evaluation in February 1970. No patient was included who underwent hypophysectomy after September 1969. All data were initially and subsequently recorded on followup forms. This material then was evaluated statistically. Regimens of postoperative endocrine management including cortisone and thyroid replacement have been described. 12 RESULTS
Survival. Thirty-four patients underwent either open or closed (cryosurgical) hypophysectomy (table 1). There was no operative mortality from cryosurgical hypophysectomy. Early in the study 2 patients (18.2 per cent) in generally poor condition died in the immediate post-open hypophysectomy period. On the basis of the subjective and objective criteria, 12 patients (35.3 per cent) had satisfactory remissions. There was a significant difference in the mean age of the hypophysectomy groups. Patients in the cryohypophysectomy group had a history of response to estrogens and castration that was shorter than that noted in the patients who underwent open operations. Table 2 details the remission rates and survival 2. Remission and survival periods following hypophysectomy for disseminated prostatic carcinoma in 34 cases
TABLE
Satisfactory: Mean ± 1 standard error Range Norm Poor: Mean ± 1 standard error Range
Norm
Subjective Remission
Objective Remission
Survival Period (mos.)
11.89 1. 84 6.0-24.0 12
8.08 1.29 3.50-17.75 12
15. 81 2.15 6.0-28.25 12
1.56 0.36 0-5. 50 22
0. 77 0.28 0-4.0 18
4.11 0. 67 0-10.25 20
HYPOPHYSECTOMY AND ADRENALECTOMY FOR DISSEMINATED PROSTATIC CARCINOMA
OPEN HYPOPHYSECTOMY o--o @---@
a mean of 4.11 months. The are no\v dead. Growth hormone responses. Absence of an increase in HGH after severe provocation with insulin-inof anduced hypoglycemia indicates terior pituitary function. 12 • 15 All cases of open hypophysectomy exhibited this feature postop-· eratively (fig. 1). In characterization of the sponse to this test, care must be taken to ascert:1in that blood sugar levels have fallen to less than 50 per cent of measured fasting levels for a sufficient period. 12 • 15 The test should not be in the early postoperative ( < 14 when edema of the operative site might false impression of the extent of pituitary ablation. On the basis of the level of HOH postcryohypophysectomy, the degree of ablation of the anterior pituitary was judged to be minirnat or extensive, intermediate or moderate, or ineffective (fig. 2). Table 3 summarizes the responses
Pre-opera!iva Pos!opero!ive
20
0 ~C 15 Q.
0
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10
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:,:
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0
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90
60
30
TIME (minutes)
Fm. 1. Typical flat HGH curve seen after open hypophysectomy.
INTERMEDIATE HUMAN GROWTH HORMONE RESPONSES TO INSULIN INDUCED HYPOGLYCEMIA
HUMAN GROWTH HORMONE RESPONSES TO INSULIN INDUCED HYPOGLYCEMIA
A
FAILURE
PRE-OPERATIVE
C
POSTOPERAT!VE
24 23
19 18
22
21
17
21
20 19
16
"0
! D
PRE-OPERATIVE
25
20
";;i"'
TO INSULIN INDUCED HYPOGLYCEMIA
POSTOPERATIVE
PRE-OPERATIVE
::;
IN HUMAN GROWTH HORMONE
RESPONSES
CRYOHYPOPHYSECTOMY
B
CRYOHYPOPHYSECTOMY
819
15
18
14
17
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12
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60
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0
30
60
90
30
60
TIME (MINUTES)
90
TIME (MINUTES)
30
60
90
30
60
90
30
60
90
TIME (MINUTES)
FIG. 2. HGH levels after cryohypophysectomy. A, maximal or extensive anterior pituitiu·y sion after cryohypophysectomy, HG H levels postoperatively are low. Maximal levels are all less 2.5 mµg. HGH per ml. plasma. B, moderate anterior pituitary suppressioa after Note moderate postoperative levels of HGH. Moderate levels are all less tha11 5 rnµg. per ml. minimal or absent anterior pituitary suppression seen after nnsuccessful cryohypophysectorny. Note failure of HGH suppression postoperatively.
data that could be determined in the 34 hypophysectomy patients from the combined open and closed series. Patients judged to have a satisfactory result from the operative intervention survived more than 15 months, in contrast to 20 patients judged to have done poorly who survived
in 19 cryosurgical patients whose follmvup has been sufficient to growth hormone 15 Roth, J., Glick, S. J\I., Yalow, R. 8. and Berson, S. A.: Hypoglycemia: a polent stirnult1s to secretion of growth hormone. i-,ciencc, 140: 987,
1963.
820
MURPHY AND ASSOCIATES
response. There was good correlation with the rates of remission and the degree of pituitary I-IGI-I suppression. In other respects the groups TABLE
3. Variations in degree of anterior pituitary ablation post-cryohypophysectomy*
No. patients Subjective remission (mos.) Objective remission (mos.) Survival (4alive) (mos.) Mean age (yrs.) Previous remission (mos.) Satisfactory remission
Minimal
Intermediate
Extensive
7 1.39 (0.47)
7 8.0 (3.46)
5 7.25 (2. 73)
0.21 (0.21)
4.45 (2.44)
4.20 (1.33)
6.55 (1.29)
12.07 (3.96)
9.50 (2.51)
63.86 (3.25) 32.67 (18.58)
65.29 (2.41) 24.54 (7.45)
67.60 (2.42) 34.50 (15. 71)
3 (42.9%)
2 (40.0%)
0
*Mean(± 1 standard error) judged by HGH response. Last operation done in September 1969.
HUMAN GROWTH HORMONE RESPONSES POST CRYOHYPOPHYSECTOMY
PRE-OPERATIVE
POSTOPERATIVE
12
2/7/69
II
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306090
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306090
TIME (MINUTES)
FIG. 3. Progressive restoration of HGH levels noted over 1 year in a patient post-cryohypophysectomy. Restoration of near normal HGH levels was associated with relapse. TABLE
described in table 3 are also similar, for example age and rate of previous remission. We observed in one post-cryosurgical patient a restoration of near normal levels of I-IGI-I (fig. 3). This level of restoration was associated with clinical relapse and recurrence of symptoms. We believe that such I-IGI-I responses suggest possible functional regeneration of the anterior pituitary. The patient's ultimate course will be followed with interest. Certain patients in this series had repeat cryosurgical hypophysectomy procedures performed on the basis of the failure to demonstrate initial postoperative diminution in HGH levels. Eventual suppression of HGH levels was attained. Other patients in 3 instances underwent open hypophysectomy after initial failure of cryosurgical hypophysectomy. Other tests. Table 4 lists the plasma testosterone concentrations noted in 14 post-hypophysectomy patients who were followed up to 1 year or to death. Plasma testosterone levels were generally low and remained so in all patients without detectable differences. Tables 5 and 6 depict the levels of FSH and LH 13 noted in the hypophysectomy patients. All patients had low levels postoperatively (table 5). It is noteworthy, however, that the low levels of LR in patients in remission were later elevated significantly when clinical evidence of relapse was apparent (table 6). Table 7 details the serial alterations in serum acid phosphatase levels noted in 31 of the hypophysectorny patients. Patients who, by other criteria, were judged to have had a satisfactory response had a slight fall in serum acid phosphatase values after the first postoperative months. Individual values, rather than group mean values, were more striking in this regard. Patients judged to have had a poor response on
4. Plasma testosterone concentration post-hypophysectomy* Postop. Followup (mos.)
Subjective Response
Preop. 3
6
12
Satisfactory:
Mean
±
1 standard error Norm Poor: Mean ± l standard error Norm
61.00 21.62 4
35.40 8. 73 5
18.33 3.48 3
55. 75 36.18 4
26.00 4.35
71.0U
52. 80 13. 10 10
48. 62 13.00 8
50. 66 23.06 6
66.00 42.00 2
Dead
Dead
* Normal 400 to l ,200 ng. per cent (adult intact male subjects). Low levels of preoperative plasma testosterone reflect prior castration and stilbestrol therapy to unknown degree.
HYPOPHYSECTOMY AND ADRENALECTOMY FOR DISSEMINATED PROSTATIC CARCINOMA
5. LH and FSH levels in hypophysectomy patients*
TABLE
Hormone
Preop. t
Postop.t
Open
LII FSH
2.300 (1.300) 4.300 (3.00)
0.212 (0.089) 0.612 (0.288)
Cryosurgical
LH FSH
6.928 (2.697) 9.200 (5.220)
0. 731 (0.214) 1.220 (0.480)
~' LH in mµg. per rnl., normal: 0.2 to 3.0. FSH in mµg. per ml., normal: <0.2 to 4.0. t Mean (± l standard error).
6. LH and FSH levels after hypophysectomy in terms of clinical response*
TABLE
Hormone
Remissiont
Relapset
p-Value
LH
0.410 (O.OfJO)
1. 250 (0. 400)
<0.05
FSH
0.753 (0.199)
1.350 (0. 863)
>0.25
* LH in
mµg. per ml.,
normal: 0.2 to 3.0. FSH in mµg. per
ml., normal: <0.2 to 4.0. t Mean (± 1 standard error). Increased LH levels were noted in both open and cryosurgical patients v;ho relapsed. TABLE
821
Table 8 gives the serial alterations in serum alkaline phosphatase levels post-hypophysectomy. All patients had postoperative elevations. ratients judged to have had a satisfactory response on the basis of other criteria had levels that fell after 1 month postoperatively. In contrast, poorly responding patients had levels of alkaline phosphatase that remained elevated. Patients judged to have a satisfactory response maintained normal levels of BUN ± 1.14 mg. per cent maximal). In contrast, poorly responding patients had progressive BUN elevations (40.3 mg. per cent maximal). Patients judged to have a satisfactory response did not exhibit anemia (lowest hematocrit 12 months postoperatively 32.2 ± 3.2 volumes per cent). Patients responding poorly did not become markedly anemic (hematocrit <30 volumes per cent) but were also given transfusions and iron, thereby limiting the validity of this prognostic sign. Erythropoietin levels have been more helpfuJ.16
7. Serum acid phosphatase levels of post-hypophysectomy* Postop. Followup (mos.)
Subjective Response
Preop. 11
Satisfactory: Mean
± 1 standard error Norm Poor: Mean ± 1 standard error
Norm
9. 87 2.33
12.41 3. G7 12
13. 10 2. 94 11
11
20.88 4. 83 1D
21.38 4. 46 16
14.GG 3.06 12
11. 88 2.48 8
11. 9.[ 3. 00
16.10 2.27
Dead
8. 40 1. 79
5 Dead
* Babson-Read units per ml., normal this laboratory 0.0 to 5.0. TABLE
8. Serum alkaline phosphatase levels post-hypophysectomy* Postop. Followup (mos.)
Subjective Response
Satisfactory: 1+.iean ± 1 standard error Norm Poor: Mean ± 1 standard error Norm :i.
Prcop.
37.55 9. 92 12
61.36 35.34 10
33.09 10.82 12
25.01 8. 98
37 .32
50. 82 8.21 17
59.27 11. 64 12
53 .50 33.28 3
5. 64
21
9
12
24. 80 14. 98
11. 78
G
Dead
19. 64
5 Dead
Besscy-Lo,vry-Brock units per ml., normal this laboratory] .7 to 5.0.
the basis of other criteria all had generally higher serum acid phosphatase levels (table 7). These elevations remained so postoperatively in individual although as a group there was some slight non-significant decline after 3 months.
Urinary androgens. Base line and followup values were obtained for urinary androgens from 16 Mirand, E. A., Kenny, G. l\I., Schoonees, H.., Reynoso, G. R. and Murphy, G. P.: Erythropoictin release in hypophysectomized, adrenalectomized man. J. Surg. Oncology, 2: G3, 19U9.
822
MURPHY AND ASSOCIATES TABLE
9. Urinary androgen fractions in patients with carcinoma of the prostate who responded with clinical remission to hypophysectomy Preop.
Androsterone Etiocholanolone Dehydroepiandrosterone Total 11-deoxy 17-ketosteroids 11-ketoandrosterone 11-ketoetiocholanolone 11-hydroxyandrosterone 11-hydroxyetiocholanolone Total 11-oxy 17-ketosteroids Total 17-ketosteroids (gas liquid chromatography)
Initial Postop.
Followup (3 mos.)
Mean
±SEM
Mean
±SEM
:Mean
±SEM
Followup (6 mos.)
. 75 1.10 0.66 2.51 0.13 1.06 1.11 0.58 2.88 5.39
.16 .07 .03 .26 .07 .21 .10 . 18 .45 .46
. 95 .80 0.22 I. 97 0.41 1.23 0.49 1.08 3.21 5.18
.31 .13 .05 .49 .11 .33 .18 .31 . 93 .84
.48 1.09 0.36 I. 93 0. 70 1.29 0. 58 0. 99 3.56 5.49
. 13 . 41 .13 . 67 .27 .41 .32 . 38 1.28 1.24
.89 0.83 0.18 1.90 0. 59 1.41 0.00 0.94 2. 94 4.84
l\Iean values from 10 patients.
TABLE
10. Urinary androgen fractions in patients with carcinoma of the prostate who jailed to show clinical remission to hypophysectomy Preop.
Androsterone Etiocholanolone Dehydroepiandrosterone Total 11-deoxy 17-ketosteroids 11-ketoandrosterone 11-ketoetiocholanolone l 1-hydroxyandrosterone 11-hydroxyetiocholanolone Total 11-oxy 17-ketosteroids Total 17-ketosteroids (gas liquid chromatography)
Initial Postop.
Followup (3 mos.)
Mean
±SEM
:Mean
±SEM
J'VIean
±SEM
Followup (6 mos.)
.86 1.35 0.53 2. 74 0.40 0.96 0.51 1.51 3.38 6.12
.26 .48 .20 . 94 .10 .30 .17 1.04 1.61 2.05
.45 . 74 0.28 1.47 0.23 0. 91 0.30 0. 79 2.23 3. 70
.10 . 19 .08 .37 .06 .30 .06 . 19 .61 . 73
.53 1.43 0.32 2.28 o. 66 2. 15 0. 95 3.22 6. 98 9.26
.23 .43 .09 . 75 .33 I. 18 . 62 2.37 4.50 3. 76
.88 1.52 0.24 2. 64 2.31 2.51 1.55 0. 93 7 .30 9.94
11:ean values from 12 patients.
all patients undergoing open hypophysectomy or cryohypophysectomy who were available for periodic study. The values indicated represent the 24-hour urinary milligram amounts excreted. These values of themselves are of greater interest in relation to those patients who were judged to have had a satisfactory response in contrast to those judged to have had a poor response (tables 9 and 10). This combines patients with open as well as closed, or cryosurgical, hypophysectomy. The major urinary androgenic fractions (androsterone, etiocholanolone, dehydroisoandrosterone) showed an immediate and sustained decrease in those patients who were in clinical remission (table 9). The 11-oxy compounds with less androgenic activity were not decreased. Similarly total 17-ketosteroid excretion was not decreased. In contrast patients not in remission post-hypophysectomy failed to exhibit significant or sustained decreases in the urinary excretion of the 3 major androgenic fractions (table 10). The 11-
oxy fractions were variably decreased. No significant or sustained decrease in total urinary 17ketosteroids was noted. Individual patients in remission were managed on daily doses of cortisone acetate of 25 to 75 mg. per day. Urinary steroids were similarly collected for measurement during these periods of different steroid dosage. Increase in steroid dosage in the individual patients in remission or in relapse affected only an increase in the 11-oxy compounds noted in the urine. The major urinary androgenic fractions (11-deoxy 17-ketosteroids) were unaffected (fig. 4). The histological differentiation of the prostatic primary tumor was recorded on a double-blind basis. There was no detectable correlation of the degree of tumor differentiation with the clinical response or androgenic urinary excretion rates. Adrenalectomy. Survival and remission results were similarly observed in patients undergoing bilateral adrenalectomy for progression of dis-
HYPOPHYSECTOMY AND ADRENALECTOMY FOR DISSEMINATED PROSTATIC CARCINOMA
seminated prostatic carcinoma. Five patients had had prior hypophysectomy. None of these patients had signs of objective remission at any time (table 11). There was one immediate postoperative death among these 5 patients due to a pulmonary embolus from metastatic prostatic tumor. In contrast 7 patients with intact pituitaries all survived the bilateral adrenalectomy procedure. This group is small and the followup period is short. The rates of response are considerably less impressive than those noted postTOTAL A/E RAT) 17-KETOS
24-HR URINE
PREOPERATIVE POSTOPERATIVE FOLLOWUP
4
12. Plasma restosterone levels postbilateral adrenaleclomy*
TABLE
Total group Hypophysectomized Pituitary intact
.63
44
56
5.04
.31
21
79
5.69
.22
14
••
PreAdrenalectomyj
PostAdrenalectomyt
79.6 (13.5) 67.2 (28.2) 89.8 (9.4)
62.5 (16.3) 46.0 (7.4) 72.4 (25. 7)
* Normal 400 to 1,200 ng. per cent (intact adult male subjects). t (± 1 standard deviation).
13. Serum acid phosphatase levels post-bilateral adrenalectomy*
TABLE
Post-Adrenalectomy PreFo!lowup (mos.) Adrenalectomy - - - - - - - - -
11-DEOXY II- OXY % %
5.02
823
Total group Hypophysectomized Pituitary intact
10.5 (2.96) 11.3 (4.34)
11.8 (3.54) 12.3 (6.42)
19.1 (1.97) 21. 7 (4.20)
9.9 (4.30)
11.5 (4.59)
17. 4 (!. 82)
* Babson-Reed units per ml. 1 normal 0.0 to 5.0, mean (± 1 standard error). 2
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hypophysectomy (table 11). The plasma testosterone levels were low in the adrenalectomy patients preoperatively (table 12). In both patient groups, including those who were hypophysectomized as well as those with intact pituitary, the level of testosterone fell following adrenalectomy. The more pronounced postoperative decline was in those patients previously hypophysectomized. None of the 12 patients exhibited marked postoperative decreases in serum acid phosphatase levels (table 13), No postoperative change m serum alkaline phosphatase was noted.
.!."' DISCUSSION
,1(
Fro. 4. Characteristic urinary androgenic excretion rates after successful open hypophysectomy.
11. Survival data post-bilateral adrenalectomy for disseminated prostatic carcinoma*
TABLE
Groups
No. patients, 12 Hypophysectomized, 5 Pituitary intact, 7
Subjective Remission (mos.)t
Objective Remission (mos.)t
-g 1.7 (0. 26) 1.6 (0.44) 4
1.3 (0.23) 1.3 (0. 45)
0.3 (0.25) 0.0
l.D (0.34)
1.3 (0.28)
0.5 (0.41)
Pts. Alive
5
Postop. Survival (mos.)t
* All operations performed during 5-month period (up to December 1969). Followup period varies from 3 months. t Mean (± 1 standard error).
Various techniques have been used to attempt pituitary ablation in the endocrine control of disseminated prostatic carcinoma.1-1°, 12 • 17 The present studies represent in part the first attempt to assess in vivo the degree of anterior pituitary ablation or suppression by measurement of HGH levels (figs. 1 and 2). Those cases with evidence for suppression of HGH response had 40 to 42.9 per cent rates of satisfactory remission. In contrast those with no evidence of HGH suppression had a O per cent satisfactory remission rate (table 3). This feature would seem to indicate that total anterior pituitary ablation is not necessary for a remission in disseminated prostatic carci17 Murphy, W. T. and Schwippert, H.: Pituitary irradiation in prostatic carcinoma. Radiology, 56: 376, 1951.
824
MURPHY AND ASSOCIATES
noma. Moreover, the measurement of HGH under controlled provocative conditions provides a reliable means of predicting and measuring the effectiveness of the hypophysectomy procedure. Subsequent measurement is also of possible merit (fig. 3). In addition the measurement of LH levels may also be of prognostic value in objective evaluation of relapse from remission states in disseminated prostatic carcinoma (tables 5 and 6). The mechanism for release of LH 13 under these conditions is unclear. It may represent pituitary regeneration (fig. 3). Urinary estrogen measurements also would aid in further evaluating this problem in these patients and are currently being completed. The levels of HGH in relapsing patients were not elevated. It would be anticipated that such HGH elevations might precede LH elevations. Further observations in this regard may be helpful. As has been emphasized by Scott, this form of endocrine therapy is by no means curative and is quite difficult to objectively evaluate in terms of response rates. 1-4 In this series patients who were older and had a shorter period of response to estrogen and castration treatment were more frequent in the cryohypophysectomy than in the open hypophysectomy group. The rates of response and duration of remission were less (tables 1 and 2). Untreated patients who relapsed or patients who relapsed after orchiectomy and estrogen therapy with disseminated prostatic carcinoma generally do poorly and die within 9 to 10 months. 12 On this basis the present series of patients with satisfactory responses would appear to have benefited also in terms of improved survival rates (table 1). Patients with disseminated prostatic and lung carcinomas are known to respond to increased cortisone dosage with increased urinary excretion of total 17-ketosteroids.18-22 The present studies 18 Sokal, J. E., Bondy, P. K., Costa, P. J., Deming, C. L. and Harvard, B. M., Jr.: Effect of cortisone on 17-ketosteroid excretion of patients with carcinoma of the prostate. Yale J. Biol. Med., 26: 345, 1954. 19 Slaunwhite, W.R., Jr., List, n. and Sokal, J. E.: The conversion of cortisone to 17-ketosteroids in patients with carcinoma of the prostate and of the lung. J. Lab. Clin. Med., 53: 737, 1959. 20 Sokal, J. K and Buchwald, K. W.: The effect of cortisone and cortisol on 17-ketosteroid excretion in carcinoma of the prostate and other neoplasms. Cancer, 12: 183, 1959. 21 Munson, P. L., Goetz, F. C., Laidlaw, J.C., Harrison, J. H. and Thorn, G. W.: Effect of adrenocortical steroids on androgen excretion by adrenalectomized orchidectomized men. J. Clin. Endocr., 14: 495, 1954.
have affirmed this observation but have found that the fraction most frequently elevated was the 11-oxy (tables 9 and 10, and fig. 4). No effect per se was detected on the major urinary androgenic substances. A decrease in total 17-ketosteroids as well as other androgenic urinary fractions has been described following orchiectomy for prostatic carcinoma. 23 · 24 The present studies have affirmed that the decreases noted post-hypophysectomy are mainly in the androgenic urinary fractions and are not consistently reflected in the total 17-ketosteroids. Similar observations were described by Scott in 19624 and others in 1966. 25 Remissions after bilateral adrenalectomy for disseminated prostatic carcinoma have been described.25-31 The clinical response rates from the documented reports appear to be limited. The present series of patients failed to demonstrate any improvement when bilateral adrenalectomy was performed post-hypophysectomy (table 11). The results thus far attained in those patients 22 Valk, W. L. and Owens, R. H.: Effect of cortisone on patients with carcinoma of prostate. J. Urol., 71: 219, 1954. 23 Scott, W.W. and Vermeulen, C.: Studies on prostatic cancer. V. Excretion of 17-ketosteroids, estrogens and gonadotropins before and after castration. J. Clin. Endocr., 2: 450, 1942. 24 Gallagher, T. F., Whitmore, W. F., Jr., Zumoff, B. and Hellman, L.: Steroid hormone metabolites before and after orchiectomy for prostatic cancer. J. Clin. Endocr., 23: 523, 1963. 25 Tamm, J., Schmidt, H., Starcevic, Z. and Klosterhalfin, H.: Urinary excretion of testosterone, 17-ketosteroids and olstrogens in male patients following orchiectomy. In: Androgens in Normal and Pathological Conditions; Proceedings, June 17-19, 1965. Edited by A. Vermeulen and D. Exley. Amsterdam: Excerpta Medica Foundation, Excerpta Medica. International Congress Series, No. 101, pp. 77-80, 1966. 26 Huggins, C. and Scott, W. W.: Bilateral adrenalectomy in prostatic cancer. Ann. Surg., 122: 1031, 1945. 27 Butler, W.W. 8., III, Grayhack, J. T., Ransom, C. L. and Scott, W.W.: Metabolic studies on the bilateral adrenalectomy patient. J. Urol., 70: 657, 1953. 28 Morales, P. A., Brendler, H. and Hotchkiss, R. 8.: The role of the adrenal cortex in prostatic cancer. J. Urol., 73: 399, 1955. 29 Pearson, 0. H., Whitmore, W. F., West, C. D., Farrow, J. H. and Randall, H. T.: Clinical and metabolic studies of bilateral adrenalectomy. Surgery, 34: 543, 1953. 30 Harrison, J. H., Thorn, G. W. and Jenkins, D.: Total adrenalectomy for reactivated carcinoma of the prostate. New Engl. J. Med., 248: 86, 1953. 31 Scardino, P. L., Prince, C. L. andMcGoldrick, T. A.: Bilateral adrenalectomy for prostatic cancer. J. Urol., 70: 100, 1953.
HYPOPHYSECTOMY AND ADRENALECTOMY FOR DISSEMINATED PROSTATIC CARCINOMA
with intact pituitaries are limited. The series is small; moreover, it is not known what benefit may be attained by hypophysectomy following relapse after bilateral adrenalectomy. In these latter instances, in view of the low risk of mortality or morbidity, a cryosurgical procedure would appear to be more feasible. Further studies on plasma LH levels and urinary androgen fraction excretion are necessary before adequate characterization is possible. At present the standard prognostic indices, for example acid and alkaline phosphatase, appear to be of little value (tables 12 and 13). The response rates appear to be less striking than those noted post-hypophysectomy. SUMMARY AND CONCLUSIONS
Open and cryosurgical hypophysectomies have been performed in 34 patients with disseminated prostatic carcinoma. Human growth hormone (HGH) levels gave advance in vivo assessment of the degree of anterior pituitary ablation which in turn correlated well with the satisfactory remission rate. HGH measurements thus permit repeat
825
cryosurgical procedures until sufficient anterior pituitary ablation is attained. Patients relapsing post-hypophyscctomy had elevated LH levels. 1J rinary androgenic fraction excretion rates were persistently depressed in patients during remission. Twelve patients underwent bilateral adrenalectomy for advanced and progressive prostatic cancer. Five patients who previously had hypophysectomy had no remission. The degree anc! response rates following bilateral adrenalectomy in patients with intact pituitaries were less than that noted post-hypophysectomy. Drs. James T. Grace and W. vV. Scott encouraged and supported these studies. Drs. L. Palma and T. Bhanalaph, and Mrs. A. Nussbaum gave assistance. Human growth hormone NIH-GH 722A was donated by the Endocrinology Section of the National Institutes of Arthritis and ~Ietabolism. The anti-human growth hormone serum A-291262 was prepared by Drs. S. N. Glick, .J. Roth, R. Yalow and S. A. Berson.
THE JOURNAL OF UROLOGY
Copyright© 1971 by The Williams & Wilkins Co.
HYPOPHYSECTOMY AND ADRENALECTOMY FOR DISSE.;.\IINATED PROSTATIC CARCINOMA G. P. MURPHY, G. REYNOSO, R. SCHOONEES, S. GAILANI, R. BOURKE, G. M. KENNY, E. A. MIRAND AND D. S. SCHALCH From the Roswell Park il/Iemorial Institute, New York State Department of Health, Buffalo and the University of Rochester School of Medicine and Strong Memorial Hospital, Rochester, New York
Scott and associates studied the effects of open hypophysectomy as a form of endocrine palliation in patients with disseminated prostatic carcinoma.1-4 They established the available criteria for judgment of objective and subjective signs of improvement in these patients. 4 A significant number of patients were benefited. 4 Concurrent clinical studies on hypophysectomized patients were made by other investigators. 5- 12 Objective and subjective signs of benefit were noted in more Accepted for publication September 1, 1970. Read at annual meeting of American Urological Association, Philadelphia, Pennsylvania, May 10-14, 1970. Supported in part by United States Public Health Service grants 5 SOl RR05648 and C-5834. 1 Scott, W. W.: Endocrine management of disseminated prostatic cancer, including bilateral adrenalectomy and hypophysectomy. Trans. Amer. Ass. Genitourin. Surg., 44: 101, 1952. 2 Scott, W.W.: Appraisal of present methods of treatment of advanced prostatic cancer. J. Urol., 72: 530, 1954. 3 Scott, W.W.: Role of pituitary in normal and abnormal proslatic growth. Trans. Amer. Ass. Genitourin. Surg., 46: 33, 1954. 4 Scott, W.W. and Schirmer, H. K. A.: Hypophysectomy for disseminated prostatic cancer. In: On Cancer and Hormones. Chicago: University of Chicago Press, p. 175, 1962. 5 Whitmore, W. F.: Hormone therapy in prostatic cancer. Amer. J. Med., 21: 697, 1956. 6 Ray, B. S.: Some inferences from hypophysectomy on four hundred fifty human patients. Arch. Neurol., 3: 121, 1960. 7 Pearson, 0. H., Ray, B. S., Harrold, C. C., West, C. D., Li, M. C., Maclean, J. P. and Lipsett, M. B.: Hypophysectomy in treatment of advanced cancer. J.A.M.A., 161: 17, 1956. 8 Ray, B. S.: The neurosurgeon's new interest in the pituitary. J. Neurosurg., 17: 1, 1960. 9 Luft, R. and Olivecrona, H.: Hypophysectomy in the treatment of malignant tumors. Cancer, 10: 789, 1957. 10 Pearson, 0. H. and Ray, B. S.: Hypophysectomy in the treatment of metastatic mammary cancer. Amer. J. Surg., 99: 544, 1960. 11 Smith, E. J. R., Gurling, K. J. and Baron, D. N.: The effect of hypophysectomy in advanced carcinoma of the prostate. Brit. J. Urol., 31: 181, 1959. 12 Murphy, G. P., Boctor, Z. N., Gailani, S. and Belmusto, L.: Hypophysectomy for disseminated prostatic carcinoma. J. Surg. Oncology, 1: 81, 1969.
than 40 per cent of the ]latients described. 1· 12 Heretofore, however, assessment of the degree of pituitary ablation was based on general clinical responses and postmortem anatomical studies. The series of observations presented herein describes new methods and results of correlation of functional ablation of the anterior pituitary with the objective and subjective signs of improvement in patients with disseminated prostatic carcinoma. These studies were further correlated with additional techniques for measurement of urinary androgen fractions. Other studies were also completed on adrenalectomized patients before and after hypophysectomy for progressive disseminated prostatic carcinoma. MATERIALS A:'sfD l\IETHODS
Adult male patients with disseminated prostatic carcinoma were selected for study. Patients were admitted randomly to protocol when they demonstrated clinical signs of progression or dissemination of histologically proved prostatic carcinoma. Progression was judged on the results of biochemical (for example acid phosphatase), radiological, symptomatic and physical examinations. Patients were treated with open or cryosurgical hypophysectomy after completion of preoperative evaluation. l)ossible bias was present to the extent that some patients underwent closed cryohypophysectomy rather than the open operation on the basis of personal selection, for example extremely poor general medical condition. Additional patients also were selected at random initially for treatment by bilateral adrenalectomy. Others underwent this form of therapy following relapse post-hypophysectomy. Evaluation studies were completed in all patients at 14 days and at 1, 3, 6 and 9 months postoperatively. Patients who were well at this time were then evaluated every 3 to 6 months. Other patients who had relapsed were evaluated earlier and at variable periods. All patients were studied while in a basal state on the urology service. The studies that were 817
818 TABLE
MURPHY AND ASSOCIATES
1. Patients treated with hypophysectomy for disseminated prostatic carcinoma Open Operation
No. patients Immediate mortality Satisfactory remission Mean age (yrs.) Previous response (mos.)
11
2 (18.2%) 7 (63.3%) 58.09 (±1.30) 43.3 (±11.29)
Cryosurgery 23 0
5 (21. 7%) 64. 91 (±1. 47) 29.00 (±6. 71)
completed preoperatively and postoperatively included human growth hormone (HGH) ,1 2 luteinizing hormone (LH), 13 follicle stimulating hormone (FSH), 13 plasma testosterone, 12 acid phosphatase, alkaline phosphatase, hematocrit, body weight and blood urea nitrogen (BUN). Total 24-hour urinary 17-ketosteroids were determined by the standard chemical procedure and by gas liquid chromatography. Total 24-hour urinary androgenic fractions were determined by the gas liquid chromatographic procedure of Haahti and associates14 following enzymatic hydrolysis and conversion of the free steroids to trimethyl sylil ethers. The procedure in our laboratory has an over-all coefficient of variation of 15 per cent (± standard deviation of the difference between replicate samples). In all cases total 17-ketosteroids, whether determined by the routine Zimmerman reaction or by the gas-chromatography procedure, were within normal limits for the age group. However, individual fractions showed significant deviations from normality. Growth hormone levels were determined in all patients during insulin-induced hypoglycemia. 12 Continuous monitoring and physician attendance are necessary during the test. Details of the technique are described in part elsewhere.12 The test represents a potential hazard in the post-hypophysectomy or adrenalectomy patient. However, despite occasional symptoms of hypoglycemia, all tests were completed without incident in this series. The criteria of clinical response in this series were those enumerated by Scott. 4 Subjective remission describes a patient who has: I) pain re13 Schalch, D. 8., Parlow, A. F., Boon, R. C. and Reichlin, S.: Measurement of human luteinizing hormone in plasma by radioimmunoassay. J. Clin. Invest., 47: 665, 1968. "Haahti, E. 0., Vandenheuvel, W. J. and Horning, E. C.: Separation of urinary 17-ketosteroids by gas chromatography. Anal. Biochem., 2: 182, 1961.
lief, 2) sensation of well-being and 3) improved appetite. Objective remission includes: 1) decrease in serum acid phosphatase, 2) delayed decrease of serum alkaline phosphatase, 3) weight gain, 4) improved radiological appearance of osseous metastases and 5) improvement of anemia. Even in terms of objective criteria obvious clinical judgment must be made in interpreting the clinical signs. In the present report we judged a patient to have had a satisfactory clinical response if remission of the previously described symptoms and/or signs occurred for more than 6 months. All patients were followed up to the present time or until death. This series was closed for purposes of evaluation in February 1970. No patient was included who underwent hypophysectomy after September 1969. All data were initially and subsequently recorded on followup forms. This material then was evaluated statistically. Regimens of postoperative endocrine management including cortisone and thyroid replacement have been described. 12 RESULTS
Survival. Thirty-four patients underwent either open or closed (cryosurgical) hypophysectomy (table 1). There was no operative mortality from cryosurgical hypophysectomy. Early in the study 2 patients (18.2 per cent) in generally poor condition died in the immediate post-open hypophysectomy period. On the basis of the subjective and objective criteria, 12 patients (35.3 per cent) had satisfactory remissions. There was a significant difference in the mean age of the hypophysectomy groups. Patients in the cryohypophysectomy group had a history of response to estrogens and castration that was shorter than that noted in the patients who underwent open operations. Table 2 details the remission rates and survival 2. Remission and survival periods following hypophysectomy for disseminated prostatic carcinoma in 34 cases
TABLE
Satisfactory: Mean ± 1 standard error Range Norm Poor: Mean ± 1 standard error Range
Norm
Subjective Remission
Objective Remission
Survival Period (mos.)
11.89 1. 84 6.0-24.0 12
8.08 1.29 3.50-17.75 12
15. 81 2.15 6.0-28.25 12
1.56 0.36 0-5. 50 22
0. 77 0.28 0-4.0 18
4.11 0. 67 0-10.25 20
HYPOPHYSECTOMY AND ADRENALECTOMY FOR DISSEMINATED PROSTATIC CARCINOMA
OPEN HYPOPHYSECTOMY o--o @---@
a mean of 4.11 months. The are no\v dead. Growth hormone responses. Absence of an increase in HGH after severe provocation with insulin-inof anduced hypoglycemia indicates terior pituitary function. 12 • 15 All cases of open hypophysectomy exhibited this feature postop-· eratively (fig. 1). In characterization of the sponse to this test, care must be taken to ascert:1in that blood sugar levels have fallen to less than 50 per cent of measured fasting levels for a sufficient period. 12 • 15 The test should not be in the early postoperative ( < 14 when edema of the operative site might false impression of the extent of pituitary ablation. On the basis of the level of HOH postcryohypophysectomy, the degree of ablation of the anterior pituitary was judged to be minirnat or extensive, intermediate or moderate, or ineffective (fig. 2). Table 3 summarizes the responses
Pre-opera!iva Pos!opero!ive
20
0 ~C 15 Q.
0
e
'.,,
10
:,_
E :,: (.!)
:,:
5
-----
0
0
90
60
30
TIME (minutes)
Fm. 1. Typical flat HGH curve seen after open hypophysectomy.
INTERMEDIATE HUMAN GROWTH HORMONE RESPONSES TO INSULIN INDUCED HYPOGLYCEMIA
HUMAN GROWTH HORMONE RESPONSES TO INSULIN INDUCED HYPOGLYCEMIA
A
FAILURE
PRE-OPERATIVE
C
POSTOPERAT!VE
24 23
19 18
22
21
17
21
20 19
16
"0
! D
PRE-OPERATIVE
25
20
";;i"'
TO INSULIN INDUCED HYPOGLYCEMIA
POSTOPERATIVE
PRE-OPERATIVE
::;
IN HUMAN GROWTH HORMONE
RESPONSES
CRYOHYPOPHYSECTOMY
B
CRYOHYPOPHYSECTOMY
819
15
18
14
17
;;
13
I
!
12
II
~
~
16 15 14 13
10 9
~
E
:zc
'-' ,:
I
~
7
I
6
5 4 3
~
2
0
30
60
90
0
30
60
90
30
60
TIME (MINUTES)
90
TIME (MINUTES)
30
60
90
30
60
90
30
60
90
TIME (MINUTES)
FIG. 2. HGH levels after cryohypophysectomy. A, maximal or extensive anterior pituitiu·y sion after cryohypophysectomy, HG H levels postoperatively are low. Maximal levels are all less 2.5 mµg. HGH per ml. plasma. B, moderate anterior pituitary suppressioa after Note moderate postoperative levels of HGH. Moderate levels are all less tha11 5 rnµg. per ml. minimal or absent anterior pituitary suppression seen after nnsuccessful cryohypophysectorny. Note failure of HGH suppression postoperatively.
data that could be determined in the 34 hypophysectomy patients from the combined open and closed series. Patients judged to have a satisfactory result from the operative intervention survived more than 15 months, in contrast to 20 patients judged to have done poorly who survived
in 19 cryosurgical patients whose follmvup has been sufficient to growth hormone 15 Roth, J., Glick, S. J\I., Yalow, R. 8. and Berson, S. A.: Hypoglycemia: a polent stirnult1s to secretion of growth hormone. i-,ciencc, 140: 987,
1963.
820
MURPHY AND ASSOCIATES
response. There was good correlation with the rates of remission and the degree of pituitary I-IGI-I suppression. In other respects the groups TABLE
3. Variations in degree of anterior pituitary ablation post-cryohypophysectomy*
No. patients Subjective remission (mos.) Objective remission (mos.) Survival (4alive) (mos.) Mean age (yrs.) Previous remission (mos.) Satisfactory remission
Minimal
Intermediate
Extensive
7 1.39 (0.47)
7 8.0 (3.46)
5 7.25 (2. 73)
0.21 (0.21)
4.45 (2.44)
4.20 (1.33)
6.55 (1.29)
12.07 (3.96)
9.50 (2.51)
63.86 (3.25) 32.67 (18.58)
65.29 (2.41) 24.54 (7.45)
67.60 (2.42) 34.50 (15. 71)
3 (42.9%)
2 (40.0%)
0
*Mean(± 1 standard error) judged by HGH response. Last operation done in September 1969.
HUMAN GROWTH HORMONE RESPONSES POST CRYOHYPOPHYSECTOMY
PRE-OPERATIVE
POSTOPERATIVE
12
2/7/69
II
:.:!!
10
U) ~
9
..J
Q.
8
u. 0
7
E
6
'.,.
::,..
5
5 4 3
:r
<.!)
:,::
2
I
0
306090
0
306090
TIME (MINUTES)
FIG. 3. Progressive restoration of HGH levels noted over 1 year in a patient post-cryohypophysectomy. Restoration of near normal HGH levels was associated with relapse. TABLE
described in table 3 are also similar, for example age and rate of previous remission. We observed in one post-cryosurgical patient a restoration of near normal levels of I-IGI-I (fig. 3). This level of restoration was associated with clinical relapse and recurrence of symptoms. We believe that such I-IGI-I responses suggest possible functional regeneration of the anterior pituitary. The patient's ultimate course will be followed with interest. Certain patients in this series had repeat cryosurgical hypophysectomy procedures performed on the basis of the failure to demonstrate initial postoperative diminution in HGH levels. Eventual suppression of HGH levels was attained. Other patients in 3 instances underwent open hypophysectomy after initial failure of cryosurgical hypophysectomy. Other tests. Table 4 lists the plasma testosterone concentrations noted in 14 post-hypophysectomy patients who were followed up to 1 year or to death. Plasma testosterone levels were generally low and remained so in all patients without detectable differences. Tables 5 and 6 depict the levels of FSH and LH 13 noted in the hypophysectomy patients. All patients had low levels postoperatively (table 5). It is noteworthy, however, that the low levels of LR in patients in remission were later elevated significantly when clinical evidence of relapse was apparent (table 6). Table 7 details the serial alterations in serum acid phosphatase levels noted in 31 of the hypophysectorny patients. Patients who, by other criteria, were judged to have had a satisfactory response had a slight fall in serum acid phosphatase values after the first postoperative months. Individual values, rather than group mean values, were more striking in this regard. Patients judged to have had a poor response on
4. Plasma testosterone concentration post-hypophysectomy* Postop. Followup (mos.)
Subjective Response
Preop. 3
6
12
Satisfactory:
Mean
±
1 standard error Norm Poor: Mean ± l standard error Norm
61.00 21.62 4
35.40 8. 73 5
18.33 3.48 3
55. 75 36.18 4
26.00 4.35
71.0U
52. 80 13. 10 10
48. 62 13.00 8
50. 66 23.06 6
66.00 42.00 2
Dead
Dead
* Normal 400 to l ,200 ng. per cent (adult intact male subjects). Low levels of preoperative plasma testosterone reflect prior castration and stilbestrol therapy to unknown degree.
HYPOPHYSECTOMY AND ADRENALECTOMY FOR DISSEMINATED PROSTATIC CARCINOMA
5. LH and FSH levels in hypophysectomy patients*
TABLE
Hormone
Preop. t
Postop.t
Open
LII FSH
2.300 (1.300) 4.300 (3.00)
0.212 (0.089) 0.612 (0.288)
Cryosurgical
LH FSH
6.928 (2.697) 9.200 (5.220)
0. 731 (0.214) 1.220 (0.480)
~' LH in mµg. per rnl., normal: 0.2 to 3.0. FSH in mµg. per ml., normal: <0.2 to 4.0. t Mean (± l standard error).
6. LH and FSH levels after hypophysectomy in terms of clinical response*
TABLE
Hormone
Remissiont
Relapset
p-Value
LH
0.410 (O.OfJO)
1. 250 (0. 400)
<0.05
FSH
0.753 (0.199)
1.350 (0. 863)
>0.25
* LH in
mµg. per ml.,
normal: 0.2 to 3.0. FSH in mµg. per
ml., normal: <0.2 to 4.0. t Mean (± 1 standard error). Increased LH levels were noted in both open and cryosurgical patients v;ho relapsed. TABLE
821
Table 8 gives the serial alterations in serum alkaline phosphatase levels post-hypophysectomy. All patients had postoperative elevations. ratients judged to have had a satisfactory response on the basis of other criteria had levels that fell after 1 month postoperatively. In contrast, poorly responding patients had levels of alkaline phosphatase that remained elevated. Patients judged to have a satisfactory response maintained normal levels of BUN ± 1.14 mg. per cent maximal). In contrast, poorly responding patients had progressive BUN elevations (40.3 mg. per cent maximal). Patients judged to have a satisfactory response did not exhibit anemia (lowest hematocrit 12 months postoperatively 32.2 ± 3.2 volumes per cent). Patients responding poorly did not become markedly anemic (hematocrit <30 volumes per cent) but were also given transfusions and iron, thereby limiting the validity of this prognostic sign. Erythropoietin levels have been more helpfuJ.16
7. Serum acid phosphatase levels of post-hypophysectomy* Postop. Followup (mos.)
Subjective Response
Preop. 11
Satisfactory: Mean
± 1 standard error Norm Poor: Mean ± 1 standard error
Norm
9. 87 2.33
12.41 3. G7 12
13. 10 2. 94 11
11
20.88 4. 83 1D
21.38 4. 46 16
14.GG 3.06 12
11. 88 2.48 8
11. 9.[ 3. 00
16.10 2.27
Dead
8. 40 1. 79
5 Dead
* Babson-Read units per ml., normal this laboratory 0.0 to 5.0. TABLE
8. Serum alkaline phosphatase levels post-hypophysectomy* Postop. Followup (mos.)
Subjective Response
Satisfactory: 1+.iean ± 1 standard error Norm Poor: Mean ± 1 standard error Norm :i.
Prcop.
37.55 9. 92 12
61.36 35.34 10
33.09 10.82 12
25.01 8. 98
37 .32
50. 82 8.21 17
59.27 11. 64 12
53 .50 33.28 3
5. 64
21
9
12
24. 80 14. 98
11. 78
G
Dead
19. 64
5 Dead
Besscy-Lo,vry-Brock units per ml., normal this laboratory] .7 to 5.0.
the basis of other criteria all had generally higher serum acid phosphatase levels (table 7). These elevations remained so postoperatively in individual although as a group there was some slight non-significant decline after 3 months.
Urinary androgens. Base line and followup values were obtained for urinary androgens from 16 Mirand, E. A., Kenny, G. l\I., Schoonees, H.., Reynoso, G. R. and Murphy, G. P.: Erythropoictin release in hypophysectomized, adrenalectomized man. J. Surg. Oncology, 2: G3, 19U9.
822
MURPHY AND ASSOCIATES TABLE
9. Urinary androgen fractions in patients with carcinoma of the prostate who responded with clinical remission to hypophysectomy Preop.
Androsterone Etiocholanolone Dehydroepiandrosterone Total 11-deoxy 17-ketosteroids 11-ketoandrosterone 11-ketoetiocholanolone 11-hydroxyandrosterone 11-hydroxyetiocholanolone Total 11-oxy 17-ketosteroids Total 17-ketosteroids (gas liquid chromatography)
Initial Postop.
Followup (3 mos.)
Mean
±SEM
Mean
±SEM
:Mean
±SEM
Followup (6 mos.)
. 75 1.10 0.66 2.51 0.13 1.06 1.11 0.58 2.88 5.39
.16 .07 .03 .26 .07 .21 .10 . 18 .45 .46
. 95 .80 0.22 I. 97 0.41 1.23 0.49 1.08 3.21 5.18
.31 .13 .05 .49 .11 .33 .18 .31 . 93 .84
.48 1.09 0.36 I. 93 0. 70 1.29 0. 58 0. 99 3.56 5.49
. 13 . 41 .13 . 67 .27 .41 .32 . 38 1.28 1.24
.89 0.83 0.18 1.90 0. 59 1.41 0.00 0.94 2. 94 4.84
l\Iean values from 10 patients.
TABLE
10. Urinary androgen fractions in patients with carcinoma of the prostate who jailed to show clinical remission to hypophysectomy Preop.
Androsterone Etiocholanolone Dehydroepiandrosterone Total 11-deoxy 17-ketosteroids 11-ketoandrosterone 11-ketoetiocholanolone l 1-hydroxyandrosterone 11-hydroxyetiocholanolone Total 11-oxy 17-ketosteroids Total 17-ketosteroids (gas liquid chromatography)
Initial Postop.
Followup (3 mos.)
Mean
±SEM
:Mean
±SEM
J'VIean
±SEM
Followup (6 mos.)
.86 1.35 0.53 2. 74 0.40 0.96 0.51 1.51 3.38 6.12
.26 .48 .20 . 94 .10 .30 .17 1.04 1.61 2.05
.45 . 74 0.28 1.47 0.23 0. 91 0.30 0. 79 2.23 3. 70
.10 . 19 .08 .37 .06 .30 .06 . 19 .61 . 73
.53 1.43 0.32 2.28 o. 66 2. 15 0. 95 3.22 6. 98 9.26
.23 .43 .09 . 75 .33 I. 18 . 62 2.37 4.50 3. 76
.88 1.52 0.24 2. 64 2.31 2.51 1.55 0. 93 7 .30 9.94
11:ean values from 12 patients.
all patients undergoing open hypophysectomy or cryohypophysectomy who were available for periodic study. The values indicated represent the 24-hour urinary milligram amounts excreted. These values of themselves are of greater interest in relation to those patients who were judged to have had a satisfactory response in contrast to those judged to have had a poor response (tables 9 and 10). This combines patients with open as well as closed, or cryosurgical, hypophysectomy. The major urinary androgenic fractions (androsterone, etiocholanolone, dehydroisoandrosterone) showed an immediate and sustained decrease in those patients who were in clinical remission (table 9). The 11-oxy compounds with less androgenic activity were not decreased. Similarly total 17-ketosteroid excretion was not decreased. In contrast patients not in remission post-hypophysectomy failed to exhibit significant or sustained decreases in the urinary excretion of the 3 major androgenic fractions (table 10). The 11-
oxy fractions were variably decreased. No significant or sustained decrease in total urinary 17ketosteroids was noted. Individual patients in remission were managed on daily doses of cortisone acetate of 25 to 75 mg. per day. Urinary steroids were similarly collected for measurement during these periods of different steroid dosage. Increase in steroid dosage in the individual patients in remission or in relapse affected only an increase in the 11-oxy compounds noted in the urine. The major urinary androgenic fractions (11-deoxy 17-ketosteroids) were unaffected (fig. 4). The histological differentiation of the prostatic primary tumor was recorded on a double-blind basis. There was no detectable correlation of the degree of tumor differentiation with the clinical response or androgenic urinary excretion rates. Adrenalectomy. Survival and remission results were similarly observed in patients undergoing bilateral adrenalectomy for progression of dis-
HYPOPHYSECTOMY AND ADRENALECTOMY FOR DISSEMINATED PROSTATIC CARCINOMA
seminated prostatic carcinoma. Five patients had had prior hypophysectomy. None of these patients had signs of objective remission at any time (table 11). There was one immediate postoperative death among these 5 patients due to a pulmonary embolus from metastatic prostatic tumor. In contrast 7 patients with intact pituitaries all survived the bilateral adrenalectomy procedure. This group is small and the followup period is short. The rates of response are considerably less impressive than those noted postTOTAL A/E RAT) 17-KETOS
24-HR URINE
PREOPERATIVE POSTOPERATIVE FOLLOWUP
4
12. Plasma restosterone levels postbilateral adrenaleclomy*
TABLE
Total group Hypophysectomized Pituitary intact
.63
44
56
5.04
.31
21
79
5.69
.22
14
••
PreAdrenalectomyj
PostAdrenalectomyt
79.6 (13.5) 67.2 (28.2) 89.8 (9.4)
62.5 (16.3) 46.0 (7.4) 72.4 (25. 7)
* Normal 400 to 1,200 ng. per cent (intact adult male subjects). t (± 1 standard deviation).
13. Serum acid phosphatase levels post-bilateral adrenalectomy*
TABLE
Post-Adrenalectomy PreFo!lowup (mos.) Adrenalectomy - - - - - - - - -
11-DEOXY II- OXY % %
5.02
823
Total group Hypophysectomized Pituitary intact
10.5 (2.96) 11.3 (4.34)
11.8 (3.54) 12.3 (6.42)
19.1 (1.97) 21. 7 (4.20)
9.9 (4.30)
11.5 (4.59)
17. 4 (!. 82)
* Babson-Reed units per ml. 1 normal 0.0 to 5.0, mean (± 1 standard error). 2
LLI
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hypophysectomy (table 11). The plasma testosterone levels were low in the adrenalectomy patients preoperatively (table 12). In both patient groups, including those who were hypophysectomized as well as those with intact pituitary, the level of testosterone fell following adrenalectomy. The more pronounced postoperative decline was in those patients previously hypophysectomized. None of the 12 patients exhibited marked postoperative decreases in serum acid phosphatase levels (table 13), No postoperative change m serum alkaline phosphatase was noted.
.!."' DISCUSSION
,1(
Fro. 4. Characteristic urinary androgenic excretion rates after successful open hypophysectomy.
11. Survival data post-bilateral adrenalectomy for disseminated prostatic carcinoma*
TABLE
Groups
No. patients, 12 Hypophysectomized, 5 Pituitary intact, 7
Subjective Remission (mos.)t
Objective Remission (mos.)t
-g 1.7 (0. 26) 1.6 (0.44) 4
1.3 (0.23) 1.3 (0. 45)
0.3 (0.25) 0.0
l.D (0.34)
1.3 (0.28)
0.5 (0.41)
Pts. Alive
5
Postop. Survival (mos.)t
* All operations performed during 5-month period (up to December 1969). Followup period varies from 3 months. t Mean (± 1 standard error).
Various techniques have been used to attempt pituitary ablation in the endocrine control of disseminated prostatic carcinoma.1-1°, 12 • 17 The present studies represent in part the first attempt to assess in vivo the degree of anterior pituitary ablation or suppression by measurement of HGH levels (figs. 1 and 2). Those cases with evidence for suppression of HGH response had 40 to 42.9 per cent rates of satisfactory remission. In contrast those with no evidence of HGH suppression had a O per cent satisfactory remission rate (table 3). This feature would seem to indicate that total anterior pituitary ablation is not necessary for a remission in disseminated prostatic carci17 Murphy, W. T. and Schwippert, H.: Pituitary irradiation in prostatic carcinoma. Radiology, 56: 376, 1951.
824
MURPHY AND ASSOCIATES
noma. Moreover, the measurement of HGH under controlled provocative conditions provides a reliable means of predicting and measuring the effectiveness of the hypophysectomy procedure. Subsequent measurement is also of possible merit (fig. 3). In addition the measurement of LH levels may also be of prognostic value in objective evaluation of relapse from remission states in disseminated prostatic carcinoma (tables 5 and 6). The mechanism for release of LH 13 under these conditions is unclear. It may represent pituitary regeneration (fig. 3). Urinary estrogen measurements also would aid in further evaluating this problem in these patients and are currently being completed. The levels of HGH in relapsing patients were not elevated. It would be anticipated that such HGH elevations might precede LH elevations. Further observations in this regard may be helpful. As has been emphasized by Scott, this form of endocrine therapy is by no means curative and is quite difficult to objectively evaluate in terms of response rates. 1-4 In this series patients who were older and had a shorter period of response to estrogen and castration treatment were more frequent in the cryohypophysectomy than in the open hypophysectomy group. The rates of response and duration of remission were less (tables 1 and 2). Untreated patients who relapsed or patients who relapsed after orchiectomy and estrogen therapy with disseminated prostatic carcinoma generally do poorly and die within 9 to 10 months. 12 On this basis the present series of patients with satisfactory responses would appear to have benefited also in terms of improved survival rates (table 1). Patients with disseminated prostatic and lung carcinomas are known to respond to increased cortisone dosage with increased urinary excretion of total 17-ketosteroids.18-22 The present studies 18 Sokal, J. E., Bondy, P. K., Costa, P. J., Deming, C. L. and Harvard, B. M., Jr.: Effect of cortisone on 17-ketosteroid excretion of patients with carcinoma of the prostate. Yale J. Biol. Med., 26: 345, 1954. 19 Slaunwhite, W.R., Jr., List, n. and Sokal, J. E.: The conversion of cortisone to 17-ketosteroids in patients with carcinoma of the prostate and of the lung. J. Lab. Clin. Med., 53: 737, 1959. 20 Sokal, J. K and Buchwald, K. W.: The effect of cortisone and cortisol on 17-ketosteroid excretion in carcinoma of the prostate and other neoplasms. Cancer, 12: 183, 1959. 21 Munson, P. L., Goetz, F. C., Laidlaw, J.C., Harrison, J. H. and Thorn, G. W.: Effect of adrenocortical steroids on androgen excretion by adrenalectomized orchidectomized men. J. Clin. Endocr., 14: 495, 1954.
have affirmed this observation but have found that the fraction most frequently elevated was the 11-oxy (tables 9 and 10, and fig. 4). No effect per se was detected on the major urinary androgenic substances. A decrease in total 17-ketosteroids as well as other androgenic urinary fractions has been described following orchiectomy for prostatic carcinoma. 23 · 24 The present studies have affirmed that the decreases noted post-hypophysectomy are mainly in the androgenic urinary fractions and are not consistently reflected in the total 17-ketosteroids. Similar observations were described by Scott in 19624 and others in 1966. 25 Remissions after bilateral adrenalectomy for disseminated prostatic carcinoma have been described.25-31 The clinical response rates from the documented reports appear to be limited. The present series of patients failed to demonstrate any improvement when bilateral adrenalectomy was performed post-hypophysectomy (table 11). The results thus far attained in those patients 22 Valk, W. L. and Owens, R. H.: Effect of cortisone on patients with carcinoma of prostate. J. Urol., 71: 219, 1954. 23 Scott, W.W. and Vermeulen, C.: Studies on prostatic cancer. V. Excretion of 17-ketosteroids, estrogens and gonadotropins before and after castration. J. Clin. Endocr., 2: 450, 1942. 24 Gallagher, T. F., Whitmore, W. F., Jr., Zumoff, B. and Hellman, L.: Steroid hormone metabolites before and after orchiectomy for prostatic cancer. J. Clin. Endocr., 23: 523, 1963. 25 Tamm, J., Schmidt, H., Starcevic, Z. and Klosterhalfin, H.: Urinary excretion of testosterone, 17-ketosteroids and olstrogens in male patients following orchiectomy. In: Androgens in Normal and Pathological Conditions; Proceedings, June 17-19, 1965. Edited by A. Vermeulen and D. Exley. Amsterdam: Excerpta Medica Foundation, Excerpta Medica. International Congress Series, No. 101, pp. 77-80, 1966. 26 Huggins, C. and Scott, W. W.: Bilateral adrenalectomy in prostatic cancer. Ann. Surg., 122: 1031, 1945. 27 Butler, W.W. 8., III, Grayhack, J. T., Ransom, C. L. and Scott, W.W.: Metabolic studies on the bilateral adrenalectomy patient. J. Urol., 70: 657, 1953. 28 Morales, P. A., Brendler, H. and Hotchkiss, R. 8.: The role of the adrenal cortex in prostatic cancer. J. Urol., 73: 399, 1955. 29 Pearson, 0. H., Whitmore, W. F., West, C. D., Farrow, J. H. and Randall, H. T.: Clinical and metabolic studies of bilateral adrenalectomy. Surgery, 34: 543, 1953. 30 Harrison, J. H., Thorn, G. W. and Jenkins, D.: Total adrenalectomy for reactivated carcinoma of the prostate. New Engl. J. Med., 248: 86, 1953. 31 Scardino, P. L., Prince, C. L. andMcGoldrick, T. A.: Bilateral adrenalectomy for prostatic cancer. J. Urol., 70: 100, 1953.
HYPOPHYSECTOMY AND ADRENALECTOMY FOR DISSEMINATED PROSTATIC CARCINOMA
with intact pituitaries are limited. The series is small; moreover, it is not known what benefit may be attained by hypophysectomy following relapse after bilateral adrenalectomy. In these latter instances, in view of the low risk of mortality or morbidity, a cryosurgical procedure would appear to be more feasible. Further studies on plasma LH levels and urinary androgen fraction excretion are necessary before adequate characterization is possible. At present the standard prognostic indices, for example acid and alkaline phosphatase, appear to be of little value (tables 12 and 13). The response rates appear to be less striking than those noted post-hypophysectomy. SUMMARY AND CONCLUSIONS
Open and cryosurgical hypophysectomies have been performed in 34 patients with disseminated prostatic carcinoma. Human growth hormone (HGH) levels gave advance in vivo assessment of the degree of anterior pituitary ablation which in turn correlated well with the satisfactory remission rate. HGH measurements thus permit repeat
825
cryosurgical procedures until sufficient anterior pituitary ablation is attained. Patients relapsing post-hypophyscctomy had elevated LH levels. 1J rinary androgenic fraction excretion rates were persistently depressed in patients during remission. Twelve patients underwent bilateral adrenalectomy for advanced and progressive prostatic cancer. Five patients who previously had hypophysectomy had no remission. The degree anc! response rates following bilateral adrenalectomy in patients with intact pituitaries were less than that noted post-hypophysectomy. Drs. James T. Grace and W. vV. Scott encouraged and supported these studies. Drs. L. Palma and T. Bhanalaph, and Mrs. A. Nussbaum gave assistance. Human growth hormone NIH-GH 722A was donated by the Endocrinology Section of the National Institutes of Arthritis and ~Ietabolism. The anti-human growth hormone serum A-291262 was prepared by Drs. S. N. Glick, .J. Roth, R. Yalow and S. A. Berson.