There was a considerable uniformity of response to ACTH and cortisone acetate. The findings of Taylor et al. (84) were confirmed in that the patients had an improved sense of well-being, an increase of appetite, but no decrease in the size or activity of the neoplasms. Bone pain was lessened by an estimated 50 per cent, but in no case was pain eliminated for more than 1 or 2 days. At a level of cortisone acetate, 100 mg. daily, or higher, there was in each person a decrease in total protein content and an increase in the least coagulable percentage of serum (Fig. 7).

Two of the patients who obtained partial relief of pain from administration of cortisone acetate were treated subsequently by adrenalectomy with complete relief of bone pain at maintenance levels of cortisone acetate of 87.5-50 mg. daily. In both of these patients there was detectable regression of the neoplasm after adrenalectomy.

Discussion

In the earlier observations on the effect of adrenalectomy on neoplastic growth, a retardation of the rate of growth of some tumors had been reported. It is impossible to prove in any given single case that the growth of a human cancer has been merely slowed. However, regression is easy to demonstrate, and this occurs in some human neoplasms after adrenalectomy.

It is of interest that bilateral adrenalectomy can induce regression of certain malignant tumors and yet is unable to influence favorably other neoplasms having the same site of origin. Evidently the functional characteristics of neoplasms vary greatly.

It should be pointed out that in this small series of patients only prostatic and mammary carcinomas, and not all of them, underwent some regression after adrenalectomy. The "miscellaneous tumors"-squamous carcinoma, melano-sarcoma, chorionic epithelioma, and an undifferentiated carcinoma-were not affected. Now it is established that sex hormones of various kinds increase the activity or cause regression of certain far advanced tumors of the prostate (19) and the male (8) and female mammary glands (1, 11). The cases in which adrenalectomy induced regression comprise tumors which already are known to be influenced in an important manner by sex hormones.

The mechanism whereby regression of some tumors occurs after adrenalectomy is not clearly established, largely because of uncertainty about normal adrenal function. For instance, there is no general agreement concerning what hormones the normal adrenal produces, in what quantity, or whether their number is few or many. We have shown (17) that the syndromes resulting from hyperfunctioning adrenal cortical tumors can be explained on the basis of androgenic, estrogenic, or corticoid effects, sometimes alone and other times in varying combinations and proportions.

Since regressions occur after adrenalectomy with maintenance of the patient on cortisone acetate, it may be inferred that steroids of this type are not responsible for continuing functional activity of the neoplasm. It is most reasonable to assume that the regressions are due at least in part to elimination of critical amounts of sex hormones. It must be pointed out, however, that adrenalectomy seems to have a nonspecific effect in retarding growth of several transplantable tumors of rodents, and this phenomenon may be partially operative in prostatic and mammary cancers.

It is known that the anti-androgenic treatment of prostatic cancer through estrogen administration or orchiectomy has three effects on prostatic cancer: (a) No retardation of the growth rate occurs in a small percentage of patients; (6) Extensive regression of primary and metastatic lesions is observed in something more than one-half of the cases; (c) Regression of the primary tumor with progression of the metastasis (14, 15). In category c, clearly there has been some control of the tumor by hormonal methods, but obviously the metastases are less susceptible to the control procedures than the primary tumor. We are of the opinion that adrenalectomy exerts more profound effects in this situation than in category a where there had been no retardation originally as a result of hormonal modification. However, as has been demonstrated, it was occasionally possible to induce regression of previously resistant primary prostatic cancer tissue.

Wilkins et al. (35) have shown that cortisone causes a decrease in the excretion of both 17-ketosteroids and "comb-growth" androgens in the urine of children with congenital adrenal hyperplasia. Our observations revealed that, although cortisone acetate produced a sense of euphoria, it did not significantly modify the course of prostatic cancer. It has been established that the administration of cortisone acetate to the dog (5) is not followed by androgenic effects.

Summary

Simultaneous bilateral adrenalectomy in man can now be done with comparative safety (29 consecutive cases without fatality.) The adrenal-less man on adequate hormonal substitution therapy presents the metabolic picture of excellent health, although adrenal insufficiency can develop rapidly when hormonal replacement is inadequate to meet the demands of the organism.

In four cases of advanced cancer of the prostate which became reactivated after previous anti-androgen control, some or all of the following effects were observed: relief of intractable bone pain, gain in body weight, reduction of considerably increased acid phosphatase levels and of the least percentage of thermocoagulable proteins, together with an increase of total protein content of serum, increased hemoglobin and erythrocyte content of whole blood, and shrinkage of the primary tumor. Two cases of prostatic cancer did not improve to any significant degree after adrenalectomy. The period of observation of these cases has been 4-9 months.

Of six cases of advanced mammary cancer with metastases, two cases were improved, one patient was moderately benefited, and there was no demonstrable evidence of regression in three cases.

In four advanced neoplasms, other than prostatic or mammary, adrenalectomy caused no detectable regression of the tumor.

Conclusion

Adrenalectomy with maintenance of the patient on cortisone acetate can cause some regression of far advanced mammary and prostatic cancers for which there has been no previous therapy available.