Bilateral Adrenalectomy for Metastatic Breast Carcinoma Peter W.
Brown, MD; Jose J. Terz, MD; Roger King, MD; Walter Lawrence, Jr., MD
Ninety-five patients who underwent bilateral adrenalectomy for metastatic breast carcinoma are reviewed. An objective remission of tumor was observed in 66% of the patients over the age of 45 years with metastasis limited to soft tissue, osseous, or pulmonary system. In those patients below the age of 45, only 19% had remission irrespective of the sites of metastasis. Thirty-three patients were admitted with no "free interval," with objective remission occurring in 42%. This observation indicates that the "free interval" is not as striking a determinant in selecting adrenalectomy candidates as had been stressed by others. The serial treatment of adrenalectomy followed by chemotherapy after adrenalectomy failure or relapse was shown to objectively benefit 74% of 72 patients evaluated. Sulfokinase activity in breast cancer tissue was studied in 17 patients. The results were not as definitive as reported by others.
for control of human cancer was first as an effective palliative procedure in breast cancer remission with 1896 when Beatson' bilateral oophorectomy. Huggins and Scott,2 in 1945, first discovered that sex steroids were reduced following adre¬ nalectomy; in 1952, Huggins and Bergenstal:; reported the beneficial response following adrenalectomy for advanced cancer of the breast. Since that time, clinical series have reported objective remissions of breast cancer to adrenal¬ ectomy ranging between 33% and 67%.41" In 1962, the Joint Committee on Endocrine Ablative Procedures and Disseminated Mammary Cancer collected 801 adrenalectomies and 390 hypophysectomies from 13 different institutions." Success achieving palliation was similar with the two procedures. Results were best in those patients with long, free intervals between curative treatment and recurrence of disease, those who lacked substantial pulmonary, hepatic, and central nervous sys¬ tem (CNS) involvement, and those who previously had shown objective response to palliative oophorectomy. This study, as well as others,' has developed basic guidelines for clinical selection of adrenalectomy candidates that are still in use. In an attempt to increase response rates to ad¬ renalectomy, several centers-s have advocated adjuvant
Endocrinrecognized e manipulation reported
Accepted
for publication August 5, 1974. From the Division of Surgical Oncology, Department of Surgery, Medical College of Virginia-Virginia Commonwealth University, Richmond, Va. Read before the 21st annual meeting of the Virginia Surgical Society, Hot Springs, Va, April 26, 1974. Reprint requests to Box 11, 1200 E Broad St, Richmond, VA 23298 (Dr.
Brown).
chemotherapy combined with adrenalectomy and have re¬ ported more favorable response rates than observed after adrenalectomy alone. This concept has been questioned by some who continue to favor selective use of chemotherapy after adrenalectomy failure or relapse. Laboratory meth¬ ods of more precisely predicting adrenalectomy response by the use of biochemical means (estrogen receptor,11 steroid sulfurylation,12 urinary steroid assays,12 and pro¬ lactin suppression by levodopa14) are actively being pur¬
sued both here and at other centers. This report includes our total experience with bilateral adrenalectomies for palliation of recurrent and metastatic breast cancer at the Medical College of Virginia over the six-year period Sept 1,1967 to Sept 1, 1973. In no case was adjuvant chemotherapy utilized as an immediate planned procedure, but subsequent chemotherapy was utilized in many of our patients following adrenalectomy failure or relapse. In most instances, patients were selected for ad¬ renalectomy by using the favorable clinical criteria re¬ ported by the Joint Committee on Endocrine Ablative Procedures and Disseminated Mammary Cancer and oth¬ ers.'
SUBJECTS AND RESULTS
Ninety-five patients with recurrent or metastatic breast cancer subjected to bilateral adrenalectomy by one of three sur¬ geons in the Division of Surgical Oncology at the Medical College of Virginia. Patients with major medical contraindications to sur¬ gery, marked pulmonary insufficiency, extensive brain metastasis, or evidence of substantial hepatic involvement were not consid¬ ered suitable candidates for adrenalectomy. Patients without prior palliative or therapeutic oophorectomy were subjected to a combined bilateral adrenalectomy and oophorectomy. Either the flank (12th rib retroperitoneal) operative approach or the abdomi¬ nal operative approach was utilized for adrenalectomy on this group of patients (Table 1). The overall complication rate was 22%, with the rates being slightly lower in the group employing the flank approach to adrenalectomies. The group with combined ab¬ dominal (for oophorectomy) and flank operative approaches were usually our "high-risk" patients, and the complication rate in this small series (five of eight patients) was substantially higher than in the overall group. Three patients died within 30 days of surgery (3% mortality), one from progression of disease and two from sus¬ pected pulmonary emboli. Clinically useful objective response to adrenalectomy was con¬ were
sidered to be a measurable remission of tumor evident for at least six months, an interval thought to be long enough to fully justify the operation. Forty-four of 95 patients (46%) experienced an ob¬ jective remission for six months or longer. An additional nine pa-
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Table
1.—Postoperative Complications: Surgical Approach Abdominal
Flank Approach for
Approach (56 Pa¬ tients)
Complications Respiratory
Adrenalectomy
With
or
Without
Oophorectomy (39 Patients)
(95 Pa¬
tients)
8 10
8
Wound infection Cardiac
Bleeding (intraoperative postoperative
Total
2 15
(27%)
7
(18%)
22
series of postmenopausal patients who were more than ten years after menopause is too small (ten patients) to make a valid judg¬ ment as to response rates (four patients, 40%) after adrenal¬
ectomy.
In 17 patients, the addition of prophylactic oophorectomy at the time of curative treatment of the primary tumor appeared to have no effect on the response to adrenalectomy. The response rate was 49% in those with prophylactic oophorectomy versus 47% in the group without prophylactic oophorectomy.
&
Total
tomy: 18 patients, 47%; with hysterectomy without oophorectomy: six patients, 86%) (zero to ten years), clearly has a better progno¬ sis for response than the menstruating woman (54% vs 27%). Our
(22%)
Free Interval The "free interval" is
tients had measurable regression of tumor lasting for three to six months, giving a 56% objective remission rate for a period greater than three months. For the purpose of evaluation of the factors affecting adrenalectomy response, "responders" in the study are arbitrarily classified as those who had objective remissions lasting six months or longer. At the time of this analysis there are 14 patients who are still alive with continued adrenalectomy remissions. Sixty-nine pa¬ tients are now dead, and there are 12 living patients with postadrenalectomy failure or relapse. The mean survival for all dead patients who did not respond to adrenalectomy was 7.7 months, with a low of less than one month and a high of 64 months. In those patients who responded to adrenalectomy for six months or greater but are now dead, the mean survival was 18.5 months with a low of six and a high of 42 months. The mean time of response to adrenalectomy in 14 patients who are still alive and in remission is 14 months, with a range of six to 66 months, but this figure will ob¬ viously increase with continued follow-up.
FACTORS INFLUENCING ADRENALECTOMY RESPONSE
Age Our
patients ranged
in age from 30 to 63 years. Only six of 32 under the age of 45 responded to endo¬ crine ablation by adrenalectomy. In contrast, 63 patients were above 45 years of age, with 60% responding by the criteria listed. It is quite obvious that patient age was a major factor in the ob¬ jective response rate, and this must have a relationship to the proximity of the patients to the menopausal state.
(19%) patients who
were
Relationship of Patients to Menopause For this analysis the menopausal state was divided into four categories: (1) premenopausal (18 patients), (2) postmenopausal (22 patients), (3) postmenopausal, artificial, from oophorectomy (38 patients), and (4) postmenopausal, artificial with hysterec¬ tomy, without oophorectomy (seven patients). The actively men¬ struating group who underwent bilateral adrenalectomy and oophorectomy had a response rate of only 27% (five patients). The reported response rate to oophorectomy alone in the actively menstruating patient with metastatic breast cancer is usually slightly higher than this. Dao11 reported a 40% response to oopho¬ a premenopausal patient and has suggested that addition of adrenalectomy in this younger group might im¬ prove response rates. Our small series suggests, however, that the combination of oophorectomy and adrenalectomy as the first endo¬ crine manipulative procedure in the premenopausal patient has no advantage over oophorectomy alone. The postmenopausal woman, whether natural (12 patients, 55%) or artificial (from oophorec-
rectomy alone for
tween initial
surgical
generally defined as the period of time be¬
treatment and the appearance of the first
metastasis or recurrence. Patients with a free interval greater than two years ( > 24 months: 26 patients, 16 responders [62%]; > 36 months: 16 patients, 11 responders [69%]) respond better than those with an interval less than 24 months (< 12 months: 24 pa¬ tients, nine responders [38%]). If we consider only those patients receiving curative therapy who then have a free interval of less than two years, 39% (14) were found to respond to adrenalectomy. Of particular interest is the objective response rate of 42% (14 pa¬ tients) in 33 patients who had no prior curative therapy and, therefore, no free interval. These data show that the free interval as an indicator to adrenalectomy response is perhaps not as strik¬ ing a factor as has been suggested in other series.
Palliative
Therapy
Prior to
Adrenalectomy
Forty-one patients underwent adrenalectomy as the first form therapy. Twenty-four of these 41 patients (59%) had a six-month objective response. Twenty-three patients had pallia¬ tive radiation therapy to metastatic sites before adrenalectomy and, of these, only 30% had adrenalectomy remission. Forty-nine patients had prior palliative treatment by either radiation, androgen, or chemotherapy; 40% of this group had a six-month objective response. Our data clearly suggest that "primary" adrenalectomy gives a better response rate than secondary adrenalectomy. Twenty-two of our patients had undergone oophorectomy for palliation prior to adrenalectomy. Twelve of these patients (55%) had no response to oophorectomy and, of these, five patients sub¬ sequently responded to adrenalectomy. Ten patients had objective response to palliative oophorectomy, with four of these patients subsequently responding to adrenalectomy at the time of oopho¬ rectomy relapse. In this small series, the presence or absence of response to therapeutic palliative oophorectomy had no predictive value for subsequent adrenalectomy for the same purpose. This does not negate findings reported in other series that oophorec¬ tomy response is a good predictor of adrenalectomy response. It does, however, suggest that prior oophorectomy response should not be a firm determinant in patient selection for adrenalectomy. of palliative
PATHOLOGIC FINDINGS OF BREAST CANCER
The pathologic findings of the breast cancer in patients in this series was predominantly infiltrating duct carci¬ noma, as would be expected. Three patients with lobular carcinoma and one with colloid carcinoma responded to adrenalectomy, whereas two patients with medullary car¬ cinoma and two of three patients with inflammatory car¬ cinoma did not respond. The number of patients with these less common histologie types is clearly too small for valid conclusions.
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PATHOLOGIC FINDINGS AT THE TIME OF ADRENALECTOMY The adrenal
gland
was
Table 2.—Effect of Pattern of Metastasis
involved with metastasis in 26
cases, with nine of these
patients responding objectively for six or more months (35%). The ovaries were involved in eight cases, with only one six-month responder. The liver had proven metastasis by biopsy examination at the time of adrenalectomy in 13 cases, with four of these patients responding for six or more months. Prior to adrenalectomy, liver metastasis was suspected in eight of these 13 cases by either clinical, biochemical, or scanning techniques. In none of the eight cases in which liver me¬ tastasis was suspected preoperatively and subsequently proved pathologically was there an objective remission. In four of the five cases of pathologically proven liver metas¬ tasis without preoperative clinical suspicion of liver me¬ tastasis, there was an objective adrenalectomy response. Altogether 15 patients in the series were thought to have liver metastasis preoperatively (including the eight proved by biopsy examination), only one of these patients responded for six or more months. At the time of surgery, this one patient had no evidence of liver metastasis. Six other patients had operative approaches through flank in¬ cisions, and the status of their liver pathologic findings was not proved. From these data we have concluded, as have others, that clinical evidence of liver metastasis makes a patient a very poor adrenalectomy prospect. SUBJECTIVE FINDINGS
Preoperative subjective complaints were present in 71 patients, while 24 patients were admitted with physical findings of recurrences without substantial symptoms. The most common complaint was bone pain, which oc¬ curred in 53 patients. When comparing the objective adre¬ nalectomy response in patients with and without subjec¬ tive complaints, there was no difference in the two groups (46% and 47%, respectively). Subjective response to endo¬ crine ablation is difficult to assess, but virtually all pa¬ tients showing evidence of objective response had im¬ provement in symptoms if symptoms were present prior to adrenalectomy. PATTERN OF METASTASIS
analysis of the effect of sites of metastasis on adre¬ nalectomy patients, this series has been separated into groups either above or below the age of 45. In patients less than 45 years of age, the response rates and length of re¬ missions after adrenalectomies were uniformly low. In pa¬ tients over 45 years of age who had soft tissue and bony metastasis, alone or in combination, there was an adrenal¬ ectomy response rate of 68%, with a mean remission pe¬ riod of 21 months (Table 2). Those patients over the age of 45 with pulmonary metastasis, with or without soft tissue and bony metastasis, had a response rate of 61% with a mean remission of 13 months. In patients with preopera¬ tive evidence of liver, visceral, and/or CNS metastasis, the adrenalectomy response rate was poor, irrespective of the age. For
on
Adrenalectomy Response No. of No. of Responders Patients (%) Below Age 45 Years
Status
Soft tissue and/or bone only Soft tissue and/or bone plus pulmonary All other (liver, viscera, CNS, and
hypercalcemia)
All
3
(25)
8
2
(20)
mo
12 1 (8) 6 (19) 32 Above Age 45 Years
cases
Soft tissue and/or bone only Soft tissue and/or bone plus pulmonary All other (liver, viscera, CNS, and
hypercalcemia)
All
12
Mean Remission of Responders,
38
26(68)
21
18
11(61)
13
(14) (60)
18
7
cases_63
1 38
RESPONSE TO CHEMOTHERAPY FOLLOWING ADRENALECTOMY FAILURE
Chemotherapy was utilized as palliative treatment af¬ adrenalectomy failure or relapse in only 55 of our 95 patients. Fourteen of our patients are in continued adre¬ nalectomy remission and have had no trials of chemother¬ apy as yet. Twenty-six patients with adrenalectomy fail¬ ure or relapse received no chemotherapy. Twenty-three of these 26 patients had adrenalectomy failure with a rapidly deteriorating course following surgery, with a mean sur¬ vival of only 2.6 months. Two patients were in adrenal¬ ectomy remission and died suddenly, while one patient has refused chemotherapy following adrenalectomy relapse. In those patients who had neither adrenalectomy or chemotherapeutic response, the mean survival was only 7.8 months. The patients who had response to adrenal¬ ectomy but no subsequent response to chemotherapy at the time of relapse had a mean survival of 18.5 months. In patients responding initially to adrenalectomy and subse¬ quently responding to chemotherapy, the mean survival ter
27 months. These data can be
was
employed to estimate the clinical re¬ planned program of serial use of adrenal¬ ectomy followed by chemotherapy only when failure or re¬ lapse becomes evident. These estimates can be utilized for comparison with data from a planned combined adrenal¬ ectomy and chemotherapy approach, as proposed by Wil¬ sponse to
son
et
a
al.5
Combining the 17 patients with adrenalectomy response who did not ever receive chemotherapy with those pa¬ tients who received chemotherapy at some time after ad¬ renalectomy, there were 72 patients on whom a response to serial treatment can be evaluated. An objective re¬ sponse to
one or
both of these treatment methods
have
(74%)
despite the fact that only 55 of these 72 patients thus far received chemotherapy. It should be stated
was seen
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patients who have received chemotherapy af¬ adrenalectomy were subjected to either multiple com¬ bined or sequential type of regimen, the former approach being the one that is now in common use. The overall chemotherapeutic response of 44% in this series is similar to others,'" although the currently employed multiple com¬ bined drug therapy is often reported as giving a higher that the 55
ter
response rate than this.
BIOCHEMICAL MEANS OF PREDICTING ADRENALECTOMY RESPONSE
The Bulbrook-Hayward discriminant,12 based on the relative urinary excretion of 17-hydroxycorticosteroids and etiocholanolone, has been used by others to attempt to choose patients more likely to have objective response to endocrine ablation. A national cooperative study of uri¬ nary steroid metabolites, in which many of our patients participated, has just been completed. A slightly higher response rate was seen when the discriminant was posi¬ tive in this study, but the differences between the positive and the negative discriminant group are minimal. On the basis of these yet unreported data, it must be considered that these urinary steroid measurements are not clinically useful in case selection for endocrine ablation. The use of other biochemical means for determining hormone dependence of breast cancer is under investiga¬ tion at the Medical College of Virginia, but most patients in this series have not had tissue assays and no patients were actually selected for adrenalectomy on this basis. All recurrent breast cancers with available tissue for assay are presently being analyzed for steroid sulfurylation ac¬ tivity and more recently for estrogen-binding protein ac¬ tivity. To date, breast cancer tissues from 17 adrenal¬ ectomy patients have been analyzed preoperatively for steroid sulfurylation activity. The efficiency of the tumor's ability to synthesize dehy¬ droepiandrosterone more efficiently than 17JS-estradiol has been reported as a ratio. Daolr> reports a ratio of 1, or greater than 1, usually correctly predicts objective adre¬ nalectomy response. Our own results comparing sulfokinase activity in tumor tissue with adrenalectomy re¬ sponses show only limited accuracy. Although 70% (seven of ten) of positive predictions with this assay were fol¬ lowed by objective adrenalectomy response, three of seven specimens (57%) with a negative predictive assay were in¬ correct in terms of the subsequent favorable clinical re¬ sponse. A refinement of this assay that may possibly im¬ prove predictability is currently being evaluated. This assay in combination with the assay of estrogen-binding protein is also being evaluated as a "predictor" without dependence on the laboratory results for the clinical deci¬ sions regarding case selection. Others have utilized these tissue assays for therapeutic decisions, but we hope our "blind" approach may yield data useful for future im¬ provements in the selection process. COMMENT Data from this series agree with previous reports that successful palliation can be achieved by adrenalectomy in
those patients with endocrine-dependent breast cancers. The quality of life is subjectively better and survival is probably prolonged in those patients who actually re¬ spond.17 Factors related to adrenalectomy response do merit review and réévaluation. Age is clearly a factor that markedly influences the ex¬ pected response of the breast cancer patient to adrenal¬ ectomy. Below the age of 45 years in this series, the ob¬ jective response rate after adrenalectomy was only 19%, whereas an objective response rate of 60% was seen in pa¬ tients above 45 years. Free interval prior to adrenal¬ ectomy, prior oophorectomy response, and the pattern of metastasis had little bearing on response in these younger patients since the overall results were so poor. Combined oophorectomy and adrenalectomy in these younger pre¬ menopausal patients was not associated with response rates that were any better than have been reported for the oophorectomy alone. These findings certainly diminish interest in the use of palliative adrenalectomy for the young premenopausal or young castrated patient with metastatic breast cancer. In patients older than 45 years, clinical factors seem much more important in the selection of adrenalectomy candidates than in the younger group. In our series, a longer free interval was clearly a favorable sign but it was not as striking an indicator of objective adrenal¬ ectomy response as reported by others. Those patients with an interval greater than two years had an objective response of 62% as compared to 41% in those with either no free interval or a free interval of less than 24 months, but the response rate of those patients initially admitted with metastatic disease (no free interval) is high enough to diminish the clinical value of the free interval in case selection. In this small series, an objective response to prior palliative oophorectomy also played a minimal role in predicting adrenalectomy response. In patients who did or did not achieve oophorectomy palliation, the response to adrenalectomy was similar and we now omit both of these clinical factors from our process of case selection. Our data confirm those of others that show that the pat¬ tern of metastasis plays a major role in the prediction of an adrenalectomy response. Patients with metastatic can¬ cer limited clinically to the soft tissue, bone, or the pulmo¬ nary system had effective palliation in about 65% of our cases. However, the length of the objective response was shorter in those patients with pulmonary metastasis as compared to those with only soft tissue or bony involve¬ ment. The patients with clinically evident liver, CNS, or visceral involvement uniformly had a very low objective response to adrenalectomy; these patterns should proba¬ bly discourage the choice of palliative adrenalectomy un¬ less current biochemical studies become established as an accurate means of prediction of the few potential "re¬ sponders" in the groups with these clinical findings. The use of adjuvant chemotherapy following adrenal¬ ectomy in patients has been urged by others" on the basis of a response rate to this combination that approaches 70%. Of the patients in this series who received adrenal¬ ectomy, with or without a response, and subsequently re-
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ceived chemotherapy, 74% had objective remission to ei¬ ther adrenalectomy or chemotherapy or both. At this time we believe that adjuvant chemotherapy for all patients has showed no real advantage over the program of the use of palliative chemotherapy following either adrenal¬ ectomy failure or relapse. In addition, our 14 patients in continued adrenalectomy remission have thus far been spared the side effects of chemotherapy, the frequent blood counts required, and the added expense. Although the routine combined use of chemotherapy and endocrine ablation has the obvious rationale of utilizing chemothera¬ peutic agents at a time when the disease may be less ad¬ vanced, the overall clinical data in this study do not ap¬ pear to demonstrate any statistical benefit from this
approach. Encouraging studies utilizing biochemical means to dis¬ tinguish tumor response to endocrine ablation by measur¬ ing urinary steroids, estrogen receptor activity, steroid sulfurylation, or prolactin suppression by levodopa have all recently been reported. Some of these laboratory means for the selection of the most appropriate palliative therapy for an individual patient are clearly important tools for the future, but experience with these methods is too recent for critical analysis at this time. Some of these factors should certainly be studied in all patients prior to the selection of palliative therapy for patients with "re¬ current" breast cancer, if biopsy material is accessible. This approach to patient selection, combined with clinical
criteria, should further increase the response rates we have observed in this series. We are unwilling to utilize these assays for case selection at this time since additional laboratory data are needed to better define their role. Nonproprietary Name and Trademarks of Drug Levodopa-i?ereorfojt)a, Bio-dopa, Dopar, Larodopa. References 1. Beatson GT: On the treatment of inoperable cancer of the Lancet 2:104-107, 1896. 2. Huggins CB, Scott WW: Bilateral adrenalectomy in prostatic
mamma.
Ann Surg 122:1031-1041, 1945. 3. Huggins CB, Bergenstal DM: Inhibition of human mammary and prostatic cancer by adrenalectomy. Cancer Res 12:134-141, 1952. 4. Fracchia AA, Randall HT, Farrow JH: The results of adrenalectomy in advanced breast cancer in 500 consecutive patients. Surg Gynecol Obstet 125:747-756, 1967. 5. Wilson RE, Piro AJ, Aliapoulios MA, et al: Evaluation of adrenalectomy and hypophysectomy in the treatment of metastatic cancer of the breast. Cancer 24:1322-1330, 1969. 6. Schmidt ML, Nemoto T, Dao T, et al: Prognostic factors affecting adrenalectomy in patients with metastatic cancer of the breast. Cancer 27:1106-1111, 1971. 7. Harris HS, Spratt JS: Bilateral adrenalectomy in metastatic mammary cancer. Cancer 24:145-151, 1969. 8. Horsley JS, Meredith A, Sears HF, et al: Adrenalectomy for metastatic mammary cancer. Ann Surg 173:906-912, 1971. 9. MacDonald I: Endocrine ablation in disseminated mammary carcinoma. Surg Gynecol Obstet 115:215-222, 1962. 10. Delarue NC, Peters V, Anderson WS, et al: A reevaluation of the place of major extirpation in the management of patients with metastatic mammary carcinoma. J Can Med Assoc 96:637\x=req-\ 651, 1967. 11. Jensen EV, Block GE, Smith S, et al: Estrogen receptors and breast cancer response to adrenalectomy, monograph 34. National Cancer Institute, 1971, pp 55-70. 12. Dao TL, Libby PR: Conjugation of steroid hormones by breast cancer tissue and selection of patients for adrenalectomy. Surgery 66:162-166, 1969. 13. Bulbrook RD, Greenwood FC, Hayward JL: Selection of breast cancer patients for adrenalectomy or hypophysectomy by determination of urinary 17 hydroxycorticosteroids and aetiocholanolone. Lancet 1:1154, 1969. 14. Minton JP: The response of breast cancer patients with bone pain to L-Dopa. Cancer 33:358-363, 1974. 15. Dao TL: Ablation therapy for hormone-dependent tumors. Ann Rev Med 23:1-18, 1972. 16. Baker LH, Vaughn CB, Al-Sarraf M, et al: Evaluation of combination vs sequential cytotoxic chemotherapy in the treatment of advanced breast cancer. Cancer 3:513-518, 1974. 17. Chamberlain A, Dao TL, Bross ID, et al: Efficacy of adrenalectomy in treatment of patients with metastatic cancer of the breast. Surg Gynecol Obstet 138:891-895, 1974. cancer.
Editorial Comment The authors have generated a well-written retrospective analy¬ sis of their institutional experience with adrenalectomy for carci¬ noma of the breast. They have, however, challenged generally ac¬ cepted dogma by suggesting that the free interval has little relationship to a response, finding no correlation of benefit from oophorectomy with subsequent response to adrenalectomy, and observing that youth diminished the likelihood of response. Jerome J. DeCosse, MD Milwaukee
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Brown, MD; Jose J. Terz, MD; Roger King, MD; Walter Lawrence, Jr., MD
Ninety-five patients who underwent bilateral adrenalectomy for metastatic breast carcinoma are reviewed. An objective remission of tumor was observed in 66% of the patients over the age of 45 years with metastasis limited to soft tissue, osseous, or pulmonary system. In those patients below the age of 45, only 19% had remission irrespective of the sites of metastasis. Thirty-three patients were admitted with no "free interval," with objective remission occurring in 42%. This observation indicates that the "free interval" is not as striking a determinant in selecting adrenalectomy candidates as had been stressed by others. The serial treatment of adrenalectomy followed by chemotherapy after adrenalectomy failure or relapse was shown to objectively benefit 74% of 72 patients evaluated. Sulfokinase activity in breast cancer tissue was studied in 17 patients. The results were not as definitive as reported by others.
for control of human cancer was first as an effective palliative procedure in breast cancer remission with 1896 when Beatson' bilateral oophorectomy. Huggins and Scott,2 in 1945, first discovered that sex steroids were reduced following adre¬ nalectomy; in 1952, Huggins and Bergenstal:; reported the beneficial response following adrenalectomy for advanced cancer of the breast. Since that time, clinical series have reported objective remissions of breast cancer to adrenal¬ ectomy ranging between 33% and 67%.41" In 1962, the Joint Committee on Endocrine Ablative Procedures and Disseminated Mammary Cancer collected 801 adrenalectomies and 390 hypophysectomies from 13 different institutions." Success achieving palliation was similar with the two procedures. Results were best in those patients with long, free intervals between curative treatment and recurrence of disease, those who lacked substantial pulmonary, hepatic, and central nervous sys¬ tem (CNS) involvement, and those who previously had shown objective response to palliative oophorectomy. This study, as well as others,' has developed basic guidelines for clinical selection of adrenalectomy candidates that are still in use. In an attempt to increase response rates to ad¬ renalectomy, several centers-s have advocated adjuvant
Endocrinrecognized e manipulation reported
Accepted
for publication August 5, 1974. From the Division of Surgical Oncology, Department of Surgery, Medical College of Virginia-Virginia Commonwealth University, Richmond, Va. Read before the 21st annual meeting of the Virginia Surgical Society, Hot Springs, Va, April 26, 1974. Reprint requests to Box 11, 1200 E Broad St, Richmond, VA 23298 (Dr.
Brown).
chemotherapy combined with adrenalectomy and have re¬ ported more favorable response rates than observed after adrenalectomy alone. This concept has been questioned by some who continue to favor selective use of chemotherapy after adrenalectomy failure or relapse. Laboratory meth¬ ods of more precisely predicting adrenalectomy response by the use of biochemical means (estrogen receptor,11 steroid sulfurylation,12 urinary steroid assays,12 and pro¬ lactin suppression by levodopa14) are actively being pur¬
sued both here and at other centers. This report includes our total experience with bilateral adrenalectomies for palliation of recurrent and metastatic breast cancer at the Medical College of Virginia over the six-year period Sept 1,1967 to Sept 1, 1973. In no case was adjuvant chemotherapy utilized as an immediate planned procedure, but subsequent chemotherapy was utilized in many of our patients following adrenalectomy failure or relapse. In most instances, patients were selected for ad¬ renalectomy by using the favorable clinical criteria re¬ ported by the Joint Committee on Endocrine Ablative Procedures and Disseminated Mammary Cancer and oth¬ ers.'
SUBJECTS AND RESULTS
Ninety-five patients with recurrent or metastatic breast cancer subjected to bilateral adrenalectomy by one of three sur¬ geons in the Division of Surgical Oncology at the Medical College of Virginia. Patients with major medical contraindications to sur¬ gery, marked pulmonary insufficiency, extensive brain metastasis, or evidence of substantial hepatic involvement were not consid¬ ered suitable candidates for adrenalectomy. Patients without prior palliative or therapeutic oophorectomy were subjected to a combined bilateral adrenalectomy and oophorectomy. Either the flank (12th rib retroperitoneal) operative approach or the abdomi¬ nal operative approach was utilized for adrenalectomy on this group of patients (Table 1). The overall complication rate was 22%, with the rates being slightly lower in the group employing the flank approach to adrenalectomies. The group with combined ab¬ dominal (for oophorectomy) and flank operative approaches were usually our "high-risk" patients, and the complication rate in this small series (five of eight patients) was substantially higher than in the overall group. Three patients died within 30 days of surgery (3% mortality), one from progression of disease and two from sus¬ pected pulmonary emboli. Clinically useful objective response to adrenalectomy was con¬ were
sidered to be a measurable remission of tumor evident for at least six months, an interval thought to be long enough to fully justify the operation. Forty-four of 95 patients (46%) experienced an ob¬ jective remission for six months or longer. An additional nine pa-
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Table
1.—Postoperative Complications: Surgical Approach Abdominal
Flank Approach for
Approach (56 Pa¬ tients)
Complications Respiratory
Adrenalectomy
With
or
Without
Oophorectomy (39 Patients)
(95 Pa¬
tients)
8 10
8
Wound infection Cardiac
Bleeding (intraoperative postoperative
Total
2 15
(27%)
7
(18%)
22
series of postmenopausal patients who were more than ten years after menopause is too small (ten patients) to make a valid judg¬ ment as to response rates (four patients, 40%) after adrenal¬
ectomy.
In 17 patients, the addition of prophylactic oophorectomy at the time of curative treatment of the primary tumor appeared to have no effect on the response to adrenalectomy. The response rate was 49% in those with prophylactic oophorectomy versus 47% in the group without prophylactic oophorectomy.
&
Total
tomy: 18 patients, 47%; with hysterectomy without oophorectomy: six patients, 86%) (zero to ten years), clearly has a better progno¬ sis for response than the menstruating woman (54% vs 27%). Our
(22%)
Free Interval The "free interval" is
tients had measurable regression of tumor lasting for three to six months, giving a 56% objective remission rate for a period greater than three months. For the purpose of evaluation of the factors affecting adrenalectomy response, "responders" in the study are arbitrarily classified as those who had objective remissions lasting six months or longer. At the time of this analysis there are 14 patients who are still alive with continued adrenalectomy remissions. Sixty-nine pa¬ tients are now dead, and there are 12 living patients with postadrenalectomy failure or relapse. The mean survival for all dead patients who did not respond to adrenalectomy was 7.7 months, with a low of less than one month and a high of 64 months. In those patients who responded to adrenalectomy for six months or greater but are now dead, the mean survival was 18.5 months with a low of six and a high of 42 months. The mean time of response to adrenalectomy in 14 patients who are still alive and in remission is 14 months, with a range of six to 66 months, but this figure will ob¬ viously increase with continued follow-up.
FACTORS INFLUENCING ADRENALECTOMY RESPONSE
Age Our
patients ranged
in age from 30 to 63 years. Only six of 32 under the age of 45 responded to endo¬ crine ablation by adrenalectomy. In contrast, 63 patients were above 45 years of age, with 60% responding by the criteria listed. It is quite obvious that patient age was a major factor in the ob¬ jective response rate, and this must have a relationship to the proximity of the patients to the menopausal state.
(19%) patients who
were
Relationship of Patients to Menopause For this analysis the menopausal state was divided into four categories: (1) premenopausal (18 patients), (2) postmenopausal (22 patients), (3) postmenopausal, artificial, from oophorectomy (38 patients), and (4) postmenopausal, artificial with hysterec¬ tomy, without oophorectomy (seven patients). The actively men¬ struating group who underwent bilateral adrenalectomy and oophorectomy had a response rate of only 27% (five patients). The reported response rate to oophorectomy alone in the actively menstruating patient with metastatic breast cancer is usually slightly higher than this. Dao11 reported a 40% response to oopho¬ a premenopausal patient and has suggested that addition of adrenalectomy in this younger group might im¬ prove response rates. Our small series suggests, however, that the combination of oophorectomy and adrenalectomy as the first endo¬ crine manipulative procedure in the premenopausal patient has no advantage over oophorectomy alone. The postmenopausal woman, whether natural (12 patients, 55%) or artificial (from oophorec-
rectomy alone for
tween initial
surgical
generally defined as the period of time be¬
treatment and the appearance of the first
metastasis or recurrence. Patients with a free interval greater than two years ( > 24 months: 26 patients, 16 responders [62%]; > 36 months: 16 patients, 11 responders [69%]) respond better than those with an interval less than 24 months (< 12 months: 24 pa¬ tients, nine responders [38%]). If we consider only those patients receiving curative therapy who then have a free interval of less than two years, 39% (14) were found to respond to adrenalectomy. Of particular interest is the objective response rate of 42% (14 pa¬ tients) in 33 patients who had no prior curative therapy and, therefore, no free interval. These data show that the free interval as an indicator to adrenalectomy response is perhaps not as strik¬ ing a factor as has been suggested in other series.
Palliative
Therapy
Prior to
Adrenalectomy
Forty-one patients underwent adrenalectomy as the first form therapy. Twenty-four of these 41 patients (59%) had a six-month objective response. Twenty-three patients had pallia¬ tive radiation therapy to metastatic sites before adrenalectomy and, of these, only 30% had adrenalectomy remission. Forty-nine patients had prior palliative treatment by either radiation, androgen, or chemotherapy; 40% of this group had a six-month objective response. Our data clearly suggest that "primary" adrenalectomy gives a better response rate than secondary adrenalectomy. Twenty-two of our patients had undergone oophorectomy for palliation prior to adrenalectomy. Twelve of these patients (55%) had no response to oophorectomy and, of these, five patients sub¬ sequently responded to adrenalectomy. Ten patients had objective response to palliative oophorectomy, with four of these patients subsequently responding to adrenalectomy at the time of oopho¬ rectomy relapse. In this small series, the presence or absence of response to therapeutic palliative oophorectomy had no predictive value for subsequent adrenalectomy for the same purpose. This does not negate findings reported in other series that oophorec¬ tomy response is a good predictor of adrenalectomy response. It does, however, suggest that prior oophorectomy response should not be a firm determinant in patient selection for adrenalectomy. of palliative
PATHOLOGIC FINDINGS OF BREAST CANCER
The pathologic findings of the breast cancer in patients in this series was predominantly infiltrating duct carci¬ noma, as would be expected. Three patients with lobular carcinoma and one with colloid carcinoma responded to adrenalectomy, whereas two patients with medullary car¬ cinoma and two of three patients with inflammatory car¬ cinoma did not respond. The number of patients with these less common histologie types is clearly too small for valid conclusions.
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PATHOLOGIC FINDINGS AT THE TIME OF ADRENALECTOMY The adrenal
gland
was
Table 2.—Effect of Pattern of Metastasis
involved with metastasis in 26
cases, with nine of these
patients responding objectively for six or more months (35%). The ovaries were involved in eight cases, with only one six-month responder. The liver had proven metastasis by biopsy examination at the time of adrenalectomy in 13 cases, with four of these patients responding for six or more months. Prior to adrenalectomy, liver metastasis was suspected in eight of these 13 cases by either clinical, biochemical, or scanning techniques. In none of the eight cases in which liver me¬ tastasis was suspected preoperatively and subsequently proved pathologically was there an objective remission. In four of the five cases of pathologically proven liver metas¬ tasis without preoperative clinical suspicion of liver me¬ tastasis, there was an objective adrenalectomy response. Altogether 15 patients in the series were thought to have liver metastasis preoperatively (including the eight proved by biopsy examination), only one of these patients responded for six or more months. At the time of surgery, this one patient had no evidence of liver metastasis. Six other patients had operative approaches through flank in¬ cisions, and the status of their liver pathologic findings was not proved. From these data we have concluded, as have others, that clinical evidence of liver metastasis makes a patient a very poor adrenalectomy prospect. SUBJECTIVE FINDINGS
Preoperative subjective complaints were present in 71 patients, while 24 patients were admitted with physical findings of recurrences without substantial symptoms. The most common complaint was bone pain, which oc¬ curred in 53 patients. When comparing the objective adre¬ nalectomy response in patients with and without subjec¬ tive complaints, there was no difference in the two groups (46% and 47%, respectively). Subjective response to endo¬ crine ablation is difficult to assess, but virtually all pa¬ tients showing evidence of objective response had im¬ provement in symptoms if symptoms were present prior to adrenalectomy. PATTERN OF METASTASIS
analysis of the effect of sites of metastasis on adre¬ nalectomy patients, this series has been separated into groups either above or below the age of 45. In patients less than 45 years of age, the response rates and length of re¬ missions after adrenalectomies were uniformly low. In pa¬ tients over 45 years of age who had soft tissue and bony metastasis, alone or in combination, there was an adrenal¬ ectomy response rate of 68%, with a mean remission pe¬ riod of 21 months (Table 2). Those patients over the age of 45 with pulmonary metastasis, with or without soft tissue and bony metastasis, had a response rate of 61% with a mean remission of 13 months. In patients with preopera¬ tive evidence of liver, visceral, and/or CNS metastasis, the adrenalectomy response rate was poor, irrespective of the age. For
on
Adrenalectomy Response No. of No. of Responders Patients (%) Below Age 45 Years
Status
Soft tissue and/or bone only Soft tissue and/or bone plus pulmonary All other (liver, viscera, CNS, and
hypercalcemia)
All
3
(25)
8
2
(20)
mo
12 1 (8) 6 (19) 32 Above Age 45 Years
cases
Soft tissue and/or bone only Soft tissue and/or bone plus pulmonary All other (liver, viscera, CNS, and
hypercalcemia)
All
12
Mean Remission of Responders,
38
26(68)
21
18
11(61)
13
(14) (60)
18
7
cases_63
1 38
RESPONSE TO CHEMOTHERAPY FOLLOWING ADRENALECTOMY FAILURE
Chemotherapy was utilized as palliative treatment af¬ adrenalectomy failure or relapse in only 55 of our 95 patients. Fourteen of our patients are in continued adre¬ nalectomy remission and have had no trials of chemother¬ apy as yet. Twenty-six patients with adrenalectomy fail¬ ure or relapse received no chemotherapy. Twenty-three of these 26 patients had adrenalectomy failure with a rapidly deteriorating course following surgery, with a mean sur¬ vival of only 2.6 months. Two patients were in adrenal¬ ectomy remission and died suddenly, while one patient has refused chemotherapy following adrenalectomy relapse. In those patients who had neither adrenalectomy or chemotherapeutic response, the mean survival was only 7.8 months. The patients who had response to adrenal¬ ectomy but no subsequent response to chemotherapy at the time of relapse had a mean survival of 18.5 months. In patients responding initially to adrenalectomy and subse¬ quently responding to chemotherapy, the mean survival ter
27 months. These data can be
was
employed to estimate the clinical re¬ planned program of serial use of adrenal¬ ectomy followed by chemotherapy only when failure or re¬ lapse becomes evident. These estimates can be utilized for comparison with data from a planned combined adrenal¬ ectomy and chemotherapy approach, as proposed by Wil¬ sponse to
son
et
a
al.5
Combining the 17 patients with adrenalectomy response who did not ever receive chemotherapy with those pa¬ tients who received chemotherapy at some time after ad¬ renalectomy, there were 72 patients on whom a response to serial treatment can be evaluated. An objective re¬ sponse to
one or
both of these treatment methods
have
(74%)
despite the fact that only 55 of these 72 patients thus far received chemotherapy. It should be stated
was seen
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patients who have received chemotherapy af¬ adrenalectomy were subjected to either multiple com¬ bined or sequential type of regimen, the former approach being the one that is now in common use. The overall chemotherapeutic response of 44% in this series is similar to others,'" although the currently employed multiple com¬ bined drug therapy is often reported as giving a higher that the 55
ter
response rate than this.
BIOCHEMICAL MEANS OF PREDICTING ADRENALECTOMY RESPONSE
The Bulbrook-Hayward discriminant,12 based on the relative urinary excretion of 17-hydroxycorticosteroids and etiocholanolone, has been used by others to attempt to choose patients more likely to have objective response to endocrine ablation. A national cooperative study of uri¬ nary steroid metabolites, in which many of our patients participated, has just been completed. A slightly higher response rate was seen when the discriminant was posi¬ tive in this study, but the differences between the positive and the negative discriminant group are minimal. On the basis of these yet unreported data, it must be considered that these urinary steroid measurements are not clinically useful in case selection for endocrine ablation. The use of other biochemical means for determining hormone dependence of breast cancer is under investiga¬ tion at the Medical College of Virginia, but most patients in this series have not had tissue assays and no patients were actually selected for adrenalectomy on this basis. All recurrent breast cancers with available tissue for assay are presently being analyzed for steroid sulfurylation ac¬ tivity and more recently for estrogen-binding protein ac¬ tivity. To date, breast cancer tissues from 17 adrenal¬ ectomy patients have been analyzed preoperatively for steroid sulfurylation activity. The efficiency of the tumor's ability to synthesize dehy¬ droepiandrosterone more efficiently than 17JS-estradiol has been reported as a ratio. Daolr> reports a ratio of 1, or greater than 1, usually correctly predicts objective adre¬ nalectomy response. Our own results comparing sulfokinase activity in tumor tissue with adrenalectomy re¬ sponses show only limited accuracy. Although 70% (seven of ten) of positive predictions with this assay were fol¬ lowed by objective adrenalectomy response, three of seven specimens (57%) with a negative predictive assay were in¬ correct in terms of the subsequent favorable clinical re¬ sponse. A refinement of this assay that may possibly im¬ prove predictability is currently being evaluated. This assay in combination with the assay of estrogen-binding protein is also being evaluated as a "predictor" without dependence on the laboratory results for the clinical deci¬ sions regarding case selection. Others have utilized these tissue assays for therapeutic decisions, but we hope our "blind" approach may yield data useful for future im¬ provements in the selection process. COMMENT Data from this series agree with previous reports that successful palliation can be achieved by adrenalectomy in
those patients with endocrine-dependent breast cancers. The quality of life is subjectively better and survival is probably prolonged in those patients who actually re¬ spond.17 Factors related to adrenalectomy response do merit review and réévaluation. Age is clearly a factor that markedly influences the ex¬ pected response of the breast cancer patient to adrenal¬ ectomy. Below the age of 45 years in this series, the ob¬ jective response rate after adrenalectomy was only 19%, whereas an objective response rate of 60% was seen in pa¬ tients above 45 years. Free interval prior to adrenal¬ ectomy, prior oophorectomy response, and the pattern of metastasis had little bearing on response in these younger patients since the overall results were so poor. Combined oophorectomy and adrenalectomy in these younger pre¬ menopausal patients was not associated with response rates that were any better than have been reported for the oophorectomy alone. These findings certainly diminish interest in the use of palliative adrenalectomy for the young premenopausal or young castrated patient with metastatic breast cancer. In patients older than 45 years, clinical factors seem much more important in the selection of adrenalectomy candidates than in the younger group. In our series, a longer free interval was clearly a favorable sign but it was not as striking an indicator of objective adrenal¬ ectomy response as reported by others. Those patients with an interval greater than two years had an objective response of 62% as compared to 41% in those with either no free interval or a free interval of less than 24 months, but the response rate of those patients initially admitted with metastatic disease (no free interval) is high enough to diminish the clinical value of the free interval in case selection. In this small series, an objective response to prior palliative oophorectomy also played a minimal role in predicting adrenalectomy response. In patients who did or did not achieve oophorectomy palliation, the response to adrenalectomy was similar and we now omit both of these clinical factors from our process of case selection. Our data confirm those of others that show that the pat¬ tern of metastasis plays a major role in the prediction of an adrenalectomy response. Patients with metastatic can¬ cer limited clinically to the soft tissue, bone, or the pulmo¬ nary system had effective palliation in about 65% of our cases. However, the length of the objective response was shorter in those patients with pulmonary metastasis as compared to those with only soft tissue or bony involve¬ ment. The patients with clinically evident liver, CNS, or visceral involvement uniformly had a very low objective response to adrenalectomy; these patterns should proba¬ bly discourage the choice of palliative adrenalectomy un¬ less current biochemical studies become established as an accurate means of prediction of the few potential "re¬ sponders" in the groups with these clinical findings. The use of adjuvant chemotherapy following adrenal¬ ectomy in patients has been urged by others" on the basis of a response rate to this combination that approaches 70%. Of the patients in this series who received adrenal¬ ectomy, with or without a response, and subsequently re-
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ceived chemotherapy, 74% had objective remission to ei¬ ther adrenalectomy or chemotherapy or both. At this time we believe that adjuvant chemotherapy for all patients has showed no real advantage over the program of the use of palliative chemotherapy following either adrenal¬ ectomy failure or relapse. In addition, our 14 patients in continued adrenalectomy remission have thus far been spared the side effects of chemotherapy, the frequent blood counts required, and the added expense. Although the routine combined use of chemotherapy and endocrine ablation has the obvious rationale of utilizing chemothera¬ peutic agents at a time when the disease may be less ad¬ vanced, the overall clinical data in this study do not ap¬ pear to demonstrate any statistical benefit from this
approach. Encouraging studies utilizing biochemical means to dis¬ tinguish tumor response to endocrine ablation by measur¬ ing urinary steroids, estrogen receptor activity, steroid sulfurylation, or prolactin suppression by levodopa have all recently been reported. Some of these laboratory means for the selection of the most appropriate palliative therapy for an individual patient are clearly important tools for the future, but experience with these methods is too recent for critical analysis at this time. Some of these factors should certainly be studied in all patients prior to the selection of palliative therapy for patients with "re¬ current" breast cancer, if biopsy material is accessible. This approach to patient selection, combined with clinical
criteria, should further increase the response rates we have observed in this series. We are unwilling to utilize these assays for case selection at this time since additional laboratory data are needed to better define their role. Nonproprietary Name and Trademarks of Drug Levodopa-i?ereorfojt)a, Bio-dopa, Dopar, Larodopa. References 1. Beatson GT: On the treatment of inoperable cancer of the Lancet 2:104-107, 1896. 2. Huggins CB, Scott WW: Bilateral adrenalectomy in prostatic
mamma.
Ann Surg 122:1031-1041, 1945. 3. Huggins CB, Bergenstal DM: Inhibition of human mammary and prostatic cancer by adrenalectomy. Cancer Res 12:134-141, 1952. 4. Fracchia AA, Randall HT, Farrow JH: The results of adrenalectomy in advanced breast cancer in 500 consecutive patients. Surg Gynecol Obstet 125:747-756, 1967. 5. Wilson RE, Piro AJ, Aliapoulios MA, et al: Evaluation of adrenalectomy and hypophysectomy in the treatment of metastatic cancer of the breast. Cancer 24:1322-1330, 1969. 6. Schmidt ML, Nemoto T, Dao T, et al: Prognostic factors affecting adrenalectomy in patients with metastatic cancer of the breast. Cancer 27:1106-1111, 1971. 7. Harris HS, Spratt JS: Bilateral adrenalectomy in metastatic mammary cancer. Cancer 24:145-151, 1969. 8. Horsley JS, Meredith A, Sears HF, et al: Adrenalectomy for metastatic mammary cancer. Ann Surg 173:906-912, 1971. 9. MacDonald I: Endocrine ablation in disseminated mammary carcinoma. Surg Gynecol Obstet 115:215-222, 1962. 10. Delarue NC, Peters V, Anderson WS, et al: A reevaluation of the place of major extirpation in the management of patients with metastatic mammary carcinoma. J Can Med Assoc 96:637\x=req-\ 651, 1967. 11. Jensen EV, Block GE, Smith S, et al: Estrogen receptors and breast cancer response to adrenalectomy, monograph 34. National Cancer Institute, 1971, pp 55-70. 12. Dao TL, Libby PR: Conjugation of steroid hormones by breast cancer tissue and selection of patients for adrenalectomy. Surgery 66:162-166, 1969. 13. Bulbrook RD, Greenwood FC, Hayward JL: Selection of breast cancer patients for adrenalectomy or hypophysectomy by determination of urinary 17 hydroxycorticosteroids and aetiocholanolone. Lancet 1:1154, 1969. 14. Minton JP: The response of breast cancer patients with bone pain to L-Dopa. Cancer 33:358-363, 1974. 15. Dao TL: Ablation therapy for hormone-dependent tumors. Ann Rev Med 23:1-18, 1972. 16. Baker LH, Vaughn CB, Al-Sarraf M, et al: Evaluation of combination vs sequential cytotoxic chemotherapy in the treatment of advanced breast cancer. Cancer 3:513-518, 1974. 17. Chamberlain A, Dao TL, Bross ID, et al: Efficacy of adrenalectomy in treatment of patients with metastatic cancer of the breast. Surg Gynecol Obstet 138:891-895, 1974. cancer.
Editorial Comment The authors have generated a well-written retrospective analy¬ sis of their institutional experience with adrenalectomy for carci¬ noma of the breast. They have, however, challenged generally ac¬ cepted dogma by suggesting that the free interval has little relationship to a response, finding no correlation of benefit from oophorectomy with subsequent response to adrenalectomy, and observing that youth diminished the likelihood of response. Jerome J. DeCosse, MD Milwaukee
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