EVALUATION OF RELATIONSHIP BETWEEN CORTICOSTEROID-INDUCED ADRENOCORTICAL SUPPRESSION AND CLINICAL EFFECTIVENESS OF CORTICOSTEROID THERAPY IN PROSTATIC CARCINOMA
SANFORD D. WEINERT, LEON J. MARKS, RICHARD CHUTE AND JOSEPH B. DOWD
From the Urology Service, Department of Surgery, and the Steroid Research Laboratory, Boston Veterans Administration Hospital, Boston, Mass.
The endocrine factors involved in the etiology and progression of carcinoma of the prostate are complex and still incompletely understood. In the case of advanced prostatic carcinoma with metastases, the most effective therapy has been based on the premise that the neoplastic tissue, like the normal gland, is stimulated to growth by androgenic hormones and is inhibited by the removal of these hormones or their biochemical neutralization by estrogens.1-3 The primary hormonal treatment has been bilateral orchiec- tomy,1 usually in combination with estrogen administration.2,3 The clinical improvement achieved by this type of therapy, while quite satisfactory for a time, is seldom permanent, and relapses usually occur within a few years. It has been suggested that the clinical exacerbation of the prostatic cancer in these patients may be explained by an extragonadal source of androgen, the adrenal.4. > Accordingly, bilateral surgical adrenalectomy has been performed on patients who had suffered a relapse following castration and estrogen therapy.6-8 These patients have
Accepted for publication November 30, 1959.
1 Huggins, C., Stevens, R. E. and Hodges, C. V .: Studies on prostatic cancer: II. Effects of castra- tion on advanced carcinoma of prostate gland. Arch. Surg., 43: 209, 1941.
2 Huggins, C. and Hodges, C. V .: Studies on prostatic cancer: I. Effect of castration, of estro- gen, and of androgen on serum phophatases in metastatic carcinoma of the prostate. Cancer Research, 1: 293, 1941.
3 Herbst, W. P .: The effects of estradiol dipro- pionate and diethylstilbestrol on malignant pros- tate tissue. Tr. Am. Assoc. Genito-Urin. Surg., 34: 195, 1941.
4 Scott, W. W. and Vermeulen, C .: Studies on prostatic cancer: V. Excretion of 17-ketosteroids, estrogens, and gonadotropins before and after castration. J. Clin. Endocrinol., 2: 450, 1942.
5 Huggins, C. and Scott, W. W .: Bilateral adre- nalectomy in prostatic cancer. Ann. Surg., 122: 1031, 1945.
6 Huggins, C. and Bergenstal, D. M .: Inhibition of human mammary and prostatic cancers by adrenalectomy. Cancer Research, 12: 134, 1952.
7 Harrison, J. H., Thorn, G. W. and Jenkins, D .: Total adrenalectomy for reactivated carci-
experienced varying degrees of subjective clinical improvement, but objective evidence of inhibition of the basic disease has been minimal. 6-8
The administration of exogenous corticos- teroids to man results in the diminution of urinary androgenic steroid excretion,9, 10 supposedly secondary to the inhibition of pituitary ACTH secretion and consequent suppression of the production of androgens by the adrenal cortex.11 Therefore, in accordance with anti-androgenic principles of therapy, cortisone and related steroids have been given to patients with incura- ble metastatic prostatic carcinoma. The clinical results from these corticosteroids, which have been considered as effecting a “medical” adrenal- ectomy, were comparable to those seen after surgical adrenalectomy.12-14 These drugs are now widely used and the clinical benefits well- recognized.12-14 It was the purpose of this present study to administer various corticosteroids to patients with disseminated prostatic cancer and to evaluate the relationship between the degree
noma of the prostate. New Eng. J. Med., 248; 86, 1953.
8 Morales, P. A., Brendler, H. and Hotchkiss, R .: Role of adrenal cortex in prostatic cancer. J. Urol., 73: 399, 1955.
9 Birke, G., Franksson, C. and Planton, L. O .: Excretion of androgens in carcinoma of the pros- tate: III. Cortisone therapy before and after orchiectomy. Acta endocrinol. (Suppl.), 17: 27, 1954.
10 Burt, F. B., Finney, R. P. and Scott, W. W .: Steroid response to therapy in prostatic cancer. J. Urol., 77: 485, 1957.
11 Salassa, R. M., Bennett, W. A., Keating, R. F. and Sprague, R. G .: Postoperative adrenal cortical insufficiency: Occurrence in patients previously treated with cortisone. J.A.M.A., 152: 1509, 1953.
12 Hayward, W. G .: The treatment of late re- lapse in prostatic carcinoma by cortisone. J. Urol., 69: 152, 1953.
13 Valk, W. and Owens, R. H .: Effect of cortisone on patients with carcinoma of prostate. J. Urol., 71: 219, 1954.
14 Miller, G. M. and Hinman, F., Jr .: Cortisone treatment in advanced carcinoma of prostate. J. Urol., 72: 485, 1954.
of adrenocortical suppression, as measured chemically, produced by these steroids and their clinical effectiveness in these patients.
MATERIALS AND METHODS
Ten patients, with carcinoma of the prostate, varying in age from 55 to 79 years, were selected for this study. Each patient had undergone bilateral orchiectomy, had received estrogenic therapy, and had roentgen evidence of osseous metastases. All were in symptomatic relapse which had proven resistant to increased doses of stilbestrol. One patient had undergone bilateral adrenalectomy, 1 year previously, from which he had experienced a remission about five months in duration before relapse occurred.
Prior to corticosteroid therapy, 24-hour urine collections were obtained on two successive days. In order to measure the degree of adrenocortical suppression, the adrenocortical capacity to respond to ACTH was tested by the administra- tion of 40 international units of zinc-ACTH intramuscularly at 8 a.m. on the second day. The urine specimens were analyzed for 17- hydroxycorticosteroids (17-OHCS) by the method of Glenn and Nelson’ and for 17- ketosteroids (17-KS) by the method of Callow and associates.16
The corticosteroids used and their daily dosage range were as follows: prednisone, 5-20 mg .; fluorocortisol, 1-4 mg .; and cortisone, 25-50 mg. In cach case stilbestrol treatment was also con- tinued. Following the start of corticosteroid therapy, the foregoing 2 day urinary steroid studies were repeated at varying intervals of time. In 6 patients serum acid phosphatase determina- tions were done prior to and during steroid therapy.
In order to judge the relationship between the degree of chemical adrenal suppression and the clinical results, a number of factors were con- sidered. Symptomatic relief from therapy was judged on the following criteria: relief of pain and decreased narcotic requirement; increase in
15 Glenn, E. M. and Nelson, D. H .: Clinical method for the determination of 17-hydroxycorti- costeroids and 17-ketosteroids in urine following hydrolysis with B-glucuronidase. J. Clin. Endo- crinol. & Metab., 13: 911, 1953.
16 Callow, N. H., Callow, R. K. and Emmens, C. W .: Colorimetric determination of substances containing the grouping-CH,.CO-in urine ex- tracts as an indication of androgen content. Bio- chem. J., 32: 1312, 1938.
appetite, weight, and strength; increased well- being and improvement of mental attitude. The clinical response was considered “excellent” when the patient experienced complete relief of pain and had improvement in all the other eri- teria. In subjects with a “good” response, the pain became slight, intermittent and readily relieved by aspirin. In a “fair” response, the patient required occasional small doses of nar- coties for relief of pain. If large amounts of narcotics continued to be required, the response was designated as “none.”
The criteria of the degree of chemical adreno- cortical suppression were as follows: In response to 40 i.u. of zine-ACTH administration, an increment in urinary 17-hydroxycorticosteroid excretion per 24 hours of less than 2.5 mg. was considered “marked” suppression; an inerement of 2.5-5.0 mg. was “moderate” suppression, and an increment of more than 5.0 mg. but less than the control increment was “minimal” suppression. If the increment was greater than 5.0 mg. and equal to or greater than the control increment, then suppression was “none.”
RESULTS
In table 1 are the results of all the urinary steroid determinations performed during this study. Urinary 17-OHCS levels both on a control day and also in response to zinc-ACTH were within the normal range in 9 patients prior to corticosteroid therapy. Urinary 17-KS values were uniformly reduced in these subjects pri marily because of the absence of the testes, but also possibly because of impaired formation of 17-KS from adrenal 17-KS precursors.17.18 This phenomenon is often seen in patients with ad- vanced metastatic cancer and malnutrition.” Thus, urinary 17-KS excretion is an indirect measurement of adrenocortical function.
Following the onset of corticosteroid adminis- tration, varying degrees of adrenocortical suppression as measured chemically developed. It appears that daily doses of at least 2 mg. of fluorocortisol or 15 mg. of prednisone are required to produce moderate to marked adrenocortical suppression. Smaller doses of these hormones.
17 Mason, H. L. and Engstrom, W. W .: The 17-ketosteroids: Their origin, determination, and significance. Physiol. Rev., 30: 321, 1950.
18 Conn, J. W., Fajans, S. S., Louis, L. H. and Siltzer, H. S .: Importance of the liver in trans- formation of administered adrenosteroidal com pounds. J. Lab. & Clin. Med., 43: 79, 1954.
| Patient | Drug | Dose | Duration | Time of Steroid Study | ACTH | 17 K-S | 17-OHCS |
|---|---|---|---|---|---|---|---|
| J. B. | mg. | wks. | wks. | I.U. | mg./24 hrs. | m.g./24 hrs. | |
| control | 0 | 1.9 | 6.4 | ||||
| 40 | 3.5 | 15.1 | |||||
| fluoro-F | 1-2 | 0-3 | 3 | 0 | 1.2 | 2.5 | |
| 40 | 1.7 | 6.9 | |||||
| 3-4 | 3-5 | 5 | 0 | 0.7 | 1.4 | ||
| 40 | 0.9 | 2.7 | |||||
| 4 | 5-7 | 7 | 0 | 0.8 | 1.6 | ||
| 40 | 1.0 | 2.1 | |||||
| W. A. | control | 0 | 3.2 | 3.8 | |||
| 40 | 5.3 | 11.7 | |||||
| prednisone | 10 | 0-12 | 1 | 0 | 2.3 | 3.6 | |
| 40 | 3.9 | 9.3 | |||||
| 3 | 0 | 1.9 | 3.2 | ||||
| 40 | 3.4 | 8.8 | |||||
| G. M. | control | 0 | 4.9 | 5.2 | |||
| 40 | 8.6 | 13.8 | |||||
| fluoro-F | 1 | 0-8 | 4 | 0 | 3.5 | 3.9 | |
| 40 | 6.2 | 9.8 | |||||
| prednisone | 10 | 8-40 | 10 | 0 | 2.1 | 4.2 | |
| 40 | 3.9 | 8.9 | |||||
| S. M. | prednisone | 20 | 0-12 | ||||
| 10 | 12-48 | 44 | 0 | 1.5 | 3.4 | ||
| 40 | 3.8 | 7.9 | |||||
| 15 | 48-72 | 52 | 0 | 0.6 | 2.3 | ||
| 40 | 1.2 | 4.7 | |||||
| 60 | 0 | 0.9 | 2.5 | ||||
| 40 | 1.5 | 4.0 | |||||
| 68 | 0 | 0.3 | 2.2 | ||||
| 40 | 1.0 | 4.3 | |||||
| A. B. | control | 0 | 3.5 | 5.7 | |||
| 40 | 5.9 | 14.6 | |||||
| prednisone | 10 | 2 | 1 | 0 | 3.2 | 5.3 | |
| 40 | 5.6 | 15.3 | |||||
| F. S. | control | 0 | 1.3 | 5.0 | |||
| 40 | 2.7 | 16.2 | |||||
| prednisone | 20 | 2 | 1 | 0 | 1.1 | 4.8 | |
| 40 | 3.2 | 15.6 | |||||
| H. P. | control | 0 | 3.4 | 4.7 | |||
| 40 | 6.1 | 14.5 | |||||
| prednisone | 10 | 0-2 | 1 | 0 | 1.9 | 3.5 | |
| 40 | 4.3 | 10.2 | |||||
| 15 | 2-8 | 3 | 0 | 1.4 | 3.1 | ||
| 40 | 3.0 | 7.4 |
| Patient | Drug | Dose | Duration | Time of Steriod Study | ACTH | 17 K-S | 17-OHCS |
|---|---|---|---|---|---|---|---|
| mg. | wks. | wks. | 1.U. | mg./24 hrs. | mg /24 hrs. | ||
| V. M. | control | 0 | 2.4 | 4.3 | |||
| 40 | 4.7 | 15.0 | |||||
| fluoro-F | 2 | 0-4 | 4 | 0) | 0.9 | 2.8 | |
| 4-8 | 40 | 2.1 | 7.7 | ||||
| none | 8-16 | 16 | 0) | 1.5 | 3.9 | ||
| 40 | 4.2 | 14.1 | |||||
| prednisone | 15 | 16-20 | 18 | 0 | 1.0 | 3.7 | |
| 40 | 2.6 | 11.5 | |||||
| E. S. | control | 0 | 2.8 | 3.2 | |||
| 40 | 5.3 | 13.5 | |||||
| prednisone | 20 | 0-4 | |||||
| 10 | 4-20 | 20 | 0) | 2.1 | 2.6 | ||
| 40 | 4.0 | 9.3 |
though they may be clinically effective, produce only a minimal degree of adrenocortical suppres- sion.
The clinical results and the degree of adrenal cortical suppression produced by corticosteroid therapy in the 10 patients studied are recorded in table 2. A significant clinical remission occurred in seven out of 9 patients with intact adrenals, in none of whom marked adrenal suppression developed during the period of improvement. One patient, J. B., who showed marked adrenal suppression on 4 mg. fluorocortisol daily, became paraplegie during the administration of this drug as a result of the relentless progression of spinal metastases. Another subject, B. K., who had undergone bilateral adrenalectomy, experi- enced no clinical benefit from 1 mg. fluorocortisol daily, although this amount of hormone sufficed to maintain electrolyte balance. In general no correlation could be convincingly demonstrated between the clinical effectiveness of the steroid therapy and the degree of adrenocortical sup- pression produced in a given patient.
Most of the patients who obtained subjective relief of pain during corticosteroid administration also manifested objective improvement in appear- ance due to weight gain and increased vigor. However, in only two of these patients was there even minimal objective evidence of an actual remission of the basie disease process. In V. M. and S. M. a slight decrease in serum acid phos- phatase levels was observed during the corticos-
teroid therapy. In no case was there demonstrated regression or clear-cut arrest of bony metastases.
Several distressing side-effects were seen from the corticosteroid hormones. In one case marked hypokalemia developed while the patient was taking fluorocortisol. Three of the 4 patients who received fluorocortisol had fluid retention in the form of peripheral edema or congestive heart failure. In two of these patients this problem became so severe as to necessitate the discon- tinuance of fluorocortisol and the substitution of prednisone, on which they fared better. One patient, J. B., manifested gastrointestinal bleed- ing after 10 days of prednisone treatment, but the bleeding ceased when the dose was reduced from 15 mg. to 5 mg. daily. In this limited series of cases it appeared that prednisone was more effective than fluorocortisol in producing a clinical remission in doses that were easily toler- ated by the patient.
DISCUSSION
Although the adrenal corticoids have proved to be a valuable therapeutic adjunct in relapsing metastatic carcinoma of prostate, their exact mode of action remains unexplained.19 Onc concept has been advanced that these hormones rely for their therapeutic effectiveness upon pituitary-mediated suppression of adrenal gland
19 Grayhack, J. T .: Hormonal treatment of prostatic cancer. Surg. Clinics N. Amer., 39: 13. 1959.
| Pt. | Age | Drug | Dose | Time of Ther- apy | Degree of Adrenal Suppression | Clinical Remission | Acid Phos- phatase | Remarks | ||
|---|---|---|---|---|---|---|---|---|---|---|
| Type | Dura- tion | Be- fore | Dur- ing | |||||||
| mg. | wks. | wks. | K.A.u./100 | ml. | ||||||
| J. B. | 63 | fluoro-F | 1-2 | 0-3 | moderate | none | 4.8 | 5.3 | Rapid downhill course with paraplegia | |
| 3-4 | 3-7 | marked | none | |||||||
| prednisone | 15 | 7-8 | none | G.I. bleeding occurred | ||||||
| 5 | 8-12 | none | Died of disease | |||||||
| W. A. | 79 | prednisone | 10 | 0-12 | minimal | good | 6 | 4.2 | 8.4 | Died of disease |
| G. M. | 62 | fluoro-F | 1 | 0-8 | minimal | good | 8 | Pulmonary edema de- veloped | ||
| prednisone | 10 | 8-40 | moderate | good | 32 | Died of myocardial infarction | ||||
| S. M. | 55 | prednisone | 20 | 0-12 | excel- lent | 12 | ||||
| 10 | 12-48 | moderate | excel- lent | 34 | 7.5 | 1.7 | ||||
| 15 | 48-72 | marked | fair | 8 | Died of disease | |||||
| A. B. | 58 | prednisone | 10 | 0-2 | none | none | Died of disease | |||
| F. S. | 58 | prednisone | 20 | 0-2 | none | good | 2 | Died of myocardial infarction | ||
| H. P. | 70 | prednisone | 10 | 0-2 | minimal | fair | 2 | Had good pain relief | ||
| 15 | 2-8 | moderate | fair | 6 | but became para- plegic | |||||
| cortisone | 25 | 8-40 | fair | 24 | Died of disease | |||||
| V. M. | 68 | fluoro-F | 1-2 | 0-8 | moderate | fair | 8 | Pulmonary edema de- | ||
| none | 8-16 | none | veloped | |||||||
| prednisone | 15 | 16-20 | minimal | good | 4 | 18 | 13 | |||
| 10 | 20-36 | good | 4 | Died of disease | ||||||
| E. S. | 64 | prednisone | 20 | 0-4 | good | 4 | 177 | 189 | ||
| 10 | 4-20 | minimal | good | 16 | Alive and doing well | |||||
| B. K .* | 63 | cortisone | 25-50 | 0-56 | good | 20 | 7.2 | 6.0 | ||
| fair | 36 | |||||||||
| fluoro-F | 1 | 56-60 | none | 7.5 | 17.0 | Died of disease | ||||
* This patient had undergone bilateral adrenalectomy prior to the study.
secretion.7, 8 However, our results indicate that unless corticosteroids are administered in moder- ately high dosage over a period of weeks, the degree of adrenocortical suppression produced by these drugs is incomplete and often negligible. In contrast to the observation that marked corticosteroid-induced adrenal suppression cannot be demonstrated chemically until after several weeks of therapy, the beneficial clinical effects of the adrenal corticosteroids often become manifest within a period of days. Furthermore, there appears to be no correlation between the clinical effectiveness and the degree of adrenal cortical suppression, as measured chemically, produced by different corticosteroids.
Following the administration of corticosteroids, a diminution in urinary androgenic steroid excretion has been demonstrated.9, 10 In a disease where androgens are known to have a deleterious effect, it seems logical to assume that a decrease in circulating androgen levels could be of benefit to the patient.1, 2 However, it is difficult to recon- cile the rapid and dramatic improvement so frequently seen in the patient’s symptoms with the often minimal and tardy drop in urinary androgenic steroid values induced by small to moderate doses of corticosteroids. Even if the well-known euphoric effect induced by adrenal corticoids is added to their anti-androgenic action, the explanation of their clinical effectiveness in
patients with carcinoma of the prostate is inadequate. The conclusion is reached that the beneficial clinical effects of corticosteroids in this disease are mediated in a manner which remains undemonstrated.
SUMMARY
Ten patients with disseminated carcinoma of the prostate, who originally had experienced relief of pain and general clinical improvement from orchiectomy combined with oral stilbestrol administration, but in whom relapse subsequently occurred, were placed on corticosteroid therapy in varying dosage. Urinary 17-hydroxycorticos-
teroid and 17-ketosteroid levels were measured before and during corticosteroid administration both on a control day and also in response to zine-ACTH. Although in 8 cases the symptoms improved on this regimen, no correlation could be demonstrated between the onset and degree of clinical benefit and the time and degree of cor- ticosteroid-induced adrenal suppression as meas- ured chemically.
The authors would like to thank the Schering Corporation and the Squibb Institute for Medical Research for supplying the prednisone and the fluorocortisol used in this study.