An evaluation of prophylactic castration in the treatment of mammary carcinoma. An analysis of 152 patients

AN EVALUATION OF PROPHYLACTIC CASTRATION I N THE TREATMENT OF MAMMARY CARCINOMA

An Analysis of 152 Patients NORMAN TREVES, M.D.

N 1914 and 1915 two separate reports from I LWO different clinics revived a latent interest in castration, especially surgical, as an adjunct to the treatment of primary operable mammary carcinoma. l‘he first of these, by 1. S. Hordey,l7 reported on twenty-five patients with breast cancer who were prophylactically castrated by bilateral oophorectoniy. However, only one patient had been observed for five years, while fourteen had been followed for a maxinium ot only two years. Horsley’s observation that only two patients had developed reciirrences was not, tliercfore, conclusive cvi- deiice of cure. The iesults of the procedure impressed him so favorably, however, that he routinely performed it on all women with breast canccr who were still menstruating, de- clining to perform the primary operation iE the patient refused castration. This work was carried out by his son G. W. Horsley, whose reports are referred to subscquently.

T h e second report was from the Breast Serv- ice of Memorial Hospital; though published in 19+5;3 it was read in 1944. Of 335 women studied, twenty-four received ovarian radiation as a prophylactic measure. More than 60 per cent of these (fifteen patients) were lcss than 40 years of age. Improvement beyond the expected course was recorded for 37 per cent o f these patients, the survival being from three and a half to fourteen years after castration. This was a small and selected group, since they were predominantly young women with aggres- sire and/or extensive mammary cancer. In- cluded in the group were thirty-two patients with breast cancer who had ovarian irradiation because of menorrhagia incident to uterine niyomas; 22 per cent (seven) were possibly improved. In twelve instances pregnancy com-

From the Breast Service, Mcmorial Center for Cancer and Allied Diseases, New Yo&, New York.

Presented at the Ninth Annual Cancer Symposium of the James Lwing Soriety, April 5, 1956.

Acknowledgment is made of grants-in-aid hy 5. Bernard Joseph and Co. a n d Mr. Maurice Joseph, New York, New York.

Received for publication, January 16, 1957.

plicated the course of breast cancer. Eleven of these patients received pelvic radiation as a prophylactic measure. Seven lived less than one year; the others had been living two, three, four and a half, and eight years respectively.

At the time of the report the authors com- mented: “Owing to the vagaries of the can- cerous diseases and because of the human soil in which the cancer grows and as the result of many other factors, evaluation of castration will always remain out of the realm of exact scientific evaluation. On the other hand, one may obtain a general idea of the value of castration on purely clinical grounds.”S It has taken a period of twelve years to obtain suffi- cient material to assess more fully the value of prophylactic castration.

REVIEW OF THE LITERATURE

Schinzinger,24* 26 reviewing predominantly English reports on therapeutic castration lor mammary cancer, suggested that it might be advisablc to castrate all women of child-bearing age as soon as the diagnosis 01 malignant tumor was made, rather than to wait until recurrence or metastasis appeared. In 1896 Beatson advocated therapeutic ~as t ra t ion ,~ and in 1901 he and some of the discussants of his paper ex- pressed the opinions that a combination of mastectomy and castration might be justified as primary treatment and that castration should not be reserved for patients with disease so advanced as to be generally considered inoperable.6 However, by 191 1, Beatson’s experience with therapeutic castration had convinced him that this procedure should be used only in selected cases.7 Hc did not mention prophylactic castration. There is no evidence that eithcr Schinringer or Beatson ever actually per- Lormed a prophylactic castration; and, indeed, it is not clear that Schinzinger even did the operation as a therapeutic measure. So far as can be asccrtained, castration continued to be used onIy as a therapeutic or paIliative measure in advanced and inoperable cases, in order to retard the progress of metastases or recur-

393

rences that appeared arter the primary operation for breast cancer.

About the middle of the decade from 1931 to 1940, experience with therapeutic ( astration having demonstrated its value to a certain degree, the idea of using the operation to prevent the all-towfrequent recurrences and metastases that lollowed mastectomies with most favorable settings was again conridei-rd. In 1936, SVitherspoon37 suggested that it might be beneficial but stated that clinic a1 experiencc was still lacking. In the same year Dresserll reported that because of the encouraging results of therapeutic castration, he had been routinely irradiating, about ten days alter rnastectomy, the ovaries of women with operable breast cancer, as well as the field of operation and the lymph drainage areas. IYhile none of his patients had been followed long enough at the time of his report to justify actual conclusions, he observed that prophylactic castration appeared at least to delay the appearance of local recurrence or metastasis. He has never ieported fui ther on the value of the method. SittenfielcP advocated sterilimtion as a routine rneasuie in all cases 01 malignant breast tumor. In the course of two and a half years, he used radium kor castration of eleven patients between the ages of 28 and 42 years. He observed that results were more favorable for these patients than for those not castrated and suggested that ooyhorectomy might also be beneficial. In short papers published in I934 and 1935, G. W. Taylor30.31 considered that prophylactic castration by irradiation might be of value. By 1939,33 however, his experience with the procedure showed that the survival 01 prophylactically castrated patients did not differ significantly from that of the unsterilized. For that reason he abandoned secondary therapy.

Nathanson, Rice, and ILfeigsZZ stated that since 1930 certain clinics in the Hal-vard group have routinely castrated by roentgen rays all premenopausal patients with breast cancer. They kelt that sterilization by irradiation was successful il a correct dose was used, and that the dose varied with age-larger doses being required for younger women. Thev also found that urine assay and endometrial biopsy gave uscful inforination on the presence of follicle- stimulating hormones and estrogens and that the information so obtained aided in judging the effectiveness of the irradiation. Successful treatment in thi? series was followed by char- acteristic menopausal symptoms.

394 CANCER kfarrh-dpr.il 1957 Vol. 10

In 1987 Herrell obqeived that breast cancer occurred ten times as often in noncastraie as in castrate women but that i t did appear in 1.5 per cent of the latter. Dargent, writing twelve yeais laler, corroborated a~rrlost exactly Her- rell’s estimate of the proportion of sterile 1% mien who developed malignant le5ions of the breast alter castration-in his series, 1.6 per cent. The analysis of his group indicated that when breart cancer did appear in castiated women, the prognosis was poor. Among women sterilized about the time of the menopause, there was likely to be an extieme delay in the appearance of the breast lesion. The number of castrated patients older than 60 years of age who developed breast cancer was notably high, and he considered that the prognosis was uncertain for this age group.

Costa reported on seven patients prophylactically castrated arid observed for only two and a half years. Because of the small size of the series and the short period of observation, he was not able to draw conclusions from his experience. However, since several authors have suggested that castration of postmenopausal women warrants study, Costa’s series is o l interest because it includes three women who had passed the menopause eighteen month5 to twenty years earlier and in these instances the surgeon had felt that the procedure might have been beneficial. Olch found that menstruation had continued after the age of 50 in 54.7 per cent ok women with breast cancer who were older than 50; this was an incidence five times greater than that of the general population. For this reason he recommended that prophylactic sterilization be considered for wonien of this age, especially for patients showing any sign5 of involutional breast changes.

The first extensive study of prophylactic castration with five-year-survival rates was published by G. W. HorsleylB in 1917.15 This report continued the previously mentioned woik of his father. In 1951,16 he reported on 21 1 patients treated by radical mastectomy only and fifty-five patients who had radical mastectomy plus prophylactic oophorectomy. Of 152 without node involvement at the time of operation, 83.6 per cent (sixty-six) of the noncastrated and 94.1 per cent (sixteen) of the castrated patients lived five or more years. Of the 114 with node involvement at the time of operation, 39.4 per cent (twenty-six) of those receiving mastectomy alone and 63.2 per cent (twelve) of those also castrated survived at least five years. Trout, commenting on Horsley’s

No. 2 PROPHYLACTIC CASTRATION IN BREAST CANCER - Treves 395

paper, remarked that he had carried out cssen- tially the same procedure.

Lehman, discusGng Horsley’s report, stated that he had prophylactically castrated a total of twenty patients, by roentgen rays before 1942 and by oophorectomy since that date. Six of his patients had survived five or more years and nine four or more years. The rest had been more recently operated on. Significantlv, the favorable results occurred almost entirely among those without axillary-node involvement. Lehman lelt that his experience did not definitely prove the advisability of prophylactic castration; however, he was continuing to use the proccduie conservatively until more el. iclence became available.

Siegert carried out prophylactic castration by irradiation in 347 cases of premenopausal breast cancer arid found that patients in this group lived free from recurrence or metastasis on an average of one year and four months longer than did 260 patients not prophylactically castrdted. T h c difference remained regardless o l age, method ok breast treatment, or other factors. Siegert belie1 ed that all patients with breast cancer who were still menstruating should receive oval ian radiation routinely.

Sommers and his associates observed that regardless ol age, 82 per cent of 125 patients with breast tamer treated by mastectomy alone and studied postmortem showed evidence of cortical stromal hyperplasia of the ovaries, a phe- nomenon that he attributed to activity of the hypophysis. Further study of nineteen patients indicated that when oophorectomy was performed with radical mastectomy, those with oval-ian strornal hyperplasia survived an average of forty-seven months, while those with atrophied ovaries livcd only twenty-nine months. Evidence obtained by Sommers et al. also indicated that abnormally active ovarian tissue might be present alter the menopause, $0 that oophorectomy should be considered for older women a5 well as for the younger ones. Women in the older age groups who are definitely postmenopausal but whose vaginal smears show positive evidence of estrogen activity should most certainly be considered as candidates for ovarian ablation. On the Ereast Service at Memorial Hospital, a study on ovarian cortical stromal hyperplasia is at present in progress and will be reported at a later date.

Among 739 patients with breast cancer reported by Smith and Smith, sixty had been prophylactically castrated by oophorectomy either before the appearance of breast cancer,

TARLE 1 DESCRIPTION OF THE SERIES

Total 5-yr. 10-yr. group follow-up follow-up

~ ~ _ _ ~

Years Yeari Years

Group pt. lowcd pt. lowed pt. lowed NO. fol- NO. fol- NO. fol-

Controls* 2893 1935- 2893 1935- 1253 1935- 1945 1945 1940

Prophylactic 152 1932- 111 1932- 76 1932- castration 1955 1950 1945 arid radical mastectomy Irradiation 84 77 52 Oophorcc- 68 34 24

-~~ ~

tomy ._ ~ ~~ ~~

*As controls we have used thc 2893 patients with primary operable breast cancer treated by radical mastectomy at iliIemorial Hospitdl between 1985 and 1945 (1935 and 1940 for ten-year-surbivdl studies).

concurrently with the radical bredst surgeiy, 01

before the appearance of recurrence at a later date. Because of Sornmers, Teloh, and Gold- man’s report or1 the high incidence of cortical slroinal hyperplasia in postmeiiopausal women, Smith and Smith included in their group elepen women who had passed the menopause, 91 per cent of whom had this con- dition. Particularly when axillary nodes were involved and regardless of the type of mds- tectomy, the survival of castrdted patients was significantly longer when compared with that ol noncastrated patients. The poorest results in the group were among those castrated during the five to ten years before and after menopause. Even among them, results were satisfac- tory enough to suggest castration as a routine nicasurc. These authors remarked that these poorer results during the climacteric suggest that “changes referable to the physiologic in- volution of the ovaries augment the clinical malignancy of mammary cancer still furthei.”

DEFINITION OF PROPHYI~ACTIC CASTRATION

Prophylactic castration in this report is de- fined as a surgical or irradiation procedure that totally removes or represses ovarian function and is employed as an adjunct to radical mastectomy lor the purpose of preventing or de- laying metastases or recurrences. Any castration performed before or after mastectomy is also considered prophylactic so long as there is no clinical evidence of residual malignant tumor, recurrence, or metastasis at the time of castration. Prophylactic castration is distinguished from therapeutic castration, the latter being a

396 CANCER illarch-April 1957 Vol. 10

ABLE 2 INTERVAL BETWEEN MhSTECTO1LZY

AND CASTRATION

Castration after Castration before mastectomy, mo. mnstcctoni), mu.

Castration -___~__ - -

group Rv. Med Range Av. Rled. Range

Irradiation 8 7 4 2 1-69 5 6* 5 0 1-9 Oophorec- 12 2 4 4 1-69 -? -

~ ~~ -

tomy

*Five cases only. tone case only, interval unknown.

~- - ~ ~~ -~

procedure perlormed to affect known metastasis or recurrence favorably, thereby preventing progression or causing regression of the lesions. There is inevitably a point at which the difference is confused, since it is possiblc that un- recognized metastasis may be present at the time of prophylactic castration. Indeed, in instances of very prompt recurrence, this seems highly probable.

THE hfEi\lOKI 4 L H c x m T A L SERIES

One hundred and fifty two patients Ljith breast cancer were prophylaLtically castrated at Neniorial Hospital between 1932 and 1955. 4 description of tlie series is given in Table 1. It should be noted that the five-year-survival group is larger than the ten-year group: we continued to collect additional fivc-year-sur- viva1 rates among the admissions from 1945 to 1950, in order to have as many as possible. For controls we have used 2893 patients with primary operable breast cancer treated by radical mastectomy at Memorial Hospital between 1935 and 1945, with the necessary selections for survival studies. Table 2 shows the time a t which castration was done; this ranges from less than one month to sixty nine months after mastectomy. In addition, six patients had been castrated before mastectomy, at intervals o l one to nine months, 101 benign ovarian or uterine lesions. The last full year of follow-up was 1955, though somc patients have been followed into 1956. Eightylour 01 these patient5 received ovarian irradiation, and sixty-eight had oophorectomy to eliminate ovarian function. Forty-two prophylactic castrations were performed during the period 1932 to 1940, seven of them surgical. Since that datc there has been a rather steady decrease in the proportion 01 irradiation and an increase in the proportion of surgical castrations. By 1950 arid 1951, more than half oT the patients were being treated by oophorectomy, and very few have

been treated by irradiation since that time. The review of the literature suggests that this preference represents a general trend. In our series the change was influenced by the observation that twenty-six of tlie patients “castrated” by irradiation menstruated regularly for various lengths 01 time before amenorrhea supervened. This was probably because of in- adequate doses. The doses used by us arc given in Table 3. This ever-present possibility oi in- adequate dosage is another example of and reason for the inferiority of irradiation castration in comparison to surgical castration. Ces- sation of menstruation is desired immediately in these cases, since the setting is usually so unfavorable as to warrant immediate inter- fercricc with ovarian function. Unfortunately, among many radiologists, amenorrhea produced by roentgen rays seems, incorrectly, to be considered synonymous with castration.

FACTORS OF POSSIBLE PKOGNO5TlC SIGNIFICANCE

The following lactors have been analyzed to determine whether they are of prognostic significance: age of patient, size of lesion, node involvement, level of node involvement, location of lesion, pelvic complications, age at puberty, regularity of menstruation, number of children, breast feeding, prel ious administration of hormones, and duration of symptoms before treatment.

Age of Patient. In accordance with widely lield views that the prognosis for breast cancer in young women is poor, it has been the policy at Memorial Center to castrate chiefly premenopausal women. We have, however, also castrated womcn past the menopause when the individual situation seemed to warrant it.

TABLE 3 IRRADIATION DOSE TJSEO TN PROPHYLACTIC CASTRATION*

~-~

Roentgen ray Radium - ~ ~ -~ ______

ATn. DOSP, NO. nose, r Pt. mc. - hr. Pt.

~ - -

300-399 4 1000 1 400-499 2 1200 4 500-599 1 1300 1 600-699 2 1500 5 700-799 G 1800 2 800-899 2 900-999 .5

1000-1 499 41 1 500-1 599 2 1 600-1 699 2 1800-1 899 1

*Average dose, 892 r ; inediai~ dose, 1000 r.

No. 2 PROPHYLACTIC CASTRATION IN BREAST CANCER - Treves 397

TABLE 4 SIZE O F LESION I\- PROPHYLACTICALLY

CASTRATED PATIENTS

Size of lesion, cm.

Castration group Av. Mcd. Range

Irradiation 3 . 0 3.0 0.5-12.5 Oophorectomy 4 .1 3 .0 1.0-11.0

The agcs ol the women in the oophorectomy ancl irradiation groups differ very little. The average and median ages ok the eighty-four who received ovarian irradiation were 37.6 and 37.5 years; the youngest was 24 and the oldest 55. 01 the sixty-eight surgically castrated patients, the avcrage and mcdian ages were 37.8 and 38.5 years; the youngest was 27 and the oldest 57. Thus, age could have little influence on any difference between the two groups in survival time.

Size of Lesion. T h e average size of the lesions was 1.1 cm. larger in the surgically castrated group than in the irradiated; that is, 3 cm. in the irradiated series and 4.1 cm. in the surgically castrated group (Table 4). The median values wcrc 3.0 cm. for both. Ranges varied only slightly. If size ot lesion is considered a criterion for degree ot malignancy, the difference in average sizes may be considered a sign of poorer prognosis in the surgically castrated group.

Node Inuol-iiement. Harrington’s s t idy l3 demonstrated the widely accepted observation that the presence of axillary-node involvement is a more reliable index of prognosis than any other factor. In the present study, axillary node$ were involved in 66.7 per cent 01 the patients castrated by irradiation, 72.1 per cent of those castrated by oophorectomy, and 69.1 per cent of the total castration series (Table 5). The percentage of patients with node involvement in tlic total control group is 57.6 per cent. Thus, on the basis of axillary-node involvement, it is obvious that the total series of castrated patients had a poorer initial prognosis than the controls and that the oophorectomy group had a poorer prognosis than the irradi-

TABLE 5 NODE INVOLVEMENT

Involve- No in- Arot ment volvement stated Total

Castration groiip No. I, No. % No. % No. %

Irradiation 56 66.7 26 30.9 2 2 . 4 84 55.3 Oophorectomy 49 72.1 18 26.5 1 1.4 68 44.7

TOTAL 105 69.1 44 28.9 3 2.0 152 100.0 - -_ - -

ated group. This is to be remembered in con- junction with the finding, discussed more com- pletely later, that survivals and intervals before recurrence were both longer among the oophorectomy group.

Level of Node Involi~ement. Bccause in the earlier years of the study, lcvcl of node involvement was not noted, we have data on this factor for only eighty-eight patients (Table 6). Among the fifty-six irradiated patients, the level of involvement was noted for forty-onc. For 26.8 per cent of the fifty-six, the level was not stated. Inx,oolvement was at level I in 7.1 per cent, level I1 in 17.9 per cent, and level I11 in 48.2 per cent. Of the forty-nine in the surgically castrated group, node involvement was at level I for 14.3 per cent, lcvel I1 for 22.4 per cent, and level IT1 for 59.2 per rent; level was not stated for 4.1 per cent. These observations corroborate Harrington’s findings that among cases with node involvement, there tends to be a greater percentage with the higher levels of involvement.

TABLE 6 LEVEL OF NODE IYVOLVEMENT

Not Level I Level TI Level I11 stated

Castrat,ion -~ ~ ___ ~~ Total, No. % hTo. C& No. No. R no.

Jrradiation 4 7.1 10 17.0 27 48.2 15 26.8 56 Oophorectomy 7 14.3 11 22.4 29 59 .2 2 4.1 49

TOTAL 11 10 .5 21 2 0 . 0 56 5 3 . 3 17 16.2 105

~~ .~ group -~

- - - - -

Location of Lesion. The largest proportion of breast lesions occur in the upper outer quadrant 01 the breast. According to figures collected by Lewison, betwecn 45 and 60 per cent of all breast cancer develops in this region. In our total castrated group (Table 7), tlie percentage of lesions lying in tlie upper outer quadrant, 50.0 per cent, is somewhat closer to Lewison’s lower limit than to his upper one. T h e 59.6 per cent for the irradiated series lies close to his upper limit, and the 38.2 per cent for the oophorectomy series falls below his lower level. Statistically, the difference between these two figures might well occur by chance; i t is therefore not conclusive.

Other reports collected by Lewison indicated that between 12 and 14 per cent of lesions occur in the lower outer quadrant, a percentage considerably higher than that (5.3 per cent) found €or our series.

Lewison’s review indicated that in general between 17 and 20 per cent of lesions are found in the upper inner quadrant. In our series, the

398 Vol. 10 CANCER , lfarch-Apiil 1957

TARIX 7 LOCATION OF LESION

.- _ _ _ ~ Irradiation Oophorertom y Total

-___ ____ 07 Location p\ 0. /c No. 70 h-0. /o

c7

Outer quadrant 53

Inner quadrant 12

Center 12 Entire breast 3 Unkriown 4

TomL 84

Upper 50 59.6 Lvwer 3 3 . 5

Upper 10 11.9 Lower 2 2 . 4

-

63.1 26 5

10 3

14.3

14.3 3.5 4 . 8

100.0

31 45.6 84 55.3

4.4 22 32.3

1 1 . 5 1 1 . 5

68 100.0 -

20 13.1 5 3 . 3

34 22.4 4 2 . 6 5 3 .3

152 100.0 __

lesion wa5 in this location in 14.7 per tent ok the oophorectomy cases and 11.9 per Cent of the irradiation cases, both figurcs below Lewi- son's range. Lesions in the lower inner quadrant were also lewer, 3.3 p c ~ ccnt for the total group as compared with 5 and 6 per cent for other total series. The most conspicuous deviation trom other series was the strikingly high percentage of central lesions in the oophorectomy group, 32.3, compared with 9 to 22 per cent for other series. I t is also o f interest that lesions in the inner and central regions of the breast werc more numerous in the oophorectomy than in the irradiation series.

Urban, studying a series 01 350 cases of breast cancer lrom Memorial Hospital, found that result? of operation werv particularly poor among patients ~7i th lesions in the inner quadrants and in the subareolar area. The former he explained as resulting from the proximity of the lesion to lymphatics leading into the internal mammary nodes; the latter from the increase in the nurnbcr of lymphatic vessels that had a wider distribution to multiple regional nodes. In this study, the [act that 31.4 per cent of all patients and 52.9 per cent of those castrated by oophorectomy had lesions in the inner quadrants. in the subareolar ai ea, or inkolving the entire breast suggests a poorer prognosis. However, the statistically small nuinbcr of such lesions (fifty-eight) among 152 cases may not justify positive conclusions.

Pelvic Complicatzons. Among patients castrated by irradiation, 19.0 per cent were treated because of benign pelvic conditions. In six in- stdnccs sterilization was carried out between one and nine months before mastectomy; and in fifteen, between less than one month and sixty-nine months after the primary operation. In only three instances was oophorectomy performed for pelvic complications, at periods of three, thirteen, and seventeen months respcc- tively after mastectomy. Tn addition, two patients werc surgically castratcd because of pregnancy.

Age a t Puberty. According to Crosscn and Crossen, the age at which menstruation begins varies considerably. I t rarely begins belore 10 years of age, ordinarily occurs during the twclfth to fourteenth years; dclay into the six- teenth year may-but not necessarily-indicate a menstrual abnormality.

Using these observations as a basis for comparison, age at puberty has been studied to learn whether there might be any abnormali- ties among the group that might suggest a pre- disposition to cancer of the breast, the possibility of estrogenic imbalance being the most likely association. This factor ~7as recorded for 152 patients. The data are given in Table 8; 43.6 per cent of the irradiated and 35.9 per cent of the castrated deviated from the average for age at puberty. Such variations occur, of course, among women who do not have brcast

TSRLE 8 rZGE OF PITBERTY AND MENSTRU.\L HISTORY

Menstruation ~

No. pt. reaching puberty aC age: No. Av. Med. Regular Irreg. Rec. irreg. Unknown Total

Castration g u m ~ 9 10 11 12 13 14 15 16 17 18 known yr. y r . NO. Yc NO. % NO. % KO. % NO. "/o un- age, age, -__ - - ~

Irradiation 1 1 4 10 13 8 9 4 4 1 29 13.4 13.7 5 2 61.9 9 10 .7 5 5.9 18 21.5 84 100 Oophorectomy 0 4 6 15 13 6 4 3 0 2 15 1 2 . 9 13 .4 56 82 .4 3 4 . 4 3 4 . 4 6 8 . 8 68 100

TOTAL 1 5 10 25 26 14 13 7 4 3 44 13.2 13.5 108 71.1 1 2 7 . 9 8 5 . 2 24 15.8 152 100 - - - - - _ _ _ _ _ _ _ _ _ _ _

No. 2 PROPHYLACT~C CASTRATION IN BREAST CANCF.R - Treves 399

cancer. We have not found studies that assist us in ascertaining whether or not our deviation incidence is higher than might be expected.

Regularity of iVlenstruation. hlenstruation was reported as regular in 61.9 per cent ot patients sterilized by irradiation and irregular only recently in 5.9 per cent (Table 8). The recent irregularities were usually in patients nearing the menopause. Among the surgically castrated patients, menstruation was regular in 82.4 per cent and irregular only recently in 4.4 per cent. (For 21.5 per cent of the irradiated and 8.8 per cent of the surgical group this information was not stated.) The difference be-

T-4BLE 9 HISTORY OF CHILDBEARING

Oophorec- Irradiation tomy Total ____-

Group No. !& No. % No. % Patientswith 21 25 .0 19 2 7 . 9 40 26.3

Patients with 61 72.6 48 70 .6 109 71.8 no children

children Unknown 2 2 . 4 1 1 . 5 3 1 . 9

TOTAL 84 100.0 68 100.0 152 100.0 ,4vcrage num-

__ -~ _-

berofchildren 2 . 1 2 . 3 2 . 2

tween the two groups is too slight to be significant in a serics of this size. Except for irregu- larity, no information in regard to menstruation was recorded.

N u m b e r of Children. The 1940 data for average size of lamily in the United States,35 while not exactly comparable, serve at least as a rough yardstick for comparimn with our data, 1910 lalling at the approximate mid- point of our years studied. In 1910, about 25.8 per cent ot. American women were single. hlar- ried women had an average of 2.2 children each; 21.2 per cent had only one child, and only 3 pcr cent of all children belonged to families with six to nine children. Whether these averages represent “normal” or not we do not know.

The data for our series are in Table 9. 01 the irradiated patients, the percentage with no children (25.0) is almost identical with the national figure for unmarried women. Slightly more (27.9 per cent) of the surgically castrated women were childless. In view of the small size of our series the differcnce cannot be called significant, and we cannot offer evidence that childbearing is or might be related to the breast cancer.

The average size of family was also tlose to the national average (Table 9). The average number of children is 2.2 both for the national group and for our series. In coniparison with the national average, both our groups had more patients with only a single child; 22.9 per cent for irradiated and 27.1 per cent tor surgically castrated. Among the women treated surgically, one each had seven and ten children, while only one irradiated patient had as large a iamily (nine). In sum, the average family size is about the same in the two series, and in general there is no significant difference from the average for this factor.

Breast Feediitg. Rcports concerning breast feeding were available for forty-eight of the sixty-one mothers castrated by irradiation. Of these, 66.7 per cent reported that they nursed their babies and 33.3 per cent that they did not. Of the forty-eight surgically castrated mothers, information on breast feeding was a \ ailable for thirty-three. Of these, 60.6 prr cent stated that they nursed their childrcn. In this series, the proportion of mothers who nursed their babies is very much higher than was reported by Adair; 8.5 per cent of his patients had an “apparently normal mammary history.”l

Hormones Administered Prior to Develop- ment of Breast Cancer. Estrogens have been implicated as contributing to the development of breast canccr. In our irradiated wries, 4.8 per cent had received lemale hormones prior to development of breast rancei in order to

TABLE 10 PIIE\‘IOTIS HORMONE THER 4PV

-

Irradiation Oophorcrtomp Total ~ _____ Hormone

therdpy NO. %> NO. % NO. % Todry upbreast5 4 4 8 2 2 9 6 3 9 Forotherreasons 2 2 4 7 10 3 9 5 9 None 78 92 8 59 86 8 137 90 2

Toi %L 81 100 0 68 100 0 152 100 0 ~ - __

terminate lactatioa, and 2.3 per cent received them for other reasons (Table 10). 0 1 the oophorectorny group, 2.9 per cent received them to terminate lactation and 10.3 per cent for reasons not associated with bieast conditions. These figures are far too few to suggest that the administration of hormones is respon- sible for the development of breast cancer. D u rut io n of Symptoms U r f ore Trea 1 t17 en t .

The irradiation group noted symptoms of cancer on an average 01 8.7 months prior to mas-

400 CAKCER Ma?-ch-April 1957 Vol. 10

TABLE 11 NODE INVOLVEMENT AND SURVIVAL FIVE AND TEN YE.4RS -4FTER MASTECTOMY,

ACCORDING TO CASTRATTON*

Controls Irradiation Oophorrctomy Total _ _ _ _ _ _ _ ~ ~~~~ -

Siirvivals Survivals Survivals Survivals No. h-0. s o . ~ '__ h-0. pt No. % pt. No. 4;: pt. No. pt. No.

5-year survzval Node involvement 1749 689 39 4 51 22 43 1 21 16 76 1 72 38 52 7 No node involre-

ment 1141 884 77 4 25 20 80.0 12 11 91 6 37 31 83 7 TOTAL 2893 1575 54 4 77* 43* 58 1 34' 27 79 4 l l l t 70* 64 8

10-yeav survzval Node involvement 769 163 21 2 30 7 23 3 15 6 40 0 45 13 28 8 No node involve-

ment 481 259 53 8 21 15 71 4 9 8 88 8 30 23 76 6 TOTAL 1253 423 33 8 52* 22 42 3 2 1 14 58 3 76* 36 47 3 *Node involvement unknown in 1 case.

tectomy. The median was less than halt this time, 3.3 months; the range was two weeks to five years. The average duration of symptoms in the surgically castrated series was 12.2 months, the median 3.0 months, and the range one week to six years. Thus, the extreme range has affected the average in both groups. There is no significant difference between the two groups for this factor.

Comment. Judged by the accepted factor ol node involvement, the entire series of castrated patients, especially those treated by ovarian ablation, appears to include a larger than usual proportion of patients with more cxtensive disease. There is also evidence that the oophorectomy group contained a larger percentage of patients with poor prognosis, as evidenced by location of the lesion and the size, the latter of possible prognostic significance. In the case of other factors analyzed, differences between the two series and from normal control value5 were too slight to be statistically significant.

SUR171VAL RATES AFTER hfASTECT0MY

In order to determine the relative merit of the two procedures utilized, five- and ten-year- survival rates, and these in relation to node involvement, have been compiled.

As 1955 was the last full year of follow-up, all patients operated on before and during I950 and adequately followed could have survived hve or more years: therefore patients operated on between 1932 and 1950 have been included in the five-year-survival study. Those operated on between 1932 and 1945 are included in the ten-year-survival study. We do not have enough cases for comparative fifteen- year-survival rates.

tNode involvemerit uriknomii i n 2 cases.

COlltrO15 were the 2893 patients with primary operable breast cancer treated by radical mastectomy at Memorial Hospital between 1935 and 1945 (1935 and 1940 tor ten-year- survival studies). In this series there has been an irregular, but still definite, improvement in survival rate over the years. Since the series of prophylactically castrated patients is 01 somewhat more recent date than the control group, considerable caution is necessary in drawing conclusions from slight, or ex en moderate, dif- terences in statistics.

Fzve-Year-Survival Rates. One hundred and eleven patients were included in the study on five-ycar survival. For the total group, the rates appear improved relative to those of the controls, 64.8 per cent and 54.4 per cent respectively (Table 11). However, as stated, the difference may not be too significant statistically. As seen from Table 11, node involvement definitely lowers survival in both control and castrated groups. The relatively unimpressive results in the total series appear to be due to the fact that in the large group of irradiated patients followed (seventy-seven), the five-year- survival rate is similar to that for the controls (58.1 and 54.4 per cent respectively). The first clear-cut and qtatiqtically significant improve-

T.4RI.E 12 NUMBER OF RECURRENCES IN PROPHY-

LACTI CALLY CASTRATED PAT1 ENTS, ACCORDING TO NODE INVOLVEMENT

~~

Irradi- Oopho- Nodc involvement ation rectoniy Total

Node involvement 38 25 63 No node involvement 9 2 11 Not stated 2 1 3

T O T ~ L 49 28 77 - - -

No. 2 PROPHYLACTIC CASTRATION IN BREAST CANCER - Treves 40 1

ment appears in the group that was surgically castrated: survival rates for both group, tho5e with and those without node involvement, ale considerably higher than survival rates for controls. The patients with node involverrient showed the most outstanding gain, 76.1 per cent survival as compared to 39.4 per cent survival among the controls. The 91.6 per cent survival for no nodc involvcrrient appears very encouraging. Thus it appeals that at the five- year level, irradiation improves slightly, and oophorectorny consider ably, the survival rates, especially in cases of node involvement.

Tun- Year-Suw iun 1 Rn 1 es. Seventy& patients were included in the ten-year-survival study. At the ten-year period there was a change. In the total group of all castrated patients there was a signihcant improvement; 47.3 per cent of the castrated versus 33.8 per cent of the controls libing ten or more years (Table 11). However, at this period, the total improvement depends to a large extent on the group without node involvcment, while those with node involvement have failed to maintain the significant gains mariifcsted at the five- year period. In the irradiated group, the total group shows some difference from the controls: the group with node involvement, little dil- ference from controls; among those without node involvement, the survival rate (71.4 per cent) is significantly better than that of the controls (53.8 per cent). In the surgically castrated group, the survival rate for all patients is clearly better than that for the controls. The

survival rate of patients in the surgically castrated group who had node involvcmerit is 40.0 pcr cent, compared with 21.2 per cent among the controls, but for patients without involvement, 88.8 per cent of the castrated versus 53.8 per cent of the controls survived. T h u s it becomes apparent that the improvement in the total series of surgically castrated patients depends largely on the small number of those without node involvement, eight o f the total of nine living ten or more years. Altogether, the study of the ten-year-survival rates suggests that the improvement in surgically castrated patients notcd at the five-year l e ~ e l represents a definite postponement ot recurrence and a prolongation of life, but not a cure. Continued improvement was found only in the survival of twenty-three of the thirty patients without node involvement.

It is of interest that of thirty-six patients living ten or more years and followed now lor ten to twenty years, only two have had recurrences. One of these, a 44-year-old woman who had irradiation, died thirteen years after mastectomy; the other, a 35-year-old patient who was surgically castrated, died sixteen years alter the primary operation. Both were without node involvement at the time of mastectomy. These facts may indicate that castration may effect a “curc” in a limited number of cases. However, statistics of survival beyond the ten- year period are too few and thirty-six patients too small a number for judging the effectiveness of the operation.

TSRIX 13 RECURRENCE INTERVALS ACCORDING TO METHOD OF TREXTAZENT AND NODE

INVOLVEMENT

Interval

~

Node imolvement No node involvement __ No. Ar . , Med., No. -Xv., Med., pt. mo. mo Range pt. mo. nio. Range Total

~ _ _ _ _ _ -

28 surgically castrattd patients* Castration to 1st subjective symptom 24 25.3 16.0 2-75 2 81.0 - 30-132 26* Mastectomy to recurrence 24 32.7 27.0 3-82 2 105.0 - 4-167 26* Survival after 1st subjcctive symptom 24 13.6 11.0 2-35 2 13.0 - 12-14 26* To death of discasc 22 47.9 42.5 5-113 1 177.0 - - To death of other causes, cancer present 1 27.0 - Living with disease 2 48.5 - 29-68 0 ~ 2 49 irradiation-treated patients 7 Castration to 1st subjective symptom 38 19.6 10.0 1-82 9 39.8 24.0 2-96 471 Mastectomy to recurrence 38 23.3 13.5 1-83 9 50.6 27.0 12-156 47t Survival after 1st subjectire symptom 38 9 . 5 7 . 5 1-50 9 10.8 11.0 2-32 47t To death of disease 33 27.9 20.0 2-89 8 66.8 43.5 19-156 41

4 2 Lii-ing with disease 2 81.3 - 8-83 0 -

23 2 - 1 59.0 ~

- ~ -

To death of other causes, cancer present 3 48.0 42.0 15-87 1 18.0 - - - -

- ~

*On 1 patient with node iiivolvement we had no data on the various intervals; node involvement was unknown for a second patient. Neither patient is included in the study on average, median, and range, though the first is included in the died of disease group.

tOn 2 patients neither node involvement nor course is known.

STUDY OF CASES WITH RECURRENCE AFTER CASTRATION

Since the study of survival rates suggested that the castration delayed recurrences, rather than effecting cure, it was decided to consider separately the group with recurrences. Of the entire group of 152 patients, seventy-seven developed recurrences (Table 12). Extensive data on recurrence are in Table 13. Forty-nine irradiated patients (58.3 per cent 01 the total eighty-four) and twenty-eight surgically castrated patients (41.2 per cent of the total sixty- eight) had recurrences. Only nine (18.3 per cent) of the total irradiated patients with recurrences were without node involvement at the time of mastectomy and only two (7.1 per cent) of those surgically castrated. A large proportion of the surgically castrated patients were operated on too recently to have developed recurrences, since the average interval to recurrence after mastectomy in this group was nearly three years, with a range cd three to eighty-two months. Node involvement was not recorded for one surgically castrated and two irradiated patients. Altogether, results 01 the analysis seem more likely to be significant if the study is based primarily on the twenty-five surgically castrated arid the thirty-eight irradiated patients who had involvement of the axillary nodes.

Delay Before Trentment. The average delay before coming for treatment in the group ol surgically castrated patients with node involvement was nine months; that of the irradiated patients was almost Tix months; thc median delays were six and three months, and the ranges less than one month to seventy-two months and less than one month to forty-eight months respectively. The few cases of exceptionally long delay in the oophorectorny group may have had a definite influence upon the average. However, the average delav before treatment, irrespective of node involvement, is 6.3 months for the irradiated group and 8.7 months for the surgically castrated group, with median values of three and five months respectively. Since ranges become more nearly equal in these total groups, it seems probable that there was a somewhat greater delay before coming for treatment among patients treated by surgery than among those treated by irradiation.

Jnterual Between Mastectomy and Cnstra- tion. In patients with node involvement at the- time of mastectomy, the average interval be-

402 CANCER March-April 1957 Vol. 10

tween mastectomy and castration was 5.0 -

months in the irradiated and 10.4 months in the surgically castrated group. Median values were three months for both. Since the longest period was sixty-nine months in the surgically castrated group and twenty-four months in the irradiated group, it is possible that a few cases OP exceptionally long delay bekore castration have affected the average 01 the oophorectoniy series, and the median values may be mole accurate. However, considering the entire series, irrespective ok node involvement, the difference in averages continues, and the ranges become more nearly cqual. Thrre was no great difference in the interval between mastectomy and castration in the two series, but the inteival before castration was somewhat longer among patients treated by oophorectomy.

Interval Betwceii CaJtrntion and Recur- rmce. The average interval between cast1 atioii and the appearance of- the first symptom ol recurrence was longer in the oophorectomy se ries, 25.3 months, than in the irradiated series, 19.6 months (Table 13). This difference is corroborated by the medians: 16.0 and 10.0 respectively. These figurco suggest that wrgical castration causes a gieater delay in the appearance of recuirence than does ovarian irradiation.

Inteioal Betroren hlastectomy lrnd Recul- rencc. The surgically castrated patients lived frce of disease an average of 32.7 months after mastectomy: the irradiated group lived free of disease an average of 23.3 months (Table 13). The medians were 27.0 and 13.5 rcspec- tively. The shortest period free of disease in the surgically castrated series was three months

TABLE 14

SITES OF RECURRENCE -%ND METAUTASIS First Latcr

recurrence, no. recurrence, no. Total

Site of Irradi- Oopho- Irradi- Oopho- recurrence ation rectomy ation rectomv No. 76 ~

Ronc Lung &

pleura Soft parts

& skin Liver Ovaries 8z

uterus Peritoneum Pancreas Stomach Unknown

TOTAL

21 17 4 1 43 40.7 I0 2 4 5 21 19.8

7 4 2 2 15 14.1

5 2 4 2 13 12.3 2 0 2 1 5 4 . 7

1 1 1 0 3 2.8 1 0 0 0 1 0.9 0 0 1 0 1 0.9

0 0 4 3.8

49 28 18 11 106 100.0 - - -

2 2 - -

No. 2 PKOYHYLACTIC CASTRATION IN BREAST CANCER - TPeues 403

TABLE 15 P.%TIEN'TS DYING THREE OR LESS YEARS AND LIVING FIVE AND TEN YEARS AFTER

Alive 10 or more years

h.1 ASTECTOM Y - ~

Dead within 3 years Alive 5 or more years ~~ ~. - __ ____ ____ __

Dead :\live Alive ~- - _ _ ~ ~~~ .. Type of

Fr castration KO. followed No. %b No. followed No. % No. followed No. :L

Irradiation 84 29 34 5 7 7 43 5 8 1 52 22 42 3 14 58 3 Oophorectomy 49* 9 18 4 34 27 79 4 24

TOTAL 133 38 2 8 5 111 70 6.2 8 76 36 47 3 ~ - - __ -

*Nineteen of the 152 patients were admitted after 1952 and cannot be included in survival-rate studies.

and the longest eighty-two rnonths. In the irradiated group, the shortest was one month and the longest eighty-three months. Since the iange is so great, the median values appear to give a more reasonable conclusion, and the median and average values are quite ron- sistent. Thus, patients surgically castrated in this series survived lree of disease after mastectomy approximately nine months longer than those treated by irradiation.

Sur-~&daE After First Synzptom. The interval that patients with node involvement survived alter the appearance of the first symptom of recurrence averaged 9.5 months for the irradiation and 13.6 months foi- the surgery group, with medians of 7.5 and 11.0 iespectively. The ranges were approximately the same and shorter than for man) of the other factors studied. T h u s , the median values may be more accurate. Survival after the appearance of the first symptom ol ieciirrenre was definitely longer alter oophorectomy than a t ter irradiation.

Tota l SuwivaZ. Surgically castrated patients with node involvement at the time ot niastec- tomy who died of disease lived an average of 47.9 months, while those irradiated lived only an average ot 27.9 months, with medians of 42.5 and 20.0 and ranges of five to 113 months and two to eighty-nine months respectively. Thus, patients with node involvenient who had either recurrence or metastatic disease appeared to live almost twice as long it they were surgically castrated than those who received ovarian irradiation.

Sztey of Rec ime17re. As was expected, bone was the most lrequent site of recurrcnce, 40.7 per cent, irrespective of the method of castration. The first recurrence was in bone in twenty-one patients who received ovarian irradiation and in seventeen of those surgically castrated. Subsequent recurrences in bone appeared in four irradiated patients and in one

surgically castrated. Data on site of recurrence, first and subsequent, are given in Table 14.

PROGNOSTIC FACTORS IN CASTRATED PATIENTS DYING W l T H I N THREE YEARS AND TIIOSE

LIVING FIVE AND T E N OR hIORE YEARS AFTER MASIXCXOMY

Patients dying within three years of mastectomy are compared with those living five or more years and ten or more years after radical mastectomy, with respect to the following factors of possible prognostic importance: type of castration, size of lesion, node involvement, breast quadrant involved, delay before treatment, time betwecn mastectomy and castration, age, age at puberty, children il any, including number of them, and administration of estrogens prior to development of cancer.

Of the eighty-four patients treated by irradiation, 34.5 per cent died within three years of mastectomy, compared with 18.4 per cent of those treated by surgical castration (Table 15). The five-year survivals were 58.1 per cent and 79.4 per cent, and the ten-year survivals, 42.3 and 58.3 per cent respectively. Thus, the earlier evidence that surgical castration prolongs life more successfully than sterilimtion by irradiation appears to be corroborated.

Thirty-four patients-all but four of the total thirty-eight (92.3 per cent)-dying within three years had axillary-node involvement at the time of mastectomy. I n comparison 52.7 per cent of the five-year survivors and 36.1 per cent of the ten-year survivors had node involvement (Table 16). This difference was definitely expected.

The si7es of the lesions of those dying within three years averaged 4.7 cm., with a median value of 3.5 cm. The average si7e of lesion was 3.6 cm. and 3.2 crn. for the five- and ten-year survivors respectively. The largest lesion, which measured 12.5 crn., occurred in the group dy-

404 CANCER Maiclz -Afml 1957 Vol 10

TARI F 16 LESION SIZE, NODE Ih\70LVEMENT, i lND QUADR,’INT 4hlOUG THE SURVIVAL GROIJPS

~ __ Breast quadrant involvedt

Size of lesion, Node - Lm * involb ement Inner Outer Center Diffuse

Surbival group No. -4v. Ned. Range KO. NO. % No uo No. % NO. % Dying within

Surbiving 5

Surviving 10

_ _ ~ - - _ _ _ _ _ _ ~ _ _ _ _ _ _ -

_ _ ~

3 yr. 38 4 7 3 5 0.5-12 5 31 92 3 5 13 8 23 63 9 6 16 7 2 5 6

or more yr. 70 3 6 3 4 1-9 38 52 7 14 20 6 36 52 9 17 25 0 1 1 5

or more yr. 36 3 2 3 1 1-7 13 3 6 1 9 2 5 7 17 4 8 6 9 2 5 7 0 - ~

*Site of lesion unknown for 5 patients dying within 3 years, 8 surviving 5 or more years, and 6 surviving 10 or

tQuadrant unknown for 2 patients dying within 3 years; 2 surviving 5 or more years, and 1 surviving 10 or more yedrs.

more years.

ing within three years. These figures corroborate the earlier evidence that the larger lesions in this particular study are probably associated with poor prognosis (Table 16).

Data on breast quadrant involved are $’ riven for the three survival groups in Table 16. The figures do not corroborate the earlier observation that lesions in the inner and central areas are more likely to be associated with poor prognosis than those in the outer quadrants. However, the groups are small, and the differences so slight that the evidence should probably not be coiisidered as seriously con- tradictory, especially in the light of Urban’s report referred to earlier in this paper.

T h e average delay before treatment was 5.8 months among those dying within three years of mastectomy, 6.7 months for the five- year siirvivors, and 4.1 for the ten-year survivors (Table 17). Median values were 1.0, 3.0, and 2.5 months respectively.

Patients dying within three years after mastectomy were castrated on an average of 4.6 months after operation, with a median of 3.1 months. The averages for the five-year and ten- year survivors were 17.0 and 9.6; the medians, 22.9 and 20.0. This considerable gap is indic- ative only of the fact that the patients with poorer prcgnoses, because of age, extent 01 disease, rapidity ol growth, and similar factors, were castrated more promptly than those with more favorable prognoses.

Data for age at admission and age at puberty are listed in Table 18. Patients dying within three years were slightly younger than those living longer, but variations are so slight and the groups so relatively small that differences may not be significant. The age at which puberty occurred is almost identical in the three groups. Thus, age 01 puberty does not appear

in this series to be associated statistically with prognosis.

Data 011 children were available on thirty- seven patients dying within three years, seventy living five or inore years, and thirty-six living ten or more years (Table 19). As can be seen from the table, there was little difference among the groups. Breast feeding was reported in so few instances that analysis would be in- conclusive.

Five patients (13.2 per cent) of the ,group of thirty-eight who died within three years after radical mastectomy had been previously given estrogens; two out of seventy (2.8 per cent) living five years or more and only one out o f the group of thirty-six (2.8 per cent) living more than ten years had received hormones.

DlSCUSSION

The group of prophylactically castrated patients was comprised of patients with a poor clinical setting tor cure, as evidenced by higher degrees of malignancy, slightly larger than average lesions, and an unusually high proportion (38.8 per cent) of lesions in the inner and central parts of the breast. In two patients cancer was especially aggrrssive because of (on- tomitant pregnancy. For this reason it is possible that we should interpret our findings somewhat more liberally than we have lelt justifiable. On the other hand, even though the series is exceptionally large arid the period of observation unusually long, there arc not enough cases to give conclusive information according to methods of statistical analysis. We feel, however, that the improvement in survival rates and the prolongation of life indicated by the study are clear and consistent enough to substantiate our clinical imprewion.

No. 2 PROPHYLACTIC CASTRATION IN BREAST CANCER * Tt-eves 405

recurrences and metastases after radical mastectomy.

Since this analysis does not indicate that prophylactic castration as an adjunct to mastectomy results in cure in a majority of instances, the question arises whether it would be better to withhold castration as a prophylactic procedure and use it only as a therapeutic measure when necessary. However, what is most im- portant is that prophylactic castration apparently does prolong life when the surgical form is used. Patients with node involvement in this series who were treated by oophorectomy lived about nine months longer free from disease than those treated by irradiation, and their total survival time free from recurrence was nearly twice as long. The decision must for the prrsent depend on a carcful clinical evaluation of the patient. However, it doe5 appear that in patients destined to have recurrences, prophylactic oophorectomy delays the recurrence and prolongs life significantly. There- fore, at least in the group with node involvement who are prenienopausal, the pro( edure seems worthy of trial.

T A B L E 17 DELAY BEFORE TREATMENT AND INTERVAT, BETWEEN MASTECTOMY AND CASTRATION

hhlONG THE SIJKVIVAL GROUPS Delay before lnterval between mastectomy, castration 8:

mo.* mastectomy, mo.* Survival group No. Av. bled. Range 417. Med. Range

Dying within 3 vr. 38 5.8 4.0 1-24 4 .6 3 . 1 1-18

Sui‘viving 5 or

Surviving 10 more yr. 70 6.7 3 .0 1-72 17.0 9 . 6 1-69

or more vr. 361 4 . 1 2 .5 1-32 22.9 20.0 2-69

*The following patients were castrated before rdther than after mastectomy and are not included in this data, though the totals include them: 2 patients dyjng within 3 years; 1 surviving 5 or more years, 1 surviving 10 or more years. (The fifth patient with premastectomy castration died between 3 and 5 year5 later.)

?Delay unknown for 1 patient surviving 10 years.

Our finding that irradiation of the ovaries was considerably less effective than oophorec- toiny was not unexpected. It has been our obscrvation that “roentgen-ray castration” does not neutralize ovarian function as desired. It may havc eventual effect, but in these patients iminedzate cessation of the ovarian iunction is desired. Wc have found that the procedure tend? to produce amenorrhea rather than com- pletc cessation of function. In a number of instances, patients so treated have resumed menstruation after a period ol amenorrhea. Vaginal sinears made after treatment have recorded the effect of irradiation as beneficial, but later smears have revealed a return to a normal pattern.

In one instance a patient whose ovaries had been irradiated and who did not men- struate for two years subsequently was deliv- ered at full term ot a normal child. In some instances, after ovarian irradiation, bone metastases definitely regressed but later they were reactivated and were subsequently controlled by oophorectomy. These experiences indicate clinically that surgical castration is prelerable to pelvic irradiation as a method of altering function in an attempt to prevent 01 control

SUMMARY A N D CONCLUSIONS

In patients with breast cancer, two prophylactically castrated groups (irradiation and surgical castration) are compared to each other and to a control group having radical mastectomy only. The series of prophylactically castrated patients, especially the surgically castrated group, included a larger proportion of patients with poor prognosis than did the control Memorial Hospital series patients with primary operable breast cancer treated by radical mastectomy alone.

The survival rates of patients surgically castrated appear to be improved at the five-year level as compared with the control series and the improvement is especially notable among those with node involvement at the time of mastectomy. There appears little evidencc that irradiation improves survival rates, except pos-

TABLE 18 AGE AT ADMISSION .WID AGE AT PUBERTY AMONG THE SURVIl’:\L GROUPS

Age, years No. with Age a t puberty, years -- puberty -

Survival group No. Ax-. Med. Range age known* Av. Med. Range

D37ing within 3 yr. 38 37.0 37.0 24-55 29 13.1 13.2 11-18 Surviving 5 or more yr. 70 38.0 37.7 28-53 47 13.6 1.2 2 9-18 Surviving 10 or more yr. 36 39.3 39.5 28-53 25 13.4 13.6 9-18

*The age of puberty was not stated for thc remainder of the patients in the survival groups.

TA4BLE 19 HISTORY OF CHILDREN AMOKG THE

SURVIVAL GROUPS LVitli Without No. children

children children in family ____ Survival group No. No. o/o No. % Av. Med. Range

Dying within 3 yr. 38* 28 73.7 9 2 3 . i 2 . 1 2 . 0 1-4 Surviving 5 or

more yr. 70 52 74.3 18 25.7 2 . 1 2 . 5 1-10 Surviving 10 or

more IT. 36 23 63.9 13 3 6 . 1 2 . 2 2 . 0 1-9

*No informatkm was available for 1 patient dying wi ihh 3 years.

sibly among those without node involvement. At the ten-j ear level, the improvement is much less, closer to that among the controls. How- ever, if one remembers that the patients in our series had a poorer-than-average prognosis, the surkival rates take on extra meaning even though they may not be outstanding.

The small group of patients without node involvement lived longer if they were castrated, especially by ovarian ablation, than did an equivalcrit group with radical mastectomy alone.

Recurrences after mastectomy in this series appeared on an average of nine months later after bilateral oophorectomy than alter ovarian iri adiation. Patients with recurrences survived ncarly twice as long after mastectomy if they

406 CANCER MarckApr iL 1957 Vol. 10

REFERESCES

had ovarian ablation than iT they had ovarian irradiation.

Comparison of patients dying within three ycars after mastectomy with those living five or more and ten or more years showed that the only striking piognostic factor was node involvement at the time of mastectomy, though delay before treatment, size of lesion, and age of patient were shown to be of some use in prognosis. Evidence for other I'actors was not conclusive.

In our mind it is still an undecided problem whether it would be advisable to reserve castration [or therapeutic use when need arises, or whether, in view of the prolongation of life as indicated by this study, surgical castration should be used as a prophylactic procedure in all cases with very guardcd prognoses, relying on adrenalectomy at a later date should further exclusion of estrogens by ablation be ncccs- sary. The encouraging five-year survivals kor surgically castrated patients with nodc involvcment makes UF feel, however, that the procedure i s worthy ot trial for premenopausal patients with node involvement.

The decision must for the present depend upon a carelul evaluation of the clinical setting of the individual patient.

1. ADAJR, F. E.: Etiological factors of mammary cancer in 200 women; also a control study of 100 norrrial American women. IYew York State /. M e d . 34: 61-68, 1931.

2. ADAIR, F. E.: Cancer of the breast. S. Cli71. LVortit Anrerica 33: 313-327. 1955.

3. ADAIR, F. E.; TREVES, N.; FARROW, J. H., and SCHARNAGEL, I. M.: Clinical effects of surgical and x-ray castration in mammary cancer. J . A . M. A. 128: 161-166; disc. 166.167, 1945.

4. BEATSOS, G. T.: On the treatment of inoperable cases of carcinoma of thc mamma: suggcstions for a new method of treatincnt, with illustrative cases. L.ci72cel 2: 104-107; 162-165, 1896.

5. BFA.I.SON, G. T.: T h e treatment of caucer of the breast by .oophorectorriy arid thyroid extract. Brit. M. J . 2 : 1145-1147; disc. 1147-1148, 1901.

6. BEATSON, G. T.: Cases of carcinoma of the breast treated by X-rays and thyroid extract. Glasgou! M. J. 59: 281-285, 1903.

7. R E . ~ T S O ~ , G . T.: Thc treatment of inoperable carcinoma of the female inamma. Glnsgoru M . J . 76: 81-87, 1911.

8. COSTA, V.: (:astration et hormonothkrapie an- drogkne dam le cancer pFiniitiE du sein de la femme et dam ses metastases. Gynec. et obst. 50: 125-1.58, 1951.

9. CROSSEN, 13. S . , and CROSSEN. R. 1.: Diseases of Women. 9th ed. St. Louis. C. V. hdosby Co. 1941; pp. 760-792.

In. D , i w w r , If.: Carcinoma of the breast in castrated women. Brit. M . J, 2: 54-56, 1949.

11. DRESSER, R.: T h e efCect of ovarian irradiation on

the h i i e metastases of cancer of the breast. Am. J. Roentgenol. 35: 384-388; disc. 388-391, 1936.

12. HARRINGTOS, S. W.: Survival rates of radical mastectomy for unilateral and bilateral carcinoma of the breast. Surgery 19: 164-166, 1916.

13. HARRINGTON, S. W.: Fifteen-year to forty-year survival rates following radical mastectomy for cancer of the breast. A m . Surg. 137: 843-849, 1953.

14. HFRRELL, b'. E.: The relative incidence of mpho- rectomv in women with and without carcirionia of the breast.'Arrc. J . Cancal- 29: 659.665, 1937. i5. HORSLEY, C . W.: Trcatinent of cancer of the

breast in prcmcnopausal patients with radical amputa- tian and bilateral oo'phorectomy. Ann. Siwg. 125: 703- i l l ; disc. 712-717, 1947.

16. HORSLEY, G. W.: Carcinoma of the breast: radical mastectomy, oophorectomy and hormone therapy. Vir- ginia M. Monthly 78: 226-230; disc. 230-231, 1951.

17. HORSLEY, J. S.: Bilateral oophorectomy with radical operation for canccr of the breast. Surgery 15: 590- 601, 1944.

18. HCGGINS, C., and DAO, T. L-Y.: Adrenalectomy and 'oophorectomy in treatment of advanced carcinoma of the brcast. J . A. 34. A . 151: 1388-1394, 1953.

19. IXHMAN, E. P.: Discussion of Horsley, G. W . 1 5 20. TXWISON. E. F.: The problem of prognosis in

cancer of the breast. Surgery 37: 479-506, 195.3. 21. NATIKAKSON, 1. -1.: T h e relationship of hormones

to diseases of the breast. In TWOMBLY, G. H., and PACK, G. T., Eds.: Endocrinology of Neoplastic Diseases; a Symposium by Eighteen Authors. New York. Oxford University Press. 1947; pp. 138-178.

No. 2 PROI'HYIAC 1'1C CASTRATION IN BREAST CANCER ' T 7 C U t . S 407

22. NATHANSON, I. T.; RICE, C., arid MEIGS, J. V.: Horrnonal studies in artificial menopause produced by roentgen rays. Am. J. Obst. & Gynec. 40: 93F-945, 1940.

23. OLCH, I. Y.: T h e menopausal age in women with cancer of the breast. Ant. J . Cancer 30: 563-566, 1937.

24. SCHINZINGTR: Uber Carcinoma mammae. [Abstr.] Centralbl. f. Chir . 16 (29: Bcilage): 35-56, 1889.

25. SCHINZIXGER: Das Karziriorri der Marrima. Miin- cheii. med. TVclinschr. 52: 1724.1 723, 1905. 26. SIEGERT, '1.: Kastration und Mamma-Ca. Strnhleti-

therufiie 87: 62-G4, 1952. 27. Sri IENFIFJ .~ , M. J.: Sterilization of the ovaries as

an auxiliary treatment in cancer of the hreast. Radial . Rev. $- Mis&sifi$i Volley M . J. 5 k 41-43, 1937.

28. SMITH, G. V., and SJII I'H, 0. W.: Carcinoma of the breast; results, evaluation omf X-radiation, and relation of age and surgical castration to length of snrvival. Surg., Gynec. Q Obst. 97: 508-51G, 1953.

29. SOMMERS, S. C.; TELOH, H. A., and GOLDMAT, G.: Ovarian iuflucnce upon survival in breast cancer. A. ,%I. A. Arch. Surg. F7: 91F-919, 1953.

30. TAI-LOR, G. W.: Artificial menopause in carcinoma

of the breast. iVew Bnglnnd J . M e d . 211: 1138-1140, 1934.

31. [TAYLOR, G. It'.]: T h e value of artificial menopause in cancer of the breast. New England J . 1Vfd.

32. 'TavLoK, C;. W.: The rationale of artificial iiieiio- pause in carcinoma of the brcast. A m . J . Roentgenol. 39: 419-421; disc. 421.426, 1938.

33. I'AYLOK, G. W,: Evaluation of ovarian sterilization for breast cancer. Surg., Gynec. b Obst. 68: 452-466, 1939.

34. TROUT, H. H.: Discussion of Horsley, G. W.15 35. UNITED Nxrroxs; STA I'ISTICAT. OFFICE: Demo-

graphic Yearbook 1949-1950; Second Issue. New York. United Nations. 1950; Tables 6 and 7, pp. 215, 224.

36. URBAN, J. A,: Radical mastcctomy in continuity with en bloc resection of the internal inainmary lyrnph- node chain: a new procedure for primary operable cancer of the breast. Cancer 5 : 992-1008, 1952.

37. WITHERsrooN, J. T.: Roentgen irradiation of the ovaries as supplement to surgical and radium thcrapy for tnaniiiiary cancer. Arch. S w g . 33: 554-39, 193F.

213: 1202-1203, 1935.

Documents

An evaluation of prophylactic castration in the treatment of mammary carcinoma. An analysis of 152 patients