Charles Huggins and Delbert M. Bergenstal (Ben May Laboratory for Cancer Research and the Department of Medicine, University of Chicago, Chicago 37, III.).

It is known that excision of the adrenal glands with maintenance of the animal on sodium chloride has two opposite effects on tumors. Adrenalectomy stimulates the growth of lymphoid tumors in the rat and mouse while retarding the growth rate of many other neoplasms in these species; a decrease in the size of established tumors has not been reported. It will be demonstrated in this paper that adrenalectomy with maintenance of the organism on cortisone acetate can cause some regression of neoplasms, namely, certain cancers of the breast and prostate of man.

The depression of the growth rate of transplantable tumors by adrenalectomy has been observed several times. Joannovics (23) observed that transplanted sarcomas in adrenalectomized mice were slightly over 20 per cent less in weight than in intact controls. Roffo (80) reported a decrease in the growth rate of a transplanted sarcoma and carcinoma of rats following excision of the adrenals. Bischoff and Maxwell (2) did not find that adrenalectomy significantly affected the growth behavior of Walker carcinoma 256 in rats. However, Ingle and Baker (21), with more precise methods, found that adrenalectomy significantly retarded the rate of tumor growth of Walker carcinoma 256 in force-fed ovariectomized rats and in intact males; in this laboratory we have been able to confirm these findings. Funk et al. (10) also found that the Walker tumor grows at a reduced rate in adrenalectomized rats. Ingle and Baker ascribed the retardation of neoplastic growth to the theory that rapidly growing tissues cannot attain a "peak rate of anabolism" in adrenally insufficient animals.

* This study was aided by grants from the Jane Coffin Childs Memorial Fund for Medical Research, the American Cancer Society on recommendation of the Committee on Growth of the National Research Council, and the Damon Runyon Memorial Fund for Cancer Research. The authors are grateful to Dr. Thomas L. Y. Dao, Donald F. Tapley, Mrs. Anne S. Cleveland, and Prof. Eleanor M. Humphreys for assistance. Cortisone acetate was generously provided by the Medical Division of Merck & Co., Rahway, N.J.

Apart from rodents, the only observations on the growth of tumors in adrenalectomized creatures have been on a human neoplasm. Huggins and Scott (20) demonstrated retardation of growth in a man with prostatic cancer after total adrenalectomy, and Cox (4) later observed "a dramatic if temporary clinical improvement" in a patient with this tumor after subtotal removal of the adrenals.

Acceleration of the growth of neoplasms by adrenalectomy was discovered by Murphy and Sturm (27, 32), who found that the number of "takes" of a transplantable lymphatic leukemia was greatly increased and the length of life of successfully inoculated rats was less following adrenalectomy than in intact rats. Law et al. (25) observed that adrenalectomy considerably increased the incidence and the time of appearance of spontaneous lymphoid leukemia in C58 mice.

Heilman and Kendall (12) found that the administration of 11-dehydro-17-hydroxycorticoster-one caused a rapid, profound, yet temporary regression of a transplanted lymphosarcoma in mice; furthermore, when injections of this compound were begun soon after inoculation of the tumor, its growth was delayed for as long as Compound E was given. The growth rate of the following transplantable tumors has been depressed after the injection of 11-oxygenated steroids: three types of lymphosarcoma (33, 7); two osteogenic sarcomas (33); rhabdomyosarcoma (13); ependymoma (3); and various other sarcomas (33). Ingle, Prestrud, and Baker (22) found that cortisone acetate caused a suppression of the growth rate of the Walker 256 tumor in tube-fed rats.

Pituitary adrenocorticotrophin (ACTH) and cortisone acetate have been administered to patients with malignant disease. Pearson et al. (28) observed a dramatic and progressive but temporary decrease in the size of enlarged lymph nodes and the spleen of six patients with lymphomatous tumors after the administration of these agents; there was no obvious clinical response in two patients with metastatic cancer of the breast and prostate, respectively. Eliel et al. (6) reported no demonstrable shrinkage of tumors in seven patients with advanced carcinoma of various kinds following treatment with ACTH or cortisone acetate. Postlethwait et al. (29) found that the course of malignant disease appeared to be completely unaltered by cortisone in nine patients with advanced carcinoma of the digestive tract. Spies et al. (81) stated that there was a reduction in size and a decrease in pain in a patient with carcinoma of the lip following ACTH; no histologic modifications were detected in the tumor in this case. Taylor et al. (84) treated 26 patients who had advanced neoplastic diseases with cortisone acetate or ACTH and were able to confirm the finding of regressions of lymphomatous tumors observed earlier; most of the patients manifested striking temporary improvement in their general condition with lessening of fever, when present, increased appetite, and improved strength and sense of well-being, but no control of the carcinoma was observed.

Methods

Bilateral adrenalectomy was carried out on eighteen patients with the following neoplasms: prostate, seven cases; breast, seven; miscellaneous cancers, four. All the patients had far advanced neoplasms with extensive metastases.

The gonads of all the patients with mammary or prostatic cancers had been excised prior to adrenalectomy except in one woman who was in the postmenopausal state. All the prostatic cases had had a clinical remission induced by orchiectomy with a subsequent relapse; all had been treated in addition with estrogenic substances, mostly di-ethylstilbestrol, for long periods. These patients have been observed for 4-9 months after adrenalectomy. The miscellaneous cancers were squamous carcinoma of the urethra, melanosarcoma, chorionic epithelioma, and an undifferentiated carcinoma, presumably of pulmonary origin. These patients were studied over periods of 1-3 months after adrenal excision.

We have published (17) the-medical and surgical methods involved in one-stage bilateral adrenalectomy in man and maintenance of these patients by medicines. These technics were followed precisely in this series. No substances with hormonal activity were administered except cortisone acetate and desoxycorticosterone acetate (DOCA).

The total protein content of the least thermo-coagulable percentage of serum (16, 18) was determined twice each week. Acid and alkaline phosphatases were measured by the method of King and Armstrong (24); glucose tolerance and insulin tolerance (9) and the water diuresis test (26) were determined pre- and post-operatively in all cases.

Results

Metabolic and clinical status of the adrenal-less man.-There were two post-operative deaths in this series of eighteen adrenalectomized patients with cancer. However, bilateral adrenalectomy has now been carried out by us for one or another reason in 29 consecutive cases without operative fatality.

Following the rather large replacement doses of cortisone acetate and DOCA required to insure the prevention of adrenal insufficiency during and after adrenalectomy, the patient within a week was placed on a hormonal substitution program which in most cases proved to be the future maintenance regimen. Criteria for adequate substitution were the prevention of any sign or symptom of adrenal insufficiency. The maintenance of electrolyte and carbohydrate balance and of adequate blood pressure without orthostatic hypotension were the best indicators.