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Hormonal treatment of metastatic carcinoma of the breast
Hormonal Treatment of Metastatic Carcinoma of the Breast* WILLIAM H. BAKER, M.D., RITA M. KELLEY, M.D. AND WILLIAM Massachusetts
ARCINOMA of the breast is the most common maIignant tumor of human beings. Approximate17 26 per cent of al1 cancer in females originates m the breast, and about 4 per cent of al1 adult females acquire this neopIasm sometime during their Iife span [I]. RegardIess of initiaI therapy, onIy 40 per cent of patients with carcinoma of the breast are free of the disease at the end of ten years [9]. Thus, a majority of such patients become candidates for some form of paIIiative treatment, such as radiation, hormones or chemotherapy. FolIowing the original observations of Beatson in 1896 on the effects of castration on human mammary carcinoma, it has now become we11 estabIished that certain malignant tumors of the breast can be inffuenced by a change in their hormona1 environment [6J. Indeed, foIIowing Huggins’ observation in 1942 on the effect of castration in human prostatic carcinoma, a number of different carcinomas have been found to respond to a change in their hormona1 environment and, in generaI, they are carcinomas that arise in tissue which in the norma state is under hormona1 inff uence. MaIignant human tumors that have responded to hormonal environmenta1 change are those originating in the foIlowing tissues: breast, prostate, thyroid, reticuIoendotheIiaI system and uterus (endometrium) 1131. At present, the wealth of information on studies of cIinica1 response stands in contrast to
C
* This is pubIication No. 988 of the Cancer Commission of Harvard HospitaI. Journal
of Surgery,
Volume
99. April.
1960
SOHIER,
M.D., Boston,
the dearth of knowledge concerning the effect of hormones on the metabolism of ceIIs, both norma and neopIastic. Recent progress in this direction has been made, however [21,23], and promises to be of fundamenta1 importance to the whoIe probIem of growth in carcinoma [8]. Thus, the use of hormones in the treatment of carcinoma of the breast must be empiric, but it is of great importance to emphasize the folIowing concepts based on cIinica1 experience: I. Hormone therapy is not curative and shouId be considered onIy when a tumor is beyond hope of cure by means of surgery or radiation. 2. Hormone therapy should be started onIy after the hormona1 status of the patient and the rate of tumor growth have been ascertained as accurateIy as possibIe. The natura1 history of carcinoma of the breast with its diverse bioIogic predetermination indicates that many patients with metastatic disease may Iive asymptomaticaIIy for many years; some may be worsened by the institution of hormone therapy. 3. UntiI we11 controIIed studies have demonstrated the additive effect of combined therapy, such as surgery pIus castration, abIative therapy pIus hormones, or two hormones together, hormona1 therapy is better carried out in sequence. Indeed, not infrequentIy the withdrawa of hormones no Ionger effective may produce a partiaI remission. 4. As a coroIIary of the previous statement, there is no good evidence that prophyIactic therapy with hormones or abIative surgery following radica1 mastectomy can prevent or defer the appearance of metastases [22]. 5. The administration of hormones may be
From the Jobn Collins Warren Laboratories of the Huntington Memorial Hospital of Harvard University at tbe Tumor Clinic of the Massachusetts General Hospital, Boston, Massachusetts; and Pondville Hospital, Walpole, Massachusetts. Tbis investigation was supported by a National Cancer Institute Research Grant, No. C 2421.
American
D.
538
University
and pubIication No. 214 of PondviIIe
HormonaI Treatment of Metastatic Carcinoma of Breast accompanied by serious compIications, some of which are the direct result of acceIeration of tumor growth. The alteration of the hormonal environment of patients with carcinoma of the breast can be achieved in two ways: (I) ablative surgery in which the site of endogenous production of sex hormones is removed, such as castration, adrenalectomy or hypophysectomy; (2) the administration of pharmacoIogic doses of hormones which upset the hormonal balance of the host, making a less favorable miIieu for neoplastic proliferation of hormone-dependent ceIIs. Both procedures may be equaIIy effective in serected patients and also in the same patient. The sequence and choice of therapy depend primariIy on the age of the patient and the nature and extent of disease. (Table I.) It is now generaIIy agreed that the menstruating femaIe with metastatic carcinoma of the breast should have castration as the first form of therapy. We presentIy prefer surgica1 castration to radiation, since it is quicker and more predictable in its effect. FolIowing this therapy, there is no genera1 agreement as to the treatment of choice. In generaI, those patients who have had a favorabIe response to surgical castration, as evidenced by shrinkage of tumor masses and recalcification of bony Iesions (30 to 40 per cent), are the ones who wiII benefit from other therapy, either abIative or hormonal. Most of those premenopausa1 patients who do not achieve good resuIts from surgica1 castration wiI1 usuaIIy receive no significant objective benefit from other types of hormone therapy. In this group, further operative procedures are not indicated but hormones, such as corticosteroids, and chemotherapy may be of paIIiative symptomatic benefit. The response to surgical castration is therefore the best means of seIecting patients for future hormona1 therapy. In the postmenopausal group of patients, no such convenient guidepost exists. However, those patients who respond to one hormone are probabIy the ones who will later respond to other changes in their hormona1 environment. We have foIlowed up a few patients for as Iong as tweIve years, during which time each change in the hormona1 environment brought about an objective remission Iasting anywhere from nine months to two years. It is obvious that the seIection of patients for hormona1 therapy and, indeed, the specific hormone is IargeIy empiric,
TABLE I SEQUENCE OF TREATMENT FOR OF
ADVANCED
CANCER
BREAST
Premenopausal 1. Surgical castration Remission: If no remission try: 2. Corticosteroids 2. Androgens 3. Androgens 3. Chemotherapy 4. Hypophysectomy MeonopausaI and up to s years’ postmenopausa1 Establish IeveIof f&cIe-sti&Iating ‘hormone Corn&cation of vagina1 smear a. If follicle-stimmating hormone is low and smear cornihed (over 30 per cent ceIIs) treat as premenopausa1 6. If foIIicIe-stimmating hormone is high and smear not cornihed (Iess than go per cent ceIIs) treat as postmenopausa1 Corticosteroids Remission: If no remission try: 4. Oophorectomy 4. Androgens 5. Hypophsectomy 5. Androgens 6. Chemotherapy 6. Chemotherapy Postmenopausal Remission: 2. Androgens 3. Corticosteroids 4. Hypophysectomy
I. Estrogens If no remission try: 2. Androgens 3. Corticosteroids 4. Chemotherapy
and one must be guided by the previous response to abIative surgery or hormones. Numerous attempts to select patients on the basis of urinary estrogens [7], urinary gonadotropins [r5], metaboIism of tumor tissue as measured by radioactive isotope uptake [5], uptake of nucleic acid precursors [20] and measurements of estrogen-sensitive enzyme systems [IO] have not yet been usefur in bringing about a clear-cut selection of patients for therapy. Our present guide for sequentia1 therapy of hormones in patients with carcinoma of the breast may be seen in Table I and is subject to individua1 change depending upon the patient’s tolerance to hormones. TESTOSTERONE
The beneficial effects of the administration of testosterone to patients with carcinoma of the breast was first reported by Adair and has been we11 confirmed [2,19]. ApproximateIy 20 per cent of patients in the postmenopausa1 age group wiI1 respond to the administration of testosterone with recaIcification of bony lesions. The effect of testosterone on soft tissue lesions is often Iess, about 5 to IO per cent. In 80 to go
539
Raker,
KeIIey
TESTOSTERONE
0
I
.
Loco1
v
Total
and Sohier PROPIONATE
in menapousal age group
I
I
I
2-5
6-10
>I0
YEARS
POSTMENOPAUSAL
FIG. I. CumuIative
data obtained from the Conference on the Biological Activities of Steroids in Relation to Cancer, sponsored by the Cancer Chemotherapy NationaI Service Center at Vergennes, Vermont, September 27 to October 2, 1959,
per cent of these patients, there is symptomatic benefit with reIief of bone pain and gain in appetite and weight. However, symptomatic benefit must not be considered synonymous with objective benefit, since rapid acceIeration of growth, as demonstrated by a skeIeta1 surmarked symptomatic vey, can accompany benefit. Testosterone is most effective in patients in the postmenopausa1 age group, particuIarIy regarding the soft tissue response. (Fig. I.) Metbod of Administration. The foIIowing preparations in a dosage of 50 to IOO mg. intramuscuIarIy three times weekIy are equaIIy potent: (I) testosterone propionate, (2) dihydrotestosterone (androstanalone), and (3) 2 aIphamethy dihydrotestosterone. OraI preparations such as methy testosterone, 200 mg. every day, and fIuoxymestrone, 20 to 40 mg. every day, are much Iess effective. In a11 instances androgen therapy shouId be continued for a minimum of three months unIess there ,is definitive evidence of the progression of Iesions. In Iesions showing favorabIe objective response, it shouId be continued unti1 relapse occurs. Since oraI medication is more expensive and Iess effective, intramuscuIar administration is, at present, preferred. Undesirable Efects. Administration of an
effective dose of testosterone in femaIe patients is aImost aIways attended by virilization. Hoarseness and deepening of the voice, hirsutism of the face, arms and Iegs and occasionally over the entire body, facia1 Aush and acne, tempora1 recession and thinning of scaIp hair, and enIargement of the cIitoris with increased Iibido are a11 common. FIuid retention may aIso occur, and in eIderIy patients this may constitute a hazard to the cardiovascular system with the deveIopment of congestive failure. The use of a Iow saIt diet and diuretic therapy wiI1 usuaIIy contro1 this situation. The administration of testosterone propionate usuaIIy causes a faI1 in urinary gonadotropins, and a few patients have shown cornification of vaginal smears, pigmentation of the nippIes and withdrawa bIeeding. The Iatter estrogen-Iike effects are probabIy reIated to the metaboIism of testosterone to active estrogen which seems to be a norma minor pathway of testosterone metaboIism within the body [3]. The most serious adverse effect of testosterone is the induction of hypercaIcemia. Because of the seIection of patients with predominant bone disease for this form of therapy, the incidence of this compIication is higher with androgen (14 per cent) than with estrogen therapy (8 to IO per cent). When hypercaIcemia occurs with 540
HormonaI
Treatment
of Metastatic
testosterone therapy, it tends to occur earIy in the first two to three weeks and occasionally after onIy one or two doses of testosterone have been administered. It is usuaIIy accompanied by symptoms of dry mouth, poIydipsia and polyuria, nausea and vomiting, foIlowed by mental apathy Ieading to drowsiness, stupor and coma. Because of this serious compIication, serum calcium IeveIs should aIways be obtained before beginning testosterone therapy. Untreated hypercaIcemia may Iead to sudden death, presumabIy due to the known effects of excess caIcium on the heart muscIe as evidenced cIinicaIIy by a shortened Q-T interva1 and experimentaIIy by “caIcium rigor” of the heart. The treatment of hypercaIcemia consists of discontinuance of the offending hormone and administration of Iarge amounts of intravenous fluids and corticosteroids. The dose of corticosteroids should aIways be high, IOO to 300 mg. of cortisone or equivarent doses of derivatives such as prednisone or prednisoIone. Quite frequently the initia1 two to three injections of testosterone wiI1 cause an increase in bone pain. This must be differentiated from true acceIeration of disease by carefu1 cIinica1 and laboratory evaIuation. In such instances the pain disappears during continuance of the drug and a remission may foIIow. Since mascuIinization is a frequent undesirable effect of testosterone propionate, many Iess androgenic compounds have been devised to see whether the same objective benefit can be achieved without masculinization. These compounds have been primariIy the rg-nortestosterone derivatives, but in producing an antitumor effect they inevitably produce mascuIinization [4]. HaIogenation of testosterone to ffuoxymestrone does produce a more androgenic compound miIIigram for miIIigram but does not increase the percentage of patients responding to its administration. More recentIy, an inert testosterone derivative, deIta- I testoIoIactone, has been found to be effective in the management of carcinoma of the breast. This compound is of great interest since it presentIy appears to be devoid of a sex hormone effect. It does not change the gonadotropin IeveIs and yet seems to be effective in the paIIiative management of carcinoma of the breast in about 30 per cent of the patients [I 81. If these initia1 studies are confirmed by others, this compound may we11 be the androgen of choice, since undesirabIe mascuIinizing effects are not present. 541
Carcinoma
of Breast ESTROGENS
The paradoxic finding by Nathanson, confirmed by others [16], that estrogens couId induce remission of carcinoma of the breast was unexpected. Estrogen was initiaIIy given to cause exacerbation of this condition in an attempt to increase the tumor’s susceptibiIity to radiation. Nathanson chose as his fn-st patient an elderly femaIe who after two weeks of estrogen therapy showed pronounced regression of soft tissue disease. Because of this observation a tria1 of estrogenic hormone in a11types of patients with metastatic carcinoma of the breast was undertaken. Estrogens have been found to be beneficia1 in 40 to 45 per cent of patients who are more than five years postmenopausa1 [17]. Benefit is obtained onIy when the estrogen is used in very high pharmacoIogic dosages. The ora dose of ethiny1 estradio1 is I mg. three times a day; stiIbestroI,5 mg. three times a day; and Premarin,@ IO mg. three times a day. Lower doses give a Iower response rate, and higher dosages do not increase the response rate. Estrogens given to premenopausa1 femaIes may cause exacerbation of the disease or at times no change [I?]. This statement is based on the use of estrogen in onIy eIeven premenopausa1 femaIes. It may be of interest to study more premenopausal females using rather massive doses of estrogen. FoIIowing the administration of estrogen in the postmenopausa1 femaIe, the average Iength of objective benefit is twelve to fourteen months. Estrogens induce such remission primariIy in soft tissue. However, in 20 per cent of the cases they aIso cause recaIcification of bony Iesions. Most cIinicians interested in carcinoma of the breast believe that the direct effect of estrogens on the malignant ceII is one of stimuIation in the same way norma breast tissue is stitiuIated by a combination of estrogen, progesterone and pituitary factors [I I]. It is thought by some that estrogen may be very harmfu1 even in patients in the postmenopausa1 age groups. That the opposite frequentIy occurs may be because estrogens in high dosages suppress pituitary activity with resuItant inhibition of necessary pituitary hormones. Stress incontinence ocUndesirable Efects. curs quite frequentIy, especiaIIy in eIderIy persons, and in a smaI1 percentage of patients it may be so severe that discontinuance of the hormone becomes necessary. Pigmentation of
Baker,
KeIIey
both nippIes occurs almost universaIIy and is more pronounced in darker-skinned femaIes. Sodium retention with consequent water retention in patients with low cardiac reserve is a hazard. The weight must be carefuIIy watched. We usuaIIy put patients on a Iow salt diet when we begin estrogen therapy and administer diuretics and digitalis onIy when needed. Very rareIy do we have to discontinue estrogens because of ffuid retention when these measures are used. Rarely, increased Iibido deveIops. A smaI1 percentage of patients develop spotting and occasiona bIeeding. Withdrawal bIeeding aImost aIways occurs to some degree in patients with intact endometria. In about IO per cent of patients who have received objective benefit with administration of estrogen, withdrawa of estrogens after reIapse wil1 produce an additiona1 short-lived response. HypercaIcemia is the most serious complication of estrogen therapy and does occur in about 8 per cent of patients receiving estrogens. Withdrawal of estrogens and administration of intravenous &rids and cortisone may be necessary to counteract this complication. HypercaIcemia is thought to be reIated to acceIeration of tumor growth in bone. However, on at Ieast two occasions, we have noticed a relief of hypercaIcemia and an objective remission whiIe continuing estrogen therapy. Perhaps at first estrogen causes an exacerbation by working synergisticaIIy with pituitary hormones, but Iater inhibition of pituitary secretion takes pIace and the over-al1 effect on tumor growth is reversed. CORTICOSTEROIDS
Administration of corticosteroids to patients with metastatic carcinoma of the breast produces objective benefit in about one-third of the patients. The dose of cortisone also must be high, at least IOO to 300 mg. of cortisone or hydrocortisone, or 30 to 60 mg. of prednisone or prednisoIone. Cortisone does not seem to be effective in those patients who have active ovarian function. Cortisone or prednisone causes objective remissions Iasting as Iong as twenty-three months with a median duration of nine months [14]. It is most successfu1 in those patients who have previousIy responded to oophorectomy. The undesirabIe effects of corticosteroids, such as edema, cushingoid facies, hypertension, aggravation or induction of diabetes, peptic uIcerations and bIeeding, may occur in any of the patients receiving cortisone. At the dose necessary in the treat542
and Sohier ment of carcinoma of the breast, cushingoid facies and weight gain are frequentIy present. Once an initia1 response has occurred, the dose can be graduahy reduced, causing a reduction of side effects but no apparent Ioss in effectiveness. Cortisone has its main effect on soft tissue disease, but in a few cases it has produced recaIcification of 0steoIytic Iesions. This is paradoxic since cortisone given to patients without carcinoma of the breast usuaIIy produces hypercaIcemia or hypercaIciuria and osteoporosis, which is characteristic of Cushing’s disease. It is probable that the inhibition of the growth of ceIIs in carcinoma of the breast within the bone tips the host-tumor reIationship in favor of the host, so that repair of osteoIytic Iesions occurs in spite of the antianabolic effect of cortisone on bone matrix. Corticosteroids have aIso been found usefu1 in the treatment of cerebra1 metastases with convuIsions and, indeed, it is probably the only hormona1 agent that has been successfu1 in the management of such patients. It aIso may be of vaIue in controIIing pIeura1 and abdomina1 effusions. PROGESTERONE
The use of progesterone in the treatment of carcinoma of the breast is presentIy under intensive investigation. EarIy results with have o-alpha-bromo- r I -beta-ketoprogesterone been promising [12]. Seven of thirty-four patients showed objective improvement Iasting up to five and a haIf months. In our clinic, responses have been seen in a few patients receiving doses of 150 to 1,000 mg. of progesterone per week in the form of DeIaIutin.@* At these dosages, no evidence of estrogen effect has occurred, as indicated by nippIe pigmentation or cornification of vagina1 smears. At the present time, a survey is being made on the comparative effects of DeIaIutin and testosterone, and our initial resuIts indicate that DeIaIutin is certainIy no better than testosterone and may be sIightIy Iess effective. SUMMARY
The palliative management of metastatic carcinoma of the breast may be accomplished by either additive or ablative changes in the hormona1 environment of the patient. As yet it has not been possible to predict those patients * (I 7-alpha-hydroxyprogesterone-IT-n-caproate), E. R. Squibb & Sons, New York.
HormonaI Treatment of Metastatic Carcinoma of Breast who wiI1 and those who wiIl not respond to hormonal therapy. It has been suggested that hormona1 therapy is successfu1 because certain carcinomas of the breast retain enough of their premalignant characteristics to be responsive to progesterone, estrogen and pituitary factors incIuding growth hormone. Those patients who exhibit a response to surgical castration usually respond to another type of hormonal therapy, such as adrenaIectomy, hypophysectomy or additive therapy. Hormone therapy may be combined with other types of treatment for paIIiative effect, such as x-ray therapy and, rareIy, surgery. The conversion of an inoperable carcinoma to an operable one is probabIy not achieved by hormonal therapy. PathoIogic studies wouId seem to back this up, since biopsy during successfu1 hormonal therapy has always demonstrated smaI1 foci of tumor cells. Therefore, those tumors which are inoperable because they involve supraclavicular Iymph nodes, for example, wiI1 probabIy stiII have small metastatic foci present in the nodes after successfu1 antitumor therapy with hormones. We believe that the patients who respond to additive hormone therapy are the same group who respond to ablative hormone therapy, and that a therapeutic tria1 is the only way of distinguishing these patients. Thus, the importance of a carefuI evaluation must be re-emphasized. FinaIIy, aIthough hormonal therapy of carcinoma is palliative, it is extremely beneficial and, when successful, restores very III patients to usefu1 and productive Iives.
7. BULBROOK, R. D., GREENWOOD, F. C. and WILLIAMS, P. C. ParalIel chemical and biological assays of urinary oestrogens after adrenaIectomy and hypophysectomy. In: Endocrine Aspects of Breast Cancer. Edinburgh and London, 1958. E. & S. Livingstone Ltd. 8. ENGEL, L. L. Mechanisms of action of estrogens. In: Vitamins and Hormones, vol. 17. New York, 1959. Academic Press Inc. 9. HAAGENSEN, C. D. Diseases of the Breast. Philadelphia and London, 1956. W. B. Saunders Co. IO. HOLLANDER, V. P., JONAS, H. and SMITH, D. E. Estradiol-sensitive isocitric dehydrogenase in noncancerous and cancerous human breast tissue. Cancer, 1 I : 803, 1958. I I. Hypophysectomy. Edited by 0. H. Pearson. Springfield, III. 1957. CharIes C Thomas. 12. JONSSON, U., COLSKY, J., LESSNER, H. E., ROATH, 0. S., APLER, R. G. and JONES, R., JR. Clinical and pharmacoIogica1 observations of the effects of 9-a-bromo-1 I-Sketoprogesterone in patients with carcinoma of the breast. Cancer, 12: go9, 1959. 13. KELLEY, R. M. and BAKER, W. H. CIinicaI observations on the effect of progesterone in the treatment of metastatic endometrial carcinoma. To be pubIished. Presented at the Conference on the Biologica Activities of Steroids in ReIation to Cancer. Sponsored by the Cancer Chemotherapy National Service Center, Vergennes, Vermont,
REFERENCES I. ACKERMAN, L. V. and DEL REGATO, J. A. Cancer:
2.
3.
4.
5.
6.
Diagnosis, Treatment, and Prognosis. St. Louis. 1947. C. V. Mosby Co. ADAIR, F. E. and HERRMANN, J. B. The use of testosterone propionate in the treatment of advanced cancer of the breast. Ann. Surg., 123: 1023, 1946. BAGGETT, B., ENGEL, L. L., BALDERAS, L. and LANMAN, G. Conversion of C-14 testosterone to C-14 estrogenic steroids by endocrine tissues. Endocrinology, 64: 600, 1959. BAKER, W. H., HENNEMAN, P. H., BAGGETT, B., ENGEL, L. L., TIBBETTS, D. and BROWN, M. The metaboIic effect of 19-nortestosterone (abstr.). J. Clin. Endocrinol., 15: 848, 1956. BAKER, W. H., NATHANSON, I. T. and SELVERSTONE, B. Use of radioactive potassium (K42) in the study of benign and malignant breast tumors. New England J. Med., 252: 612, 1955. BEATSON, G. T. On treatment of inoperabIe cases of carcinoma of mamma. hncet, 2: IO&107, 162165, 1896.
543
1959. 14. LEMON, H. M. Prednisone therapy of advanced mammary cancer. Cancer, 12: 93, 1959. 15. LORAINE, J. A. Clinical Application of Hormone & L.ondon, 1958. Assay, p. 198. Edinburgh E. & S. Livingstone Ltd. 16. NATHANSON, I. T. Sex hormones and castration in advanced breast cancer. Radiology, 56: 535, 195 I. I7. NATHANSON, I. T. and KELLEY, R. M. Hormonal treatment of cancer. MedicaI progress. New England J. Med., 246: 135, 1952. 18. SEGALOFF, A., WEETH, J. B., RONGONE, E. L., MURISON, P. J. and BOWERS, C. Y. Hormonal therapy in cancer of the breast. XVI. The effect of deIta-1-testoIoIactone on cIinica1 course and hormona1 excretion. Cancer, to be pubIished. 19. SEGAI.OFF, A., GORDON, D., HORWITT, B. N., SCHLOSSER,J. V. and MURISON, P. J. Hormonal therapy in cancer of the breast. I. The effect of testosterone propionate therapy on cIinica1 course and hormona1 excretion. Cancer, 4: 319, 195 I. 20. SKY-PECK, H. H., KOFMAN, S., WINZLER, R. J. and TAYLOR, S. G. Effect of steroids on the rate of formate C-14 incorporation into normaI and neopIastic human breast tissues. Proc. Am. A. Cancer Res., 2: 250, 1957. 2 I. TALALAY, P., HURLOCK, B. and WILLIAMS-ASHMAN, H. G. On a coenzymatic function of estradioI-178. Proc. Nat. Acad. SC., 44: 862, 1958. 22. TREVES, N. and FINKBEINER, J. A. An evaIuation of therapeutic surgica1 castration in the treatment of metastatic, recurrent, and primary inoperabIe mammary carcinoma in women. Cancer, II: 421, 1958. 23. VILLEE, C. A. and HAGERMAN, D. D. On the identity of the estrogen-sensitive enzyme of human pIacenta. J. Biol. Cbem., 233: 42, 1958.
ARCINOMA of the breast is the most common maIignant tumor of human beings. Approximate17 26 per cent of al1 cancer in females originates m the breast, and about 4 per cent of al1 adult females acquire this neopIasm sometime during their Iife span [I]. RegardIess of initiaI therapy, onIy 40 per cent of patients with carcinoma of the breast are free of the disease at the end of ten years [9]. Thus, a majority of such patients become candidates for some form of paIIiative treatment, such as radiation, hormones or chemotherapy. FolIowing the original observations of Beatson in 1896 on the effects of castration on human mammary carcinoma, it has now become we11 estabIished that certain malignant tumors of the breast can be inffuenced by a change in their hormona1 environment [6J. Indeed, foIIowing Huggins’ observation in 1942 on the effect of castration in human prostatic carcinoma, a number of different carcinomas have been found to respond to a change in their hormona1 environment and, in generaI, they are carcinomas that arise in tissue which in the norma state is under hormona1 inff uence. MaIignant human tumors that have responded to hormonal environmenta1 change are those originating in the foIlowing tissues: breast, prostate, thyroid, reticuIoendotheIiaI system and uterus (endometrium) 1131. At present, the wealth of information on studies of cIinica1 response stands in contrast to
C
* This is pubIication No. 988 of the Cancer Commission of Harvard HospitaI. Journal
of Surgery,
Volume
99. April.
1960
SOHIER,
M.D., Boston,
the dearth of knowledge concerning the effect of hormones on the metabolism of ceIIs, both norma and neopIastic. Recent progress in this direction has been made, however [21,23], and promises to be of fundamenta1 importance to the whoIe probIem of growth in carcinoma [8]. Thus, the use of hormones in the treatment of carcinoma of the breast must be empiric, but it is of great importance to emphasize the folIowing concepts based on cIinica1 experience: I. Hormone therapy is not curative and shouId be considered onIy when a tumor is beyond hope of cure by means of surgery or radiation. 2. Hormone therapy should be started onIy after the hormona1 status of the patient and the rate of tumor growth have been ascertained as accurateIy as possibIe. The natura1 history of carcinoma of the breast with its diverse bioIogic predetermination indicates that many patients with metastatic disease may Iive asymptomaticaIIy for many years; some may be worsened by the institution of hormone therapy. 3. UntiI we11 controIIed studies have demonstrated the additive effect of combined therapy, such as surgery pIus castration, abIative therapy pIus hormones, or two hormones together, hormona1 therapy is better carried out in sequence. Indeed, not infrequentIy the withdrawa of hormones no Ionger effective may produce a partiaI remission. 4. As a coroIIary of the previous statement, there is no good evidence that prophyIactic therapy with hormones or abIative surgery following radica1 mastectomy can prevent or defer the appearance of metastases [22]. 5. The administration of hormones may be
From the Jobn Collins Warren Laboratories of the Huntington Memorial Hospital of Harvard University at tbe Tumor Clinic of the Massachusetts General Hospital, Boston, Massachusetts; and Pondville Hospital, Walpole, Massachusetts. Tbis investigation was supported by a National Cancer Institute Research Grant, No. C 2421.
American
D.
538
University
and pubIication No. 214 of PondviIIe
HormonaI Treatment of Metastatic Carcinoma of Breast accompanied by serious compIications, some of which are the direct result of acceIeration of tumor growth. The alteration of the hormonal environment of patients with carcinoma of the breast can be achieved in two ways: (I) ablative surgery in which the site of endogenous production of sex hormones is removed, such as castration, adrenalectomy or hypophysectomy; (2) the administration of pharmacoIogic doses of hormones which upset the hormonal balance of the host, making a less favorable miIieu for neoplastic proliferation of hormone-dependent ceIIs. Both procedures may be equaIIy effective in serected patients and also in the same patient. The sequence and choice of therapy depend primariIy on the age of the patient and the nature and extent of disease. (Table I.) It is now generaIIy agreed that the menstruating femaIe with metastatic carcinoma of the breast should have castration as the first form of therapy. We presentIy prefer surgica1 castration to radiation, since it is quicker and more predictable in its effect. FolIowing this therapy, there is no genera1 agreement as to the treatment of choice. In generaI, those patients who have had a favorabIe response to surgical castration, as evidenced by shrinkage of tumor masses and recalcification of bony Iesions (30 to 40 per cent), are the ones who wiII benefit from other therapy, either abIative or hormonal. Most of those premenopausa1 patients who do not achieve good resuIts from surgica1 castration wiI1 usuaIIy receive no significant objective benefit from other types of hormone therapy. In this group, further operative procedures are not indicated but hormones, such as corticosteroids, and chemotherapy may be of paIIiative symptomatic benefit. The response to surgical castration is therefore the best means of seIecting patients for future hormona1 therapy. In the postmenopausal group of patients, no such convenient guidepost exists. However, those patients who respond to one hormone are probabIy the ones who will later respond to other changes in their hormona1 environment. We have foIlowed up a few patients for as Iong as tweIve years, during which time each change in the hormona1 environment brought about an objective remission Iasting anywhere from nine months to two years. It is obvious that the seIection of patients for hormona1 therapy and, indeed, the specific hormone is IargeIy empiric,
TABLE I SEQUENCE OF TREATMENT FOR OF
ADVANCED
CANCER
BREAST
Premenopausal 1. Surgical castration Remission: If no remission try: 2. Corticosteroids 2. Androgens 3. Androgens 3. Chemotherapy 4. Hypophysectomy MeonopausaI and up to s years’ postmenopausa1 Establish IeveIof f&cIe-sti&Iating ‘hormone Corn&cation of vagina1 smear a. If follicle-stimmating hormone is low and smear cornihed (over 30 per cent ceIIs) treat as premenopausa1 6. If foIIicIe-stimmating hormone is high and smear not cornihed (Iess than go per cent ceIIs) treat as postmenopausa1 Corticosteroids Remission: If no remission try: 4. Oophorectomy 4. Androgens 5. Hypophsectomy 5. Androgens 6. Chemotherapy 6. Chemotherapy Postmenopausal Remission: 2. Androgens 3. Corticosteroids 4. Hypophysectomy
I. Estrogens If no remission try: 2. Androgens 3. Corticosteroids 4. Chemotherapy
and one must be guided by the previous response to abIative surgery or hormones. Numerous attempts to select patients on the basis of urinary estrogens [7], urinary gonadotropins [r5], metaboIism of tumor tissue as measured by radioactive isotope uptake [5], uptake of nucleic acid precursors [20] and measurements of estrogen-sensitive enzyme systems [IO] have not yet been usefur in bringing about a clear-cut selection of patients for therapy. Our present guide for sequentia1 therapy of hormones in patients with carcinoma of the breast may be seen in Table I and is subject to individua1 change depending upon the patient’s tolerance to hormones. TESTOSTERONE
The beneficial effects of the administration of testosterone to patients with carcinoma of the breast was first reported by Adair and has been we11 confirmed [2,19]. ApproximateIy 20 per cent of patients in the postmenopausa1 age group wiI1 respond to the administration of testosterone with recaIcification of bony lesions. The effect of testosterone on soft tissue lesions is often Iess, about 5 to IO per cent. In 80 to go
539
Raker,
KeIIey
TESTOSTERONE
0
I
.
Loco1
v
Total
and Sohier PROPIONATE
in menapousal age group
I
I
I
2-5
6-10
>I0
YEARS
POSTMENOPAUSAL
FIG. I. CumuIative
data obtained from the Conference on the Biological Activities of Steroids in Relation to Cancer, sponsored by the Cancer Chemotherapy NationaI Service Center at Vergennes, Vermont, September 27 to October 2, 1959,
per cent of these patients, there is symptomatic benefit with reIief of bone pain and gain in appetite and weight. However, symptomatic benefit must not be considered synonymous with objective benefit, since rapid acceIeration of growth, as demonstrated by a skeIeta1 surmarked symptomatic vey, can accompany benefit. Testosterone is most effective in patients in the postmenopausa1 age group, particuIarIy regarding the soft tissue response. (Fig. I.) Metbod of Administration. The foIIowing preparations in a dosage of 50 to IOO mg. intramuscuIarIy three times weekIy are equaIIy potent: (I) testosterone propionate, (2) dihydrotestosterone (androstanalone), and (3) 2 aIphamethy dihydrotestosterone. OraI preparations such as methy testosterone, 200 mg. every day, and fIuoxymestrone, 20 to 40 mg. every day, are much Iess effective. In a11 instances androgen therapy shouId be continued for a minimum of three months unIess there ,is definitive evidence of the progression of Iesions. In Iesions showing favorabIe objective response, it shouId be continued unti1 relapse occurs. Since oraI medication is more expensive and Iess effective, intramuscuIar administration is, at present, preferred. Undesirable Efects. Administration of an
effective dose of testosterone in femaIe patients is aImost aIways attended by virilization. Hoarseness and deepening of the voice, hirsutism of the face, arms and Iegs and occasionally over the entire body, facia1 Aush and acne, tempora1 recession and thinning of scaIp hair, and enIargement of the cIitoris with increased Iibido are a11 common. FIuid retention may aIso occur, and in eIderIy patients this may constitute a hazard to the cardiovascular system with the deveIopment of congestive failure. The use of a Iow saIt diet and diuretic therapy wiI1 usuaIIy contro1 this situation. The administration of testosterone propionate usuaIIy causes a faI1 in urinary gonadotropins, and a few patients have shown cornification of vaginal smears, pigmentation of the nippIes and withdrawa bIeeding. The Iatter estrogen-Iike effects are probabIy reIated to the metaboIism of testosterone to active estrogen which seems to be a norma minor pathway of testosterone metaboIism within the body [3]. The most serious adverse effect of testosterone is the induction of hypercaIcemia. Because of the seIection of patients with predominant bone disease for this form of therapy, the incidence of this compIication is higher with androgen (14 per cent) than with estrogen therapy (8 to IO per cent). When hypercaIcemia occurs with 540
HormonaI
Treatment
of Metastatic
testosterone therapy, it tends to occur earIy in the first two to three weeks and occasionally after onIy one or two doses of testosterone have been administered. It is usuaIIy accompanied by symptoms of dry mouth, poIydipsia and polyuria, nausea and vomiting, foIlowed by mental apathy Ieading to drowsiness, stupor and coma. Because of this serious compIication, serum calcium IeveIs should aIways be obtained before beginning testosterone therapy. Untreated hypercaIcemia may Iead to sudden death, presumabIy due to the known effects of excess caIcium on the heart muscIe as evidenced cIinicaIIy by a shortened Q-T interva1 and experimentaIIy by “caIcium rigor” of the heart. The treatment of hypercaIcemia consists of discontinuance of the offending hormone and administration of Iarge amounts of intravenous fluids and corticosteroids. The dose of corticosteroids should aIways be high, IOO to 300 mg. of cortisone or equivarent doses of derivatives such as prednisone or prednisoIone. Quite frequently the initia1 two to three injections of testosterone wiI1 cause an increase in bone pain. This must be differentiated from true acceIeration of disease by carefu1 cIinica1 and laboratory evaIuation. In such instances the pain disappears during continuance of the drug and a remission may foIIow. Since mascuIinization is a frequent undesirable effect of testosterone propionate, many Iess androgenic compounds have been devised to see whether the same objective benefit can be achieved without masculinization. These compounds have been primariIy the rg-nortestosterone derivatives, but in producing an antitumor effect they inevitably produce mascuIinization [4]. HaIogenation of testosterone to ffuoxymestrone does produce a more androgenic compound miIIigram for miIIigram but does not increase the percentage of patients responding to its administration. More recentIy, an inert testosterone derivative, deIta- I testoIoIactone, has been found to be effective in the management of carcinoma of the breast. This compound is of great interest since it presentIy appears to be devoid of a sex hormone effect. It does not change the gonadotropin IeveIs and yet seems to be effective in the paIIiative management of carcinoma of the breast in about 30 per cent of the patients [I 81. If these initia1 studies are confirmed by others, this compound may we11 be the androgen of choice, since undesirabIe mascuIinizing effects are not present. 541
Carcinoma
of Breast ESTROGENS
The paradoxic finding by Nathanson, confirmed by others [16], that estrogens couId induce remission of carcinoma of the breast was unexpected. Estrogen was initiaIIy given to cause exacerbation of this condition in an attempt to increase the tumor’s susceptibiIity to radiation. Nathanson chose as his fn-st patient an elderly femaIe who after two weeks of estrogen therapy showed pronounced regression of soft tissue disease. Because of this observation a tria1 of estrogenic hormone in a11types of patients with metastatic carcinoma of the breast was undertaken. Estrogens have been found to be beneficia1 in 40 to 45 per cent of patients who are more than five years postmenopausa1 [17]. Benefit is obtained onIy when the estrogen is used in very high pharmacoIogic dosages. The ora dose of ethiny1 estradio1 is I mg. three times a day; stiIbestroI,5 mg. three times a day; and Premarin,@ IO mg. three times a day. Lower doses give a Iower response rate, and higher dosages do not increase the response rate. Estrogens given to premenopausa1 femaIes may cause exacerbation of the disease or at times no change [I?]. This statement is based on the use of estrogen in onIy eIeven premenopausa1 femaIes. It may be of interest to study more premenopausal females using rather massive doses of estrogen. FoIIowing the administration of estrogen in the postmenopausa1 femaIe, the average Iength of objective benefit is twelve to fourteen months. Estrogens induce such remission primariIy in soft tissue. However, in 20 per cent of the cases they aIso cause recaIcification of bony Iesions. Most cIinicians interested in carcinoma of the breast believe that the direct effect of estrogens on the malignant ceII is one of stimuIation in the same way norma breast tissue is stitiuIated by a combination of estrogen, progesterone and pituitary factors [I I]. It is thought by some that estrogen may be very harmfu1 even in patients in the postmenopausa1 age groups. That the opposite frequentIy occurs may be because estrogens in high dosages suppress pituitary activity with resuItant inhibition of necessary pituitary hormones. Stress incontinence ocUndesirable Efects. curs quite frequentIy, especiaIIy in eIderIy persons, and in a smaI1 percentage of patients it may be so severe that discontinuance of the hormone becomes necessary. Pigmentation of
Baker,
KeIIey
both nippIes occurs almost universaIIy and is more pronounced in darker-skinned femaIes. Sodium retention with consequent water retention in patients with low cardiac reserve is a hazard. The weight must be carefuIIy watched. We usuaIIy put patients on a Iow salt diet when we begin estrogen therapy and administer diuretics and digitalis onIy when needed. Very rareIy do we have to discontinue estrogens because of ffuid retention when these measures are used. Rarely, increased Iibido deveIops. A smaI1 percentage of patients develop spotting and occasiona bIeeding. Withdrawal bIeeding aImost aIways occurs to some degree in patients with intact endometria. In about IO per cent of patients who have received objective benefit with administration of estrogen, withdrawa of estrogens after reIapse wil1 produce an additiona1 short-lived response. HypercaIcemia is the most serious complication of estrogen therapy and does occur in about 8 per cent of patients receiving estrogens. Withdrawal of estrogens and administration of intravenous &rids and cortisone may be necessary to counteract this complication. HypercaIcemia is thought to be reIated to acceIeration of tumor growth in bone. However, on at Ieast two occasions, we have noticed a relief of hypercaIcemia and an objective remission whiIe continuing estrogen therapy. Perhaps at first estrogen causes an exacerbation by working synergisticaIIy with pituitary hormones, but Iater inhibition of pituitary secretion takes pIace and the over-al1 effect on tumor growth is reversed. CORTICOSTEROIDS
Administration of corticosteroids to patients with metastatic carcinoma of the breast produces objective benefit in about one-third of the patients. The dose of cortisone also must be high, at least IOO to 300 mg. of cortisone or hydrocortisone, or 30 to 60 mg. of prednisone or prednisoIone. Cortisone does not seem to be effective in those patients who have active ovarian function. Cortisone or prednisone causes objective remissions Iasting as Iong as twenty-three months with a median duration of nine months [14]. It is most successfu1 in those patients who have previousIy responded to oophorectomy. The undesirabIe effects of corticosteroids, such as edema, cushingoid facies, hypertension, aggravation or induction of diabetes, peptic uIcerations and bIeeding, may occur in any of the patients receiving cortisone. At the dose necessary in the treat542
and Sohier ment of carcinoma of the breast, cushingoid facies and weight gain are frequentIy present. Once an initia1 response has occurred, the dose can be graduahy reduced, causing a reduction of side effects but no apparent Ioss in effectiveness. Cortisone has its main effect on soft tissue disease, but in a few cases it has produced recaIcification of 0steoIytic Iesions. This is paradoxic since cortisone given to patients without carcinoma of the breast usuaIIy produces hypercaIcemia or hypercaIciuria and osteoporosis, which is characteristic of Cushing’s disease. It is probable that the inhibition of the growth of ceIIs in carcinoma of the breast within the bone tips the host-tumor reIationship in favor of the host, so that repair of osteoIytic Iesions occurs in spite of the antianabolic effect of cortisone on bone matrix. Corticosteroids have aIso been found usefu1 in the treatment of cerebra1 metastases with convuIsions and, indeed, it is probably the only hormona1 agent that has been successfu1 in the management of such patients. It aIso may be of vaIue in controIIing pIeura1 and abdomina1 effusions. PROGESTERONE
The use of progesterone in the treatment of carcinoma of the breast is presentIy under intensive investigation. EarIy results with have o-alpha-bromo- r I -beta-ketoprogesterone been promising [12]. Seven of thirty-four patients showed objective improvement Iasting up to five and a haIf months. In our clinic, responses have been seen in a few patients receiving doses of 150 to 1,000 mg. of progesterone per week in the form of DeIaIutin.@* At these dosages, no evidence of estrogen effect has occurred, as indicated by nippIe pigmentation or cornification of vagina1 smears. At the present time, a survey is being made on the comparative effects of DeIaIutin and testosterone, and our initial resuIts indicate that DeIaIutin is certainIy no better than testosterone and may be sIightIy Iess effective. SUMMARY
The palliative management of metastatic carcinoma of the breast may be accomplished by either additive or ablative changes in the hormona1 environment of the patient. As yet it has not been possible to predict those patients * (I 7-alpha-hydroxyprogesterone-IT-n-caproate), E. R. Squibb & Sons, New York.
HormonaI Treatment of Metastatic Carcinoma of Breast who wiI1 and those who wiIl not respond to hormonal therapy. It has been suggested that hormona1 therapy is successfu1 because certain carcinomas of the breast retain enough of their premalignant characteristics to be responsive to progesterone, estrogen and pituitary factors incIuding growth hormone. Those patients who exhibit a response to surgical castration usually respond to another type of hormonal therapy, such as adrenaIectomy, hypophysectomy or additive therapy. Hormone therapy may be combined with other types of treatment for paIIiative effect, such as x-ray therapy and, rareIy, surgery. The conversion of an inoperable carcinoma to an operable one is probabIy not achieved by hormonal therapy. PathoIogic studies wouId seem to back this up, since biopsy during successfu1 hormonal therapy has always demonstrated smaI1 foci of tumor cells. Therefore, those tumors which are inoperable because they involve supraclavicular Iymph nodes, for example, wiI1 probabIy stiII have small metastatic foci present in the nodes after successfu1 antitumor therapy with hormones. We believe that the patients who respond to additive hormone therapy are the same group who respond to ablative hormone therapy, and that a therapeutic tria1 is the only way of distinguishing these patients. Thus, the importance of a carefuI evaluation must be re-emphasized. FinaIIy, aIthough hormonal therapy of carcinoma is palliative, it is extremely beneficial and, when successful, restores very III patients to usefu1 and productive Iives.
7. BULBROOK, R. D., GREENWOOD, F. C. and WILLIAMS, P. C. ParalIel chemical and biological assays of urinary oestrogens after adrenaIectomy and hypophysectomy. In: Endocrine Aspects of Breast Cancer. Edinburgh and London, 1958. E. & S. Livingstone Ltd. 8. ENGEL, L. L. Mechanisms of action of estrogens. In: Vitamins and Hormones, vol. 17. New York, 1959. Academic Press Inc. 9. HAAGENSEN, C. D. Diseases of the Breast. Philadelphia and London, 1956. W. B. Saunders Co. IO. HOLLANDER, V. P., JONAS, H. and SMITH, D. E. Estradiol-sensitive isocitric dehydrogenase in noncancerous and cancerous human breast tissue. Cancer, 1 I : 803, 1958. I I. Hypophysectomy. Edited by 0. H. Pearson. Springfield, III. 1957. CharIes C Thomas. 12. JONSSON, U., COLSKY, J., LESSNER, H. E., ROATH, 0. S., APLER, R. G. and JONES, R., JR. Clinical and pharmacoIogica1 observations of the effects of 9-a-bromo-1 I-Sketoprogesterone in patients with carcinoma of the breast. Cancer, 12: go9, 1959. 13. KELLEY, R. M. and BAKER, W. H. CIinicaI observations on the effect of progesterone in the treatment of metastatic endometrial carcinoma. To be pubIished. Presented at the Conference on the Biologica Activities of Steroids in ReIation to Cancer. Sponsored by the Cancer Chemotherapy National Service Center, Vergennes, Vermont,
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