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The Surgical Management of Breast Cancer
The Surgical Management of Breast Cancer. DAVID C. SABISTON, JR., M.D., F.A:C.S.* . WILLIAM W. SHINGLETON, M.D., F.A.C.S.**
Carcinoma of the breast continues to represent the most frequent form of cancer in women. Present reports indicate that approximately 60,000 new cases are discovered each year with 24,000 deaths recorded annually as a result of this disease. Despite much research and clinical investigation on this important disorder, considerable disagreement continues concerning the proper method of management. The extremes in opinion vary from those statisticians who suggest that surgical treatment has no demonstrable effect upon the course of this disease to those surgeons who believe that patients with carcinoma of the breast should be treated by super-radical operative techniques. Although controversy continues concerning both the extent of surgery and the use of chemotherapy, careful evaluation of the literature provides convincing eyidence that progress is being made in the understanding and management of this all too prevalent malignant disease.
HISTORICAL ASPECTS
In the latter half of the nineteenth century, the leading European surgeons directed their attention to the operative treatment of carcinoma of the breast. The inadequacy of the procedures performed was clearly documented in the alarming incidence of local recurrence reported by such masters as Billroth and von Bergmann, who published recurrences of 82 per cent and 60 per cent respectively.22 These results were quite similar to those of a number of well known surgeons in Europe at the time (Table 1). From the Department of Surgery, Duke University Medical Center, Durham, North Carolina * Professor of Surgery and Chairman of the Department ** Professor of Surgery
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.N
= =
Table 1. Local Recurrence oj Carcinoma oj Breast Following Surgical Removal Before 1900 Operator.
Biliroth ••• Czemy •••
t:1
:>-
~
Gussenbauer
p
Kilnig •••
w. :>-
KUster •••
tIj
~
Lilcke •••
~z
H.lsted ••• Reglonary"recurrence.
(From Halsted, W. S., Annals of Surgery SO: 497, 1894. By permission of J. B. Lippincott Company, Philadelphia, Pa.)
~ ~
~ ~ w.
:=
I z
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With these statistics as a background it remained for William S. Halsted to devise an operative procedure which drastically reduced the incidence of local and regional recurrences, and in 1894 he reported his classic operation. After reviewing carefully the results in other clinics, Halsted recognized the importance of en bloc removal of the entire breast, pectoral muscles and axillary lymph nodes. Applying these principles in 50 patients, Halsted reported a local recurrence rate of only 6 per cent and late regional recurrences of 16 per cent. 22 These figures provided a drastic reduction in those available up to that time, and within a short period the Halsted radical mastectomy was adopted in many centers. In his original description, Halsted emphasized fifteen points which he considered important in the performance of the operation. There can be little doubt of the fundamental contribution which Halsted made in his concept of radical mastectomy. Although minor technical changes have been advocated from time to time, the concept of en-bloc removal of the breast, pectoral muscles and axillary contents has remained a firm principle in the treatment of carcinoma of the breast. It is interesting to reflect on Halsted's own account of this contribution. In a letter to Dr. William H. Welch dated October 26, 1922, Dr. Halsted made the following remarks: "You ask me to say something of my share in the development of the operation for cancer of the breast. This is pretty clearly stated in my first paper (Johns Hopkins Hospital Reports, 1890 and 1895). Volkmann had recommended stripping the fascia from the pectoralis major 'as for a classroom dissection,' and Heidenhain (Kuster's assistant at Marburg) proposed cutting away the superficial fibers of this muscle. I advised and practised the removal of the entire muscle, leaving in most instances the upper or subclavicular bundles (those above the cephalic vein); I divided the pectoralis minor to further facilitate the cleaning of the axilla. A year or two later Willy Meyer advised removing the minor muscle as well as the major, and I, too, came independently to the conclusion that this might better be done. I insisted that all the tissues should be removed in one piece and upon the meticulous cleaning of the axilla and its aestuaries (subclavicular and supraclavicular fossae). I warned of the danger of excising pieces of malignant tumors for microscopic examination unless the operation followed immediately, and was, I think, one of the first surgeons in this country able macroscopically to make the diagnosis of the common tumors."
PATHOLOGICAL ASPECTS
It has long been recognized that a variety of histological patterns are associated with carcinoma of the breast. While suitable qualifying names for a notation of the cell type and grade of malignancy are of interest, experience has shown that the biological behavior of the tumor is of greater importance. In many instances, more than one form of cell type of differing activity is present in these malignant lesions, and the changes may vary
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considerably from one portion of the tumor to another. The older morphologic classifications such as scirrhous, adenomatous and medullary carcinoma are still employed, but increasing significance is being given the clinical grading of these lesions such as advocated by Haagensen. 18 Thus, the clinical indicators of spread which demonstrate the invasiveness of the tumor (as opposed to the resistance and containment on the part of the host) more fully demonstrate the biologic activity. One of the more important contributions is that of Foote and Stewart16 who described carcinoma in situ of the breast. These and other authors have provided convincing evidence that carcinomas of the breast do arise and can be identified in a pre-invasive state. In those instances in which definitive treatment has been withheld, the development of invasive carcinoma has been amply demonstrated. Attention has also been focused upon the fact that patients with in-situ carcinoma of the breast are apt to have multiple foci of involvement, and in addition bilateral involvement is also common. In a recent series reported by Newman, bilateral disease was present in 6 of 26 patients (23 per cent).S5 TraditioRally, clinical results have been divided into those obtained in patients who had axillary metastases at the time of operation and those who did not. However, more recently the number and location of metastases have been proved to be of considerable importance. A detailed study of axillary node involvement in carcinoma of the breast was undertaken by Pickren at the Presbyterian Hospital-Columbia Medical Center in which clearing of the axillary tissues removed at operation was performed in a consecutive series of patients undergoing radical mastectomy.4. 38 The exact location of every lymph node in the axilla was numbered and plotted on an exact location on a standard diagram. Employing this technique, he found that an average of 38 nodes were found per case, the highest number being 88 and the lowest 8. A total of 204 cases were studied of which 107 were found to have axillary metastases whereas, in the remaining, all nodes were negative. It was interesting that of 31 patients clinically free of cancer eight to ten years following operation, 27 had four or fewer nodes involved by cancer and these were invariably located in the lower two-thirds of the axilla. There were four exceptions in this group. Thus, the number and site of axillary node metastases have been clearly demonstrated to be of great significance in prognosis and should be clearly established in all patients at the time of examination of the specimen. The relationship of age has also been of considerable importance. In a recent study by McDivitt and Stewart, carcinoma of the breast was reported in a group of children. s1 The clinical presentation in each patient was that of a painless mass in the breast adjacent to the nipple and without associated endocrinopathy. The clinical behavior of this type of carcinoma was noted to be less aggressive than its adult counterpart and in no case were regional or distant metastases observed. During prolonged observation, all patients were free of disease up to 15 years. Thus, carcinoma of the
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breast differs from many other forms of malignant disease in thc young by being less invasive. In a study by Moore and Lewis, carcinoma of the breast in women 30 years of age and under was reviewed at the New York-Cornell Medical Center, and the prognosis of these patients was found to be comparable to that in older age groups.34 A majority of the women in the series had operable lesions and the most important factor affecting prognosis was found to be the extension of the disease to the axillary nodes. It was interesting that the prognosis of this disease in this age group was not worse than that for comparable patients in older age groups. Carcinoma of the breast in older age groups was studied by Papadrianos, Cooley and Haagensen.36 In a personal series of 556 patients the five- and ten-year follow-up results in patients 65 years of age and older showed a better prognosis in older women. The figures for five-year survival were considerably better in the 65 and older age group. In an interesting study of carcinoma of the breast discovered in a Cancer Detection Center, Gilbertsen J;eported that two-thirds of breast cancers which occurred in a group of women 45 years or older were found on routine annual physical examination prior to their recogQ.ition by the patient. 17 Three-fourths of these cancers were detected relatively early and were localized to the breast at the time of therapy. Following conventional surgical treatment, survival of patients approached 100 per cent of comparable persons without breast cancer. In another group of patients who were also being followed in the Cancer Detection Clinic, carcinoma of the breast made its existence known only during the interval between the Cancer Detection Center's examinations. Half of these patients had cancers which appeared to be localized to the breast at the time of therapy and these patients obtained a result similar to those in the first group. In the other half in whom breast cancers developed and were recognized only in the interval, these tumors had already spread to lymph nodes at the time of diagnosis. Most of the latter patients achieved such poor survival as to suggest that the cancer may have been biologically more malignant. In addition, they were substantially less amenable to curative therapy.
CLINICAL CLASSIFICATION OF CARCINOMA OF THE BREAST
Although a number of different classifications for carcinoma of the breast have been suggested, one of the most meaningful and useful is that devised by Haagensen. 19 This classification has been widely used and was the basis for a recent International Cooperative Study. The classification utilizes a number of clinical features of breast cancer and is as follows: Stage A. No skin edema, ulceration, or solid fixation of tumor to chest wall. Axillary nodes not clinically involved. Stage B. No skin edema, ulceration, or solid fixation of tumor to chest wall. Clinically involved axillary nodes, but less than 2.5 cm. in transverse diameter and not fixed to overlying skin or deeper structures of axilla.
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Stage C. Anyone of five grave signs of comparatively advanced carcmoma: 1. Edema of skin of limited extent (involving less than one-third of the skin over the breaflt) 2. Skin ulceration 3. Solid fixation of tumor to chest wall 4. Massive involvement of axillary lymph nodes (measuring :l.5 cm. or more in transverse diameter) 5. Fixation of the axillary nodes to overlying skin or deeper structures of axilla Stage D. All other patients with more advanced breast carcinoma, including: 1. A combination of any two or more of the five grave signs listed in Stage C. 2. Extensive edema. of skin (involving more than one-third of the skin over the breast) 3. Satellite skin nodules 4. The inflammatory type of carcinoma 5. Supraclavicular metastases (clinically apparent) 6. Parasternal metastases (clinically apparent) 7. Edema of the arm 8. Distant metastases
It should be emphasized that no distinction as to the size ofthe primary tumor and its position in the breast has been made in this classification. While these features are of importance, their meaning is insufficiently understood and too complex to permit useful classification.
THE NATURAL HISTORY OF CARCINOMA OF THE BREAST
One of the most important features of carcinoma of the breast is an understanding of its natural history. The course of untreated mammary carcinoma provides additional interesting information regarding the therapeutic approaches which have been recommended. Daland collected the histories of 100 untreated patients and found a mean duration of life of 40.5 months. I3 In a similar study, Shimkin reported a mean survival time of 36 months for untreated carcinoma of the breast in women over the age of 75. 40 More recently in a study of 250 untreated cases of breast carcinoma from the Middlesex Hospital in London, Bloom found a five-year survival rate of 26 per cent in the 60--69 age group. 7
SURGICAL PROCEDURES
Halsted's Radical Mastectomy
The basic operation upon which all others for treatment of carcinoma of the breast are to be compared is the Halsted radical mastectomy. It was the advent of this procedure which laid the basis for the modern treatment of carcinoma of the breast and was fully supported by a striking change in
'U J'J' In "
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clinical results. This operation emphasizes the importance of an en-bloc removal of the breast together with the pectoral muscles and axillary contents. Emphasis is also placed on the removal of a sufficient amount of skin to prevent local cutaneous recurrence and it also stresses the importance of complete dissection of the axilla. A majority of surgeons today continue to use this technique in the treatment of most patients with carcinoma of the breast. Although the Halsted procedure is frequently discussed, some of the features and principles of this technique are often insufficiently emphasized. For this reason, Halsted's fifteen points are quoted from his original communication :22 "The operation which has been attended with such surprisingly good results in our hands is performed as follows: 1. The skin incision is carried at once and everywhere the fat. 2. The triangular flap of skin, Fig. 1, is reflected back to its base line. There is nothing but skin in this flap. The fat which lined it is dissected back to the lower edge of the pectoralis major muscle where it is continuous with the fat of the axilla. 3. The costal insertions of the pectoralis major muscle are severed, and the splitting of the muscle, usually between its clavicular and costal portions, is begun, and continued to a point about opposite the scalenus tubercle on the clavicle. 4. At this point the clavicular portion of the pectoralis major muscle and the skin overlying it are cut through hard up to the clavicle. This cut exposes the apex of the axilla.
Figure 1. Diagram showing skin incisions, triangular flap of skin, and triangular flap of fat. (From Halsted, W. S., Annals of Surgery 20: 497, 1894. By permission of J. P. Lippincott Company, Philadelphia, Pa.)
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Figure 2. Diagram showing Halsted radical mastectomy. M, Major pectoral muscle; m, Minor pectoral muscle; S, Apex of infraclavicular fat below the subclavian vessels; Sf, Apex of fat above the vessels. (From Halsted, W. S., Annals of Surgery 20: 497, 1894. By permission of J. P. Lippincott Company, Philadelphia, Pa.)
5. The loose tissue under the clavicular portion (the portion usually left behind of the pectoralis major) is carefully dissected from this muscle as the latter is drawn upwards by a broad, sharp retractor. This tissue is rich in lymphatics, and is sometimes infiltrated with cancer (an important fact). 6. The splitting of the muscle is continued out to the humerus, and the part of the muscle to be removed is now cut through close to its humeral attachment. 7. The whole mass, skin, breast, areolar tissue and fat, circumscribed by the original skin incision is raised up with some force, to put the submuscular fascia on the stretch as it is stripped from the thorax close to the ribs and pectoralis minor muscle. It is well to include the delicate sheath of the minor muscle when this is practicable. 8. The lower outer border of the minor muscle having been passed and clearly exposed, this muscle is divided at right angles to its fibers and at a point a little below its middle. 9. The tissue, more or less rich in lymphatics and often cancerous, over the minor muscle near its coracoid insertion is divided as far out as possible and then reflected inwards in order to liberate or prepare for the reflection upwards of this part of the minor muscle. 10. The upper, outer portion of the minor muscle is drawn upward (Fig. 2) with a broad retractor. This liberates the retractor which until now has been holding back the clavicular portion of the pectoralis major muscle. 11. The small blood vessels (chiefly veins) under the minor muscle near its insertion must be separated from the muscle with the greatest care. These
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are imbedded in loose connective tissue which seems to be rich in lymphatics and contains more or less fat. This fat is often infiltrated with cancer. These blood vessels should be dissected out very clean and immediately ligated close to the axillary vein. The ligation of these very delicate vessels should not be postponed, for the clamps occluding them might of their own weight drop off or accidentally be pulled off; or the vessels themselves might be torn away by the clamps. Furthermore, the clamps, so many of them, if left on the veins, would be in the way of the operator. 12. Having exposed the subclavian vein at the highest possible sub clavicular point, the contents of the axilla are dissected away with scrupulous care, also with the sharpest possible knife. The glands and fat should not be pulled out with the fingers, as advised, I am sorry to say, in modern textbooks and as practised very often by operators. The axillary vein should be stripped absolutely clean. Not a particle of extraneous tissue should be included in the ligatures which are applied to the branches, sometimes very minute, of the axillary vessels. In liberating the vein from the tissues to be removed it is best to push the vein away from the tissues, rather than holding the vein to push the tissues away from it. It may not always be necessary to expose the artery, but I think that it is well to do this. For sometimes, not usually, the tissue above the large vessels is infiltrated. And we should not trust our eyes and fingers to decide this point. It is best to err on the safe side and to remove in all cases the loose tissue above the vessels and about the axillary plexus of nerves. 13. Having cleaned the vessels, we may proceed more rapidly to strip the axillary contents from the inner wall of the axilla-the lateral wall of the thorax. We must grasp the mass to be removed firmly with the left hand and pull it outwards and slightly upwards with sufficient force to put on the stretch the delicate fascia which still binds it to the chest. This fascia is cut away close to the ribs and serratus magnus muscle. 14. When we have reached the junction of the posterior and lateral walls of the axilla, or a little sooner, an assistant takes hold of the triangular flap of skin and draws it outward, to assist in spreading out the tissues which lie on the subscapularis, teres major and latissimus dorsi muscles. The operator, having taken a different hold of the tumor, cleans from within outwards the posterior wall of the axilla. Proceeding in this way, we make easy and bloodless a part of the operation which used to be troublesome and bloody. The subscapular vessels become nicely exposed and caught before they are divided. The subscapular nerves mayor may not be removed, at the discretion of the operator. Kuster lays great stress upon the importance of these nerves for the subsequent usefulness of the arm. We have not as yet decided this point to our entire satisfaction, but I think that they may often be spared to the patient with safety. 15. Having passed these nerves, the operator has only to turn the mass back into its natural position and to sever its connection with the body of the patient by a stroke of the knife repeating the first cut through the skin."
Superradical Mastectomy
With the passage of time, a number of modifications have been introduced in the treatment of breast carcinoma. In 1899 Halsted himself advocated supraclavicular dissection as a part of radical mastectomy, but later abandoned it since he felt the results did not warrant a procedure of
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this radical a nature. In 1952, Wangensteen reported an extended radical procedure including the supraclavicular area, the internal mammary chain and the anterior mediastinum. 44 In such a dissection, he found positive nodes in 60 per cent of the cases which otherwise would have not been suspected. Handley23 and Urban also advocated internal mammary node dissection. 43 In general, the primary indication for superradical procedures has been in those patients with interquadrant or subareolar tumors. This is associated with the fact that parasternal lymph node involvement is often the first sign of recurrence in patients with interquadrant lesions. Although there are some statistical reports of increased survival of superradical operations, the majority of surgeons do not believe their use justified, particularly in relation to the increased morbidity and mortality with which they are associated. Modified Radical Mastectomy A number of surgeons have advocated modifications of the Halsted radical mastectomy. Patey and Dyson in 1952 reported preservation of the pectoralis major muscle in performance of radical mastectomy.37 This method was also supported by Handley.23 In this country, Madden has advocated a modified radical mastectomy in which both the pectoralis major and minor muscles are retained and he feels that the results obtained justify continued use. 33 These techniques have firm advocates who believe them to be justifiable on the basis of clinical results. Simple Mastectomy Combined with Radiotherapy In 1941, McWhirter, an Edinburgh radiologist, began a significant study in collaboration with a number of surgeons in that city and region. 32 They initiated a policy of simple mastectomy combined with irradiation for the treatment of all cases of mammary carcinoma. A collective review of 1882 patients in this series between 1941 and 1947 was published by McWhirter in 1955. In this group the absolute five-year survival rate was 42 per cent and the ten-year survival rate 25 per cent. Although the figures were challenging, a number of authorities in the field, including Ackerman l and Clagett,9 have challenged this technique. For example, in studying McWhirter's patients, Ackerman found a number who had considerable morbidity associated with the irradiation. Marked changes including dermatitis, fractures, and subsequent amputation were observed. Haagensen has criticized the McWhirter technique on the basis that it is not a true simple mastectomy from the anatomical point of view but is rather a partial mastectomy.1 8 He considers the treatment primarily radiotherapeutic. Clagett has presented evidence in a comparable group of patients from the Mayo Clinic with five-year survival during the period 1941-1947 (which was the time covered by the Edinburgh experience) as showing a 59.3 per cent five-year survival for patients treated by radical mastectomy as opposed to 48.1 per cent in the Edinburgh experience by simple mastectomy
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THE SURGICAL MANAGEMENT OF BREAST CANCER
Results of Various Forms of Surgical and Radiation Treatment for Carcinoma of the Breast
Table 2.
RESULTS AUTHORS
TREATMENT
Dahl-Iversen Superradical and Tobiassen12 Mastectomy
CLASSIFICATION
NUMBER
A B C D
277 61 20 8
(Per cent 5-Year Survival) 77 48 50 37 Total: 70%
Williams and Curwen47
Radical Mastectomy plus Irradiation
A B C D
68 57 16 1
72 60 38 0 Total: 63%
Haagensen and Cooley 18
Radical Mastectomy
A B C D
344 138 63 11
84 59 43 18 Total: 72%
ButcherS
Radical Mastectomy
A B C D
216 135 48 26
76 48 48 11 Total: 60%
Handley and Thackray24
Conservative Radical Mastectomy
A B C D
77 58 8 0
75 57 25 Total: 65%
Kaae and Johansen'8
Simple Mastectomy plus Irradiation (McWhirter's Method)
A B C D
159 28 9 3
70 50 22 0
Kennedy and Miller'o
Simple Mastectomy
A B C D
115 34 18 45
62 41 22 13
Total: 64%
Total: 45% Baclesse 5
Irradiation only
A B C D
50 86 95 200
54 67 41 13 Total: 35%
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and irradiation. Although the McWhirter method attracted considerable attention and a number of followers, it now appears to be less popular than previously.
Treatment of Breast Cancer by Local Excision The first reported operations for carcinoma of the breast were essentially local excisions. The poor results attended by this procedure were well known, and it was this fact that led Halsted to the concept of the radical mastectomy. Nevertheless, interest has continued in this form of therapy, especially for well selected patients. Thus, in 1943 Adair reported results of local excision in a group of eight patients in whom this procedure alone was done with an 88 per cent five-year survival. 2 In a selected series, Porritt reported segmental mastectomy in 74 patients followed by postoperative irradiation with a five-year survival of 65 per cent. 39 In a recent discussion of this subject, Crile stated that the five-year survival rate of a group of 20 patients with carcinoma of the breast treated by local excision was 65 per cent.lO Patients were selected for local excision on the basis of peripheral location of the tumors and without evidence of metastasis. Although he does not recommend that breast carcinoma be treated in this fashion routinely, he emphasizes that in special situations a peripherally located lesion may be managed in this manner.
ADJUNCTS TO RADICAL MASTECTOMY
Several adjuncts to surgical removal of the breast have been employed for many years in treatment of patients with potentially curable carcinoma. The major adjuncts are (a) preoperative or postoperative irradiation, (b) oophorectomy and (c) chemotherapy. Unfortunately, firm statements cannot be made at this time regarding the relative efficiency of these adjuncts to radical mastectomy in treatment programs, since it is now generally agreed that valid conclusions concerning their use can be drawn only from random studies in large groups of patients. Opinions expressed on the basis of selected series, despite careful evaluation, may be misleading. These adjuncts to radical mastectomy for treatment of breast carcinoma are currently undergoing evaluation in randomized studies, participated in by teaching centers in various parts of the country. These studies should give more objective answers to the efficacy of the adjuncts currently employed. The first of these studies, begun in 1958 and completed in 1961, concerned the evaluation of the adjunctive use of a chemotherapeutic drug triethylenethiophosphoramide (Thio-TEPA) given to patients in a randomized fashion in conjunction with the standard radical mastectomy for treatment of potentially curable breast carcinoma. This study, which included approximately 830 patients with one-half treated and one-half controls, is now approaching the five-year follow-up phase in the study. The effects of
I,
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the chemotherapeutic drug on the survival rate of these patients remains to be determined. However, analysis of data concerning the time interval between operation and tumor recurrence in those patients who had recurrence revealed that the chemotherapeutic drug was of benefit in delaying onset of recurrence in one category of patients, namely, premenopausal patients who had axillary lymph node metastasis. This group of patients showed a significant delay in time of tumor recurrence when compared with controls in this same group. This benefit of the adjunctive chemotherapy, however, was not present for all patients in the study. A second cooperative study was begun in 1961 and remains in progress. This study is statistically designed to evaluate the beneficial effects of another chemotherapeutic agent (5-Fluorouracil), "prophylactic" oophorectomy in premenopausal patients, and "prophylactic" postoperative irradiation when employed with a standard radical mastectomy. No data are available concerning the benefits of these various adjuncts to operation on tumor recurrence time or survival. After a sufficient patient follow-up period, this study should be of great value to the clinician in selection of treatment programs for patients with potentially curable breast carcinoma.
Irradiation PREOPERATIVE IRRADIATION. Views are conflicting concerning the value of preoperative irradiation in potentially curable breast carcinoma. In certain European clinics, this procedure was used routinely for many years. A review of the literature on reported personal series of cases suggests some value of this procedure in some and of no benefit in others.ll A recent report on the use of preoperative irradiation has indicated that this form of treatment can be used with relative safety and without serious impairment of wound healing following radical mastectomy when operation is performed within a few weeks following the conclusion of the radiation therapy.45 The value of this form of treatment, however, cannot yet be evaluated from the standpoint of improved survival of the patients so treated. In general, preoperative irradiation has been used only to a limited extent in treatment programs. POSTOPERATIVE IRRADIATION. "Prophylactic" postoperative irradiation has been used quite extensively as an adjunct to radical mastectomy. The rationale for the use of this form of therapy is based on the assumption that since x-rays and radium have the ability to destroy carcinoma cells they also must possess the power to prevent recurrences after operation. A controversy regarding the efficacy or even the potential harm of this form of therapy has existed since 1920 when Perthes presented his statistics from the Kiel Clinic in Germany.ll This author stated that postoperative irradiation not only failed to prevent recurrences but actually favored their appearance. Dao has recently reported a study on postoperative irradiation which would support this thesis. 15 Many clinics employ postoperative irradiation only in those patients who have involvement of axillary lymph nodes, while others advocate the use of irradiation in those patients with
It
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medial quadrant lesions, the radiation being directed to the supraclavicular area and mediastinum. The question as to whether postoperative irradiation will improve survival in patients with potentially curable cancer of the breast following radical mastectomy cannot be categorically answered from studies reported in literature.
Prophylactic Oophorectomy The reports in the literature which support the thesis that oophorectomy combined with radical mastectomy in premenopausal patients increases survival rate in patients so treated represent personal series of cases without randomization of cases or adequate controlsY· 42 These studies suggest some benefit of castration combined with radical mastectomy in 900 premenopausal patients with breast cancer. However, Kennedy maintains that if a cure is achieved in such patients it is due to the radical mastectomy and that there is no rational basis to believe that the deprivation of estrogen will actually prevent recurrence of tumor growth.29 At best, one would think that there would be only a delay in this recurrence, if it develops. Thus, it is argued that the oophorectomy should be delayed until recurrence does develop, since then the procedure will afford palliation and at the same time establish whether or not the carcinoma is hormonal dependent. This has practical value since other forms of endocrine ablative therapy can then be used to achieve additional palliation. Another argument relative to the castration problem concerns whether surgery or radiation should be used for the castration effect. Endocrine studies have established that surgical castration effects a rapid and complete ablation of ovarian function, whereas radiation castration produces the effect in variable degree and requires a much longer period of time for the effect to take place. 6
Chemotherapy LOCAL CHEMOTHERAPY. Whether wound irrigation after radical mastectomy lowers the incidence of local recurrence appreciably has not been established firmly. The rationale for the procedure is based on the fact that tumor cells can often be found in operative wounds following operation for various malignancies. 3 However, whether the presence of the tumor cells within the wound have any relation to the eventual recurrence of carcinoma at the wound site has not been established. Studies in animals have suggested that wound irrigation with various chemotherapeutic drugs will prevent recurrence of tumor within the wound in these animals. 41 Until more definitive studies have been performed to establish the value of wound irrigation with chemotherapeutic agents, the value of this approach cannot be established. SYSTEMIC CHEMOTHERAPY. Reference has already been made to findings in the first breast cancer adjuvant chemotherapy study relative to the value of triethylenethiophosphoramide (Thio-TEPA) used in conjunction with radical mastectomy. Although the early results of this study do
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suggest some benefit in premenopausal patients with axillary node involve~ ment, the effects of this drug on survival rate of patients with breast carci~ noma who have received it and had radical mastectomy must await further studies. The adjuvant use of other chemotherapeutic agents has not been similarly evaluated and until such time that adequate evaluation has been performed in random studies, the use of these agents as adjuncts to radical mastectomy in potentially curable breast carcinoma will remain substanti~ ated. Suffice it to say that from data presently available it appears that patients with distinct metastatic lesions have not been cured by intravenous chemotherapy.
COMPLICATIONS OF RADICAL MASTECTOMY
Radical mastectomy may be accompanied by certain psychological reactions and cosmetic defects which do not result in major problems for the majority of patients. The complication of radical mastectomy which has been most distressing to the patient and the surgeon and which has received the greatest attention is the development of lymphedema of the arm. Halsted21 described this condition and termed it "elephantiasis chirurgica." He first called attention to the fact that the condition could result from blockage of lymphatics or occasionally from blockage of underlying veins. He recognized that infection was usually related to faulty wound healing which aggravated the condition. The role of postoperative irradiation therapy in development of lymphedema of the arm is difficult to evaluate. Recent studies reported by Danese et al. using lymphangiography indicated that postmastectomy lymphedema is a direct consequence of axillary lymphatic obstruction. 14 Regeneration of resected lymphatics appears to be inadequate to estab~ lish satisfactory flow. When obstruction to lymphatics is severe, a pro~ gressive disease occurs with disappearance of the lymphatic vessels as the end result. Approximately 50 per cent of patients after radical mastec~ tomy will show some degree of edema of the arm although in most it is slight and transient. In 5 to 10 per cent of patients the edema may be quite pronounced and even disabling. The patient with lymphedema of the arm is subject to the development of occasional bouts of lymphangitis and cellulitis of the affected extremity. The organism commonly involved is Staphylococcus aureus. l l A patient who has undergone a radical mastec~ tomy should be warned to avoid infection of the hand and the fingers, since minor infections may lead to a superficial cellulitis of the arm accompanied by pain, swelling, and redness of the upper extremity. This complication is treated with appropriate antibiotics. Many attempts have been made to improve the lymphedema which develops after mastectomy. Elevation of the extremity, centripetal massage, hand and arm exercises, and application of vasopneumatic devices have been only partially satisfactory in management of the condition. Injections
I 11'1'
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of hyaluronidase, as suggested by Habif, have been of value in some patients. 2o A more satisfactory procedure for control of this complication when it arises is needed, but the prevention of this complication by careful protection of the axillary vein during operation, by the use of hand and arm exercise (squeezing a rubber ball) following surgery, and elevation of the extremity with the first appearance of edema are each of considerable importance. CARCINOMA OF THE BREAST IN PREGNANCY
For many years, the prognosis of carcinoma of the breast developing during pregnancy was considered to be so serious that it was considered inoperable and incurable. More recently, reports appearing in the literature have indicated that, although it is true that the survival rate of patients with breast cancer in association with pregnancy is lower after radical mastectomy than in nonpregnant patients, some of these cases may be cured by operation. The coexistence of breast cancer and pregnancy is uncommon, estimated to be 2 per cent of all patients with breast cancer. 46 Several studies have shown that patients who develop carcinoma during pregnancy have a higher incidence of axillary node metastasis at the time of operation than do nonpregnant females with cancer. This probably represents a delay in diagnosis due to the fact that the breast is engorged and more difficult to examine than in the nonpregnant female. In a group of 78 patients who underwent radical mastectomy for treatment of carcinoma during pregnancy with axillary node metastasis, the five-year survival was 5 per cent. 25 In 14 additional patients in whom lymph node metastasis was not present, the five-year survival was 61 per cent and the ten-year survival was 40 per cent. There is now general agreement that a radical mastectomy should be performed immediately upon the establishment of a definite diagnosis of mammary cancer, when the condition is found during pregnancy or lactation. Further, studies have indicated that abortion cannot be clearly shown to have a favorable effect on the course of the disease. A follow-up of patients who have had a radical mastectomy for carcinoma of the breast and thereafter become pregnant shows a survival rate equivalent to that of patients who do not become pregnant after their operation. 26 On the basis of these findings, it would seem that patients who have been operated upon for carcinoma of the breast may become pregnant after their treatment without influencing their expected survivalY SUMMARY
Both interest and controversy continue to characterize the status of therapy for carcinoma of the breast. There is general agreement that removal of the breast constitutes the basic principle upon which proper
It
THE SURGICAL JVIANAGF.MEN'f OF BRF.AS'l' CANCF.R
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management is based. While some observers prefer superradical techniques and others modified or simple mastectomy with or without postoperative irradiation therapy, a distinct majority continue to prefer the standard radical mastectomy of the Halsted type. More investigation is being done in the development of adjuvants to surgical therapy. The use of chemotherapy is being evaluated in a national cooperative study, and the early results support its usefulness in slowing the rate of recurrences, especially in premenopausal patients. It is firmly recognized that more work with carefully controlled statistical studies is necessary before further conclusions can be drawn in this field. These approaches, in conjunction with surgical therapy, offer considerable optimism for the future.
REFERENCES l. Ackerman, L. V.: Evaluation of treatment of cancer of breast at University of
Edinburgh (Scotland) under direction of Dr. Robert McWhirter. Cancer 8: 883, 1955. 2. Adair, F. E.: Role of surgery and irradiation in cancer of breast. J.A.M.A. 121: 553, 1943. 3. Arons, M. S., Smith, R. R. and Myers, M. H.: Significance of cancer cells in operative wounds. Cancer 14: 1041, 1961. 4. Auchincloss, H.: Significance of location and number of axillary metastases in carcinoma of the breast: A justification for a conservative operation. Ann. Surg. 158: 37, 1963. 5. Baclesse, F.: Five-year results in 431 breast cancers treated solely by roentgen rays. Ann. Surg. 161: 103,1965. 6. Block, G. E., Vial, A. B. and Pullen, F. W.: Estrogen excretion following operative and irradiation castration in cases of mammary cancer. A preliminary report. Surgery 43: 415, 1958. 7. Bloom, H. J., Richardson, W. W. and Harries, E. J.: Natural history of untreated breast cancer (1805-1933). Brit. M. J. 5299: 213, 1962. 8. Butcher, H. R., Jr.: Radical mastectomy for mammary carcinoma. Ann. Surg. 157: 165, 1963. 9. Clagett, O. T.: Proc. Staff Meet. Mayo Clin. 32: 662, 1957. 10. Crile, G., Jr.: Treatment of breast cancer by local excision. Am. J. Surg. 109: 400, 1965. 11. Cutler, M.: Tumors of the Breast., Philadelphia, J. B. Lippincott Co., 1962, p. 300. 12. Dahl-Iversen, E. and Tobiassen, T.: Radical mastectomy with parasternal and supraclavicular dissection for mammary carcinoma. Ann. Surg. 157: 170, 1963. 13. Daland, C. M.: Untreated cancer of the breast. Surg. Gynec. & Obst. 44: 264, 1927. 14. Danese, Callisto, and Howard, J. M.: Postmastectomy lymphedema. Surg. Gynec. & Obst. 120: 797, 1965. 15. Dao, T. L. and Kovaric, J.: Incidence of pulmonary and skin metastases in women with breast cancer who received postoperative irradiation. Surgery 52: 203, 1962. 16. Foote, F. W., Jr. and Stewart, F. W.: Comparative studies of cancerous versus non-cancerous breasts. 1. Basic morphologic characters. II. Role of so-called chronic cystic mastitis in mammary carcinogenesis. Influence of certain hormones on human breast structures. Ann. Surg. 21: 6, 197, 1945. 17. Gilbertsen, V. A.: Survival of asymptomatic breast cancer patients. Surg. Gynec. & Obst. 122: 81, 1966. 18. Haagensen, C. D. and Cooley, E.: Radical mastectomy for mammary carcinoma. Ann. Surg. 157: 166, 1963. 19. Haagensen, C. D. and Cooley, E.: Treatment of early mammary carcinoma. A cooperative international study. Ann. Surg. 157: 157, 1963.
"
~:
r n·'
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20. Habif, D. Y.: Cited by Haagensen, C. D.: Diiieases of the Breast. Philadelphia, W. B. Saunders Co., 1959, p. 652. 21. Halsted, W. S.: The swelling of the arm after operations for cancer of the breast. Bull. Johns Hopkins Hosp. 32: 309, 1921. 22. Halsted, W. S.: Results of operations for the cure of cancer of the breast performed at Johns Hopkins Hospital from June 1889-January 1894. Ann. Surg. 20: 497, 1894. 23. Handley, R.: Some observations and reflections on breast cancer. J. Roy. ColI. Surgeons, Edinburgh,6: 1, 1960. 24. Handley, R. S. and Thackray, A. C.: Conservative radical mastectomy (Patey's operation). Ann. Surg. 157: 162, 1963. 25. Harrington, S. W.: Carcinoma of the breast. Results of treatment when the carcinoma occurred in the course of pregnancy or lactation and when pregnancy occurred subsequent to operation (1910-1933). Ann. Surg. 106: 690, 1937. 26. Holleb, A. 1. and Farrow, J. H.: Relation of carcinoma of the breast and pregnancy in 283 patients. Surg. Gynec. & Obst. 115: 65, 1962. 27. Horsley, J. S. and Horsley, G. W.: Twenty years' experience with prophylactic bilateral oophorectomy in the treatment of carcinoma of the breast. Ann. Surg. 155: 935, 1962. 28. Kaae, S. and Johansen, H.: Simple mastectomy plus postoperative irradiation by the method of McWhirter for mammary carcinoma. Ann. Surg. 157: 175,1963. 29. Kennedy, B. J., Mielke, P. W. and Fortuny, 1. E. Therapeutic castration versus prophylactic castration in breast cancer. Surg. Gynec. & Obst. 118: 524, 1964. 30. Kennedy, C. S. and Miller, E.: Simple mastectomy for mammary carcinoma. Ann. Surg. 157: 161, 1963. 31. McDivitt, R. W. and Stewart, F. W.: Breast carcinoma in children. J.A.M.A. 195: 388, 1966. 32. McWhirter, R.: Simple mastectomy and radiotherapy in the treatment of breast cancer. Brit. J. Radiol. 28: 128, 1955. 33. Madden, J. L.: Modified radical mastectomy. Surg. Gynec. & Obst.121: 1221, 1965. 34. Moore, S. W. and Lewis, R. J.: Carcinoma of the breast in women 30 years of age and under. Surg. Gynec. & Obst. 119: 1253, 1964. 35. Newman, W.: In situ lobular carcinoma of the breast: Report of 26 women with 32 cancers. Ann. Surg. 157: 591, 1963. 36. Papadrianos, E., Cooley, E. and Haagensen, C. D.: Mammary carcinoma in old age. Ann. Surg. 161: 189,1965. 37. Patey, D. H. and Dyson, W. H.: Prognosis of carcinoma of the breast in relation to type of operation performed. Brit. J. Surg. 2: 7, 1948. 38. Pickren, J. W.: Lymph node metastases in carcinoma of female mammary gland. Roswell Park Memorial Inst. Bull. 1: 79, 1956. 39. Porritt, A.: Early carcinoma of the breast. Brit. J. Surg. 51: 214, 1964. 40. Shimkin, M. D.: Duration of life in untreated cancer. Cancer 4: 1, 1951. 41. Thomas, G. C. and Brown, B. C.: Studies on the prevention of surgical implantation of cancer. Ann. Surg. 151: 581, 1960. 42. Treves, N.: An evaluation of prophylactic castration in the treatment of mammary carcinoma. An analysis of 152 patients. Cancer 10: 393, 1957. 43. Urban, J. A.: Clinical experience and results of excision of the internal mammary lymph node chain in primary operable breast cancer. Cancer 12: 14, 1959. 44. Wangensteen, O. H.: Super-radical operation for breast cancer in the patient with lymph-node involvement. Proc. 2nd Nat. Congress, 1952, p. 230. 45. White, E. C., Fletcher, G. H. and Clark, R. L.: A report of experience with preoperative irradiation for carcinoma of the breast. Ann. Surg. 155: 948, 1962. 46. White, T. T. and White, W. C.: Breast cancer and pregnancy: Report of 49 cases followed 5 years. Ann. Surg. 144: 384, 1956. 47. Williams, 1. G. and Curwen, M. P.: Total mastectomy with axillary dissection and irradiation for mammary carcinoma. Ann. Surg. 157: 174, 1963. Duke University Medical Center Durham, North Carolina 27706
Carcinoma of the breast continues to represent the most frequent form of cancer in women. Present reports indicate that approximately 60,000 new cases are discovered each year with 24,000 deaths recorded annually as a result of this disease. Despite much research and clinical investigation on this important disorder, considerable disagreement continues concerning the proper method of management. The extremes in opinion vary from those statisticians who suggest that surgical treatment has no demonstrable effect upon the course of this disease to those surgeons who believe that patients with carcinoma of the breast should be treated by super-radical operative techniques. Although controversy continues concerning both the extent of surgery and the use of chemotherapy, careful evaluation of the literature provides convincing eyidence that progress is being made in the understanding and management of this all too prevalent malignant disease.
HISTORICAL ASPECTS
In the latter half of the nineteenth century, the leading European surgeons directed their attention to the operative treatment of carcinoma of the breast. The inadequacy of the procedures performed was clearly documented in the alarming incidence of local recurrence reported by such masters as Billroth and von Bergmann, who published recurrences of 82 per cent and 60 per cent respectively.22 These results were quite similar to those of a number of well known surgeons in Europe at the time (Table 1). From the Department of Surgery, Duke University Medical Center, Durham, North Carolina * Professor of Surgery and Chairman of the Department ** Professor of Surgery
1265
.N
= =
Table 1. Local Recurrence oj Carcinoma oj Breast Following Surgical Removal Before 1900 Operator.
Biliroth ••• Czemy •••
t:1
:>-
~
Gussenbauer
p
Kilnig •••
w. :>-
KUster •••
tIj
~
Lilcke •••
~z
H.lsted ••• Reglonary"recurrence.
(From Halsted, W. S., Annals of Surgery SO: 497, 1894. By permission of J. B. Lippincott Company, Philadelphia, Pa.)
~ ~
~ ~ w.
:=
I z
THE SURGICAL MANAGEMENT OF BREAST CANCER
1267
With these statistics as a background it remained for William S. Halsted to devise an operative procedure which drastically reduced the incidence of local and regional recurrences, and in 1894 he reported his classic operation. After reviewing carefully the results in other clinics, Halsted recognized the importance of en bloc removal of the entire breast, pectoral muscles and axillary lymph nodes. Applying these principles in 50 patients, Halsted reported a local recurrence rate of only 6 per cent and late regional recurrences of 16 per cent. 22 These figures provided a drastic reduction in those available up to that time, and within a short period the Halsted radical mastectomy was adopted in many centers. In his original description, Halsted emphasized fifteen points which he considered important in the performance of the operation. There can be little doubt of the fundamental contribution which Halsted made in his concept of radical mastectomy. Although minor technical changes have been advocated from time to time, the concept of en-bloc removal of the breast, pectoral muscles and axillary contents has remained a firm principle in the treatment of carcinoma of the breast. It is interesting to reflect on Halsted's own account of this contribution. In a letter to Dr. William H. Welch dated October 26, 1922, Dr. Halsted made the following remarks: "You ask me to say something of my share in the development of the operation for cancer of the breast. This is pretty clearly stated in my first paper (Johns Hopkins Hospital Reports, 1890 and 1895). Volkmann had recommended stripping the fascia from the pectoralis major 'as for a classroom dissection,' and Heidenhain (Kuster's assistant at Marburg) proposed cutting away the superficial fibers of this muscle. I advised and practised the removal of the entire muscle, leaving in most instances the upper or subclavicular bundles (those above the cephalic vein); I divided the pectoralis minor to further facilitate the cleaning of the axilla. A year or two later Willy Meyer advised removing the minor muscle as well as the major, and I, too, came independently to the conclusion that this might better be done. I insisted that all the tissues should be removed in one piece and upon the meticulous cleaning of the axilla and its aestuaries (subclavicular and supraclavicular fossae). I warned of the danger of excising pieces of malignant tumors for microscopic examination unless the operation followed immediately, and was, I think, one of the first surgeons in this country able macroscopically to make the diagnosis of the common tumors."
PATHOLOGICAL ASPECTS
It has long been recognized that a variety of histological patterns are associated with carcinoma of the breast. While suitable qualifying names for a notation of the cell type and grade of malignancy are of interest, experience has shown that the biological behavior of the tumor is of greater importance. In many instances, more than one form of cell type of differing activity is present in these malignant lesions, and the changes may vary
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considerably from one portion of the tumor to another. The older morphologic classifications such as scirrhous, adenomatous and medullary carcinoma are still employed, but increasing significance is being given the clinical grading of these lesions such as advocated by Haagensen. 18 Thus, the clinical indicators of spread which demonstrate the invasiveness of the tumor (as opposed to the resistance and containment on the part of the host) more fully demonstrate the biologic activity. One of the more important contributions is that of Foote and Stewart16 who described carcinoma in situ of the breast. These and other authors have provided convincing evidence that carcinomas of the breast do arise and can be identified in a pre-invasive state. In those instances in which definitive treatment has been withheld, the development of invasive carcinoma has been amply demonstrated. Attention has also been focused upon the fact that patients with in-situ carcinoma of the breast are apt to have multiple foci of involvement, and in addition bilateral involvement is also common. In a recent series reported by Newman, bilateral disease was present in 6 of 26 patients (23 per cent).S5 TraditioRally, clinical results have been divided into those obtained in patients who had axillary metastases at the time of operation and those who did not. However, more recently the number and location of metastases have been proved to be of considerable importance. A detailed study of axillary node involvement in carcinoma of the breast was undertaken by Pickren at the Presbyterian Hospital-Columbia Medical Center in which clearing of the axillary tissues removed at operation was performed in a consecutive series of patients undergoing radical mastectomy.4. 38 The exact location of every lymph node in the axilla was numbered and plotted on an exact location on a standard diagram. Employing this technique, he found that an average of 38 nodes were found per case, the highest number being 88 and the lowest 8. A total of 204 cases were studied of which 107 were found to have axillary metastases whereas, in the remaining, all nodes were negative. It was interesting that of 31 patients clinically free of cancer eight to ten years following operation, 27 had four or fewer nodes involved by cancer and these were invariably located in the lower two-thirds of the axilla. There were four exceptions in this group. Thus, the number and site of axillary node metastases have been clearly demonstrated to be of great significance in prognosis and should be clearly established in all patients at the time of examination of the specimen. The relationship of age has also been of considerable importance. In a recent study by McDivitt and Stewart, carcinoma of the breast was reported in a group of children. s1 The clinical presentation in each patient was that of a painless mass in the breast adjacent to the nipple and without associated endocrinopathy. The clinical behavior of this type of carcinoma was noted to be less aggressive than its adult counterpart and in no case were regional or distant metastases observed. During prolonged observation, all patients were free of disease up to 15 years. Thus, carcinoma of the
THE SURGICAL MANAGEMENT OF BREAST CANCER
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breast differs from many other forms of malignant disease in thc young by being less invasive. In a study by Moore and Lewis, carcinoma of the breast in women 30 years of age and under was reviewed at the New York-Cornell Medical Center, and the prognosis of these patients was found to be comparable to that in older age groups.34 A majority of the women in the series had operable lesions and the most important factor affecting prognosis was found to be the extension of the disease to the axillary nodes. It was interesting that the prognosis of this disease in this age group was not worse than that for comparable patients in older age groups. Carcinoma of the breast in older age groups was studied by Papadrianos, Cooley and Haagensen.36 In a personal series of 556 patients the five- and ten-year follow-up results in patients 65 years of age and older showed a better prognosis in older women. The figures for five-year survival were considerably better in the 65 and older age group. In an interesting study of carcinoma of the breast discovered in a Cancer Detection Center, Gilbertsen J;eported that two-thirds of breast cancers which occurred in a group of women 45 years or older were found on routine annual physical examination prior to their recogQ.ition by the patient. 17 Three-fourths of these cancers were detected relatively early and were localized to the breast at the time of therapy. Following conventional surgical treatment, survival of patients approached 100 per cent of comparable persons without breast cancer. In another group of patients who were also being followed in the Cancer Detection Clinic, carcinoma of the breast made its existence known only during the interval between the Cancer Detection Center's examinations. Half of these patients had cancers which appeared to be localized to the breast at the time of therapy and these patients obtained a result similar to those in the first group. In the other half in whom breast cancers developed and were recognized only in the interval, these tumors had already spread to lymph nodes at the time of diagnosis. Most of the latter patients achieved such poor survival as to suggest that the cancer may have been biologically more malignant. In addition, they were substantially less amenable to curative therapy.
CLINICAL CLASSIFICATION OF CARCINOMA OF THE BREAST
Although a number of different classifications for carcinoma of the breast have been suggested, one of the most meaningful and useful is that devised by Haagensen. 19 This classification has been widely used and was the basis for a recent International Cooperative Study. The classification utilizes a number of clinical features of breast cancer and is as follows: Stage A. No skin edema, ulceration, or solid fixation of tumor to chest wall. Axillary nodes not clinically involved. Stage B. No skin edema, ulceration, or solid fixation of tumor to chest wall. Clinically involved axillary nodes, but less than 2.5 cm. in transverse diameter and not fixed to overlying skin or deeper structures of axilla.
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Stage C. Anyone of five grave signs of comparatively advanced carcmoma: 1. Edema of skin of limited extent (involving less than one-third of the skin over the breaflt) 2. Skin ulceration 3. Solid fixation of tumor to chest wall 4. Massive involvement of axillary lymph nodes (measuring :l.5 cm. or more in transverse diameter) 5. Fixation of the axillary nodes to overlying skin or deeper structures of axilla Stage D. All other patients with more advanced breast carcinoma, including: 1. A combination of any two or more of the five grave signs listed in Stage C. 2. Extensive edema. of skin (involving more than one-third of the skin over the breast) 3. Satellite skin nodules 4. The inflammatory type of carcinoma 5. Supraclavicular metastases (clinically apparent) 6. Parasternal metastases (clinically apparent) 7. Edema of the arm 8. Distant metastases
It should be emphasized that no distinction as to the size ofthe primary tumor and its position in the breast has been made in this classification. While these features are of importance, their meaning is insufficiently understood and too complex to permit useful classification.
THE NATURAL HISTORY OF CARCINOMA OF THE BREAST
One of the most important features of carcinoma of the breast is an understanding of its natural history. The course of untreated mammary carcinoma provides additional interesting information regarding the therapeutic approaches which have been recommended. Daland collected the histories of 100 untreated patients and found a mean duration of life of 40.5 months. I3 In a similar study, Shimkin reported a mean survival time of 36 months for untreated carcinoma of the breast in women over the age of 75. 40 More recently in a study of 250 untreated cases of breast carcinoma from the Middlesex Hospital in London, Bloom found a five-year survival rate of 26 per cent in the 60--69 age group. 7
SURGICAL PROCEDURES
Halsted's Radical Mastectomy
The basic operation upon which all others for treatment of carcinoma of the breast are to be compared is the Halsted radical mastectomy. It was the advent of this procedure which laid the basis for the modern treatment of carcinoma of the breast and was fully supported by a striking change in
'U J'J' In "
THE SURGICAL MANAGEMENT OF BREAST CANCER
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clinical results. This operation emphasizes the importance of an en-bloc removal of the breast together with the pectoral muscles and axillary contents. Emphasis is also placed on the removal of a sufficient amount of skin to prevent local cutaneous recurrence and it also stresses the importance of complete dissection of the axilla. A majority of surgeons today continue to use this technique in the treatment of most patients with carcinoma of the breast. Although the Halsted procedure is frequently discussed, some of the features and principles of this technique are often insufficiently emphasized. For this reason, Halsted's fifteen points are quoted from his original communication :22 "The operation which has been attended with such surprisingly good results in our hands is performed as follows: 1. The skin incision is carried at once and everywhere the fat. 2. The triangular flap of skin, Fig. 1, is reflected back to its base line. There is nothing but skin in this flap. The fat which lined it is dissected back to the lower edge of the pectoralis major muscle where it is continuous with the fat of the axilla. 3. The costal insertions of the pectoralis major muscle are severed, and the splitting of the muscle, usually between its clavicular and costal portions, is begun, and continued to a point about opposite the scalenus tubercle on the clavicle. 4. At this point the clavicular portion of the pectoralis major muscle and the skin overlying it are cut through hard up to the clavicle. This cut exposes the apex of the axilla.
Figure 1. Diagram showing skin incisions, triangular flap of skin, and triangular flap of fat. (From Halsted, W. S., Annals of Surgery 20: 497, 1894. By permission of J. P. Lippincott Company, Philadelphia, Pa.)
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Figure 2. Diagram showing Halsted radical mastectomy. M, Major pectoral muscle; m, Minor pectoral muscle; S, Apex of infraclavicular fat below the subclavian vessels; Sf, Apex of fat above the vessels. (From Halsted, W. S., Annals of Surgery 20: 497, 1894. By permission of J. P. Lippincott Company, Philadelphia, Pa.)
5. The loose tissue under the clavicular portion (the portion usually left behind of the pectoralis major) is carefully dissected from this muscle as the latter is drawn upwards by a broad, sharp retractor. This tissue is rich in lymphatics, and is sometimes infiltrated with cancer (an important fact). 6. The splitting of the muscle is continued out to the humerus, and the part of the muscle to be removed is now cut through close to its humeral attachment. 7. The whole mass, skin, breast, areolar tissue and fat, circumscribed by the original skin incision is raised up with some force, to put the submuscular fascia on the stretch as it is stripped from the thorax close to the ribs and pectoralis minor muscle. It is well to include the delicate sheath of the minor muscle when this is practicable. 8. The lower outer border of the minor muscle having been passed and clearly exposed, this muscle is divided at right angles to its fibers and at a point a little below its middle. 9. The tissue, more or less rich in lymphatics and often cancerous, over the minor muscle near its coracoid insertion is divided as far out as possible and then reflected inwards in order to liberate or prepare for the reflection upwards of this part of the minor muscle. 10. The upper, outer portion of the minor muscle is drawn upward (Fig. 2) with a broad retractor. This liberates the retractor which until now has been holding back the clavicular portion of the pectoralis major muscle. 11. The small blood vessels (chiefly veins) under the minor muscle near its insertion must be separated from the muscle with the greatest care. These
THE SURGICAL MANAGEMENT OF BREAST CANCER
1273
are imbedded in loose connective tissue which seems to be rich in lymphatics and contains more or less fat. This fat is often infiltrated with cancer. These blood vessels should be dissected out very clean and immediately ligated close to the axillary vein. The ligation of these very delicate vessels should not be postponed, for the clamps occluding them might of their own weight drop off or accidentally be pulled off; or the vessels themselves might be torn away by the clamps. Furthermore, the clamps, so many of them, if left on the veins, would be in the way of the operator. 12. Having exposed the subclavian vein at the highest possible sub clavicular point, the contents of the axilla are dissected away with scrupulous care, also with the sharpest possible knife. The glands and fat should not be pulled out with the fingers, as advised, I am sorry to say, in modern textbooks and as practised very often by operators. The axillary vein should be stripped absolutely clean. Not a particle of extraneous tissue should be included in the ligatures which are applied to the branches, sometimes very minute, of the axillary vessels. In liberating the vein from the tissues to be removed it is best to push the vein away from the tissues, rather than holding the vein to push the tissues away from it. It may not always be necessary to expose the artery, but I think that it is well to do this. For sometimes, not usually, the tissue above the large vessels is infiltrated. And we should not trust our eyes and fingers to decide this point. It is best to err on the safe side and to remove in all cases the loose tissue above the vessels and about the axillary plexus of nerves. 13. Having cleaned the vessels, we may proceed more rapidly to strip the axillary contents from the inner wall of the axilla-the lateral wall of the thorax. We must grasp the mass to be removed firmly with the left hand and pull it outwards and slightly upwards with sufficient force to put on the stretch the delicate fascia which still binds it to the chest. This fascia is cut away close to the ribs and serratus magnus muscle. 14. When we have reached the junction of the posterior and lateral walls of the axilla, or a little sooner, an assistant takes hold of the triangular flap of skin and draws it outward, to assist in spreading out the tissues which lie on the subscapularis, teres major and latissimus dorsi muscles. The operator, having taken a different hold of the tumor, cleans from within outwards the posterior wall of the axilla. Proceeding in this way, we make easy and bloodless a part of the operation which used to be troublesome and bloody. The subscapular vessels become nicely exposed and caught before they are divided. The subscapular nerves mayor may not be removed, at the discretion of the operator. Kuster lays great stress upon the importance of these nerves for the subsequent usefulness of the arm. We have not as yet decided this point to our entire satisfaction, but I think that they may often be spared to the patient with safety. 15. Having passed these nerves, the operator has only to turn the mass back into its natural position and to sever its connection with the body of the patient by a stroke of the knife repeating the first cut through the skin."
Superradical Mastectomy
With the passage of time, a number of modifications have been introduced in the treatment of breast carcinoma. In 1899 Halsted himself advocated supraclavicular dissection as a part of radical mastectomy, but later abandoned it since he felt the results did not warrant a procedure of
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this radical a nature. In 1952, Wangensteen reported an extended radical procedure including the supraclavicular area, the internal mammary chain and the anterior mediastinum. 44 In such a dissection, he found positive nodes in 60 per cent of the cases which otherwise would have not been suspected. Handley23 and Urban also advocated internal mammary node dissection. 43 In general, the primary indication for superradical procedures has been in those patients with interquadrant or subareolar tumors. This is associated with the fact that parasternal lymph node involvement is often the first sign of recurrence in patients with interquadrant lesions. Although there are some statistical reports of increased survival of superradical operations, the majority of surgeons do not believe their use justified, particularly in relation to the increased morbidity and mortality with which they are associated. Modified Radical Mastectomy A number of surgeons have advocated modifications of the Halsted radical mastectomy. Patey and Dyson in 1952 reported preservation of the pectoralis major muscle in performance of radical mastectomy.37 This method was also supported by Handley.23 In this country, Madden has advocated a modified radical mastectomy in which both the pectoralis major and minor muscles are retained and he feels that the results obtained justify continued use. 33 These techniques have firm advocates who believe them to be justifiable on the basis of clinical results. Simple Mastectomy Combined with Radiotherapy In 1941, McWhirter, an Edinburgh radiologist, began a significant study in collaboration with a number of surgeons in that city and region. 32 They initiated a policy of simple mastectomy combined with irradiation for the treatment of all cases of mammary carcinoma. A collective review of 1882 patients in this series between 1941 and 1947 was published by McWhirter in 1955. In this group the absolute five-year survival rate was 42 per cent and the ten-year survival rate 25 per cent. Although the figures were challenging, a number of authorities in the field, including Ackerman l and Clagett,9 have challenged this technique. For example, in studying McWhirter's patients, Ackerman found a number who had considerable morbidity associated with the irradiation. Marked changes including dermatitis, fractures, and subsequent amputation were observed. Haagensen has criticized the McWhirter technique on the basis that it is not a true simple mastectomy from the anatomical point of view but is rather a partial mastectomy.1 8 He considers the treatment primarily radiotherapeutic. Clagett has presented evidence in a comparable group of patients from the Mayo Clinic with five-year survival during the period 1941-1947 (which was the time covered by the Edinburgh experience) as showing a 59.3 per cent five-year survival for patients treated by radical mastectomy as opposed to 48.1 per cent in the Edinburgh experience by simple mastectomy
1275
THE SURGICAL MANAGEMENT OF BREAST CANCER
Results of Various Forms of Surgical and Radiation Treatment for Carcinoma of the Breast
Table 2.
RESULTS AUTHORS
TREATMENT
Dahl-Iversen Superradical and Tobiassen12 Mastectomy
CLASSIFICATION
NUMBER
A B C D
277 61 20 8
(Per cent 5-Year Survival) 77 48 50 37 Total: 70%
Williams and Curwen47
Radical Mastectomy plus Irradiation
A B C D
68 57 16 1
72 60 38 0 Total: 63%
Haagensen and Cooley 18
Radical Mastectomy
A B C D
344 138 63 11
84 59 43 18 Total: 72%
ButcherS
Radical Mastectomy
A B C D
216 135 48 26
76 48 48 11 Total: 60%
Handley and Thackray24
Conservative Radical Mastectomy
A B C D
77 58 8 0
75 57 25 Total: 65%
Kaae and Johansen'8
Simple Mastectomy plus Irradiation (McWhirter's Method)
A B C D
159 28 9 3
70 50 22 0
Kennedy and Miller'o
Simple Mastectomy
A B C D
115 34 18 45
62 41 22 13
Total: 64%
Total: 45% Baclesse 5
Irradiation only
A B C D
50 86 95 200
54 67 41 13 Total: 35%
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and irradiation. Although the McWhirter method attracted considerable attention and a number of followers, it now appears to be less popular than previously.
Treatment of Breast Cancer by Local Excision The first reported operations for carcinoma of the breast were essentially local excisions. The poor results attended by this procedure were well known, and it was this fact that led Halsted to the concept of the radical mastectomy. Nevertheless, interest has continued in this form of therapy, especially for well selected patients. Thus, in 1943 Adair reported results of local excision in a group of eight patients in whom this procedure alone was done with an 88 per cent five-year survival. 2 In a selected series, Porritt reported segmental mastectomy in 74 patients followed by postoperative irradiation with a five-year survival of 65 per cent. 39 In a recent discussion of this subject, Crile stated that the five-year survival rate of a group of 20 patients with carcinoma of the breast treated by local excision was 65 per cent.lO Patients were selected for local excision on the basis of peripheral location of the tumors and without evidence of metastasis. Although he does not recommend that breast carcinoma be treated in this fashion routinely, he emphasizes that in special situations a peripherally located lesion may be managed in this manner.
ADJUNCTS TO RADICAL MASTECTOMY
Several adjuncts to surgical removal of the breast have been employed for many years in treatment of patients with potentially curable carcinoma. The major adjuncts are (a) preoperative or postoperative irradiation, (b) oophorectomy and (c) chemotherapy. Unfortunately, firm statements cannot be made at this time regarding the relative efficiency of these adjuncts to radical mastectomy in treatment programs, since it is now generally agreed that valid conclusions concerning their use can be drawn only from random studies in large groups of patients. Opinions expressed on the basis of selected series, despite careful evaluation, may be misleading. These adjuncts to radical mastectomy for treatment of breast carcinoma are currently undergoing evaluation in randomized studies, participated in by teaching centers in various parts of the country. These studies should give more objective answers to the efficacy of the adjuncts currently employed. The first of these studies, begun in 1958 and completed in 1961, concerned the evaluation of the adjunctive use of a chemotherapeutic drug triethylenethiophosphoramide (Thio-TEPA) given to patients in a randomized fashion in conjunction with the standard radical mastectomy for treatment of potentially curable breast carcinoma. This study, which included approximately 830 patients with one-half treated and one-half controls, is now approaching the five-year follow-up phase in the study. The effects of
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the chemotherapeutic drug on the survival rate of these patients remains to be determined. However, analysis of data concerning the time interval between operation and tumor recurrence in those patients who had recurrence revealed that the chemotherapeutic drug was of benefit in delaying onset of recurrence in one category of patients, namely, premenopausal patients who had axillary lymph node metastasis. This group of patients showed a significant delay in time of tumor recurrence when compared with controls in this same group. This benefit of the adjunctive chemotherapy, however, was not present for all patients in the study. A second cooperative study was begun in 1961 and remains in progress. This study is statistically designed to evaluate the beneficial effects of another chemotherapeutic agent (5-Fluorouracil), "prophylactic" oophorectomy in premenopausal patients, and "prophylactic" postoperative irradiation when employed with a standard radical mastectomy. No data are available concerning the benefits of these various adjuncts to operation on tumor recurrence time or survival. After a sufficient patient follow-up period, this study should be of great value to the clinician in selection of treatment programs for patients with potentially curable breast carcinoma.
Irradiation PREOPERATIVE IRRADIATION. Views are conflicting concerning the value of preoperative irradiation in potentially curable breast carcinoma. In certain European clinics, this procedure was used routinely for many years. A review of the literature on reported personal series of cases suggests some value of this procedure in some and of no benefit in others.ll A recent report on the use of preoperative irradiation has indicated that this form of treatment can be used with relative safety and without serious impairment of wound healing following radical mastectomy when operation is performed within a few weeks following the conclusion of the radiation therapy.45 The value of this form of treatment, however, cannot yet be evaluated from the standpoint of improved survival of the patients so treated. In general, preoperative irradiation has been used only to a limited extent in treatment programs. POSTOPERATIVE IRRADIATION. "Prophylactic" postoperative irradiation has been used quite extensively as an adjunct to radical mastectomy. The rationale for the use of this form of therapy is based on the assumption that since x-rays and radium have the ability to destroy carcinoma cells they also must possess the power to prevent recurrences after operation. A controversy regarding the efficacy or even the potential harm of this form of therapy has existed since 1920 when Perthes presented his statistics from the Kiel Clinic in Germany.ll This author stated that postoperative irradiation not only failed to prevent recurrences but actually favored their appearance. Dao has recently reported a study on postoperative irradiation which would support this thesis. 15 Many clinics employ postoperative irradiation only in those patients who have involvement of axillary lymph nodes, while others advocate the use of irradiation in those patients with
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medial quadrant lesions, the radiation being directed to the supraclavicular area and mediastinum. The question as to whether postoperative irradiation will improve survival in patients with potentially curable cancer of the breast following radical mastectomy cannot be categorically answered from studies reported in literature.
Prophylactic Oophorectomy The reports in the literature which support the thesis that oophorectomy combined with radical mastectomy in premenopausal patients increases survival rate in patients so treated represent personal series of cases without randomization of cases or adequate controlsY· 42 These studies suggest some benefit of castration combined with radical mastectomy in 900 premenopausal patients with breast cancer. However, Kennedy maintains that if a cure is achieved in such patients it is due to the radical mastectomy and that there is no rational basis to believe that the deprivation of estrogen will actually prevent recurrence of tumor growth.29 At best, one would think that there would be only a delay in this recurrence, if it develops. Thus, it is argued that the oophorectomy should be delayed until recurrence does develop, since then the procedure will afford palliation and at the same time establish whether or not the carcinoma is hormonal dependent. This has practical value since other forms of endocrine ablative therapy can then be used to achieve additional palliation. Another argument relative to the castration problem concerns whether surgery or radiation should be used for the castration effect. Endocrine studies have established that surgical castration effects a rapid and complete ablation of ovarian function, whereas radiation castration produces the effect in variable degree and requires a much longer period of time for the effect to take place. 6
Chemotherapy LOCAL CHEMOTHERAPY. Whether wound irrigation after radical mastectomy lowers the incidence of local recurrence appreciably has not been established firmly. The rationale for the procedure is based on the fact that tumor cells can often be found in operative wounds following operation for various malignancies. 3 However, whether the presence of the tumor cells within the wound have any relation to the eventual recurrence of carcinoma at the wound site has not been established. Studies in animals have suggested that wound irrigation with various chemotherapeutic drugs will prevent recurrence of tumor within the wound in these animals. 41 Until more definitive studies have been performed to establish the value of wound irrigation with chemotherapeutic agents, the value of this approach cannot be established. SYSTEMIC CHEMOTHERAPY. Reference has already been made to findings in the first breast cancer adjuvant chemotherapy study relative to the value of triethylenethiophosphoramide (Thio-TEPA) used in conjunction with radical mastectomy. Although the early results of this study do
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suggest some benefit in premenopausal patients with axillary node involve~ ment, the effects of this drug on survival rate of patients with breast carci~ noma who have received it and had radical mastectomy must await further studies. The adjuvant use of other chemotherapeutic agents has not been similarly evaluated and until such time that adequate evaluation has been performed in random studies, the use of these agents as adjuncts to radical mastectomy in potentially curable breast carcinoma will remain substanti~ ated. Suffice it to say that from data presently available it appears that patients with distinct metastatic lesions have not been cured by intravenous chemotherapy.
COMPLICATIONS OF RADICAL MASTECTOMY
Radical mastectomy may be accompanied by certain psychological reactions and cosmetic defects which do not result in major problems for the majority of patients. The complication of radical mastectomy which has been most distressing to the patient and the surgeon and which has received the greatest attention is the development of lymphedema of the arm. Halsted21 described this condition and termed it "elephantiasis chirurgica." He first called attention to the fact that the condition could result from blockage of lymphatics or occasionally from blockage of underlying veins. He recognized that infection was usually related to faulty wound healing which aggravated the condition. The role of postoperative irradiation therapy in development of lymphedema of the arm is difficult to evaluate. Recent studies reported by Danese et al. using lymphangiography indicated that postmastectomy lymphedema is a direct consequence of axillary lymphatic obstruction. 14 Regeneration of resected lymphatics appears to be inadequate to estab~ lish satisfactory flow. When obstruction to lymphatics is severe, a pro~ gressive disease occurs with disappearance of the lymphatic vessels as the end result. Approximately 50 per cent of patients after radical mastec~ tomy will show some degree of edema of the arm although in most it is slight and transient. In 5 to 10 per cent of patients the edema may be quite pronounced and even disabling. The patient with lymphedema of the arm is subject to the development of occasional bouts of lymphangitis and cellulitis of the affected extremity. The organism commonly involved is Staphylococcus aureus. l l A patient who has undergone a radical mastec~ tomy should be warned to avoid infection of the hand and the fingers, since minor infections may lead to a superficial cellulitis of the arm accompanied by pain, swelling, and redness of the upper extremity. This complication is treated with appropriate antibiotics. Many attempts have been made to improve the lymphedema which develops after mastectomy. Elevation of the extremity, centripetal massage, hand and arm exercises, and application of vasopneumatic devices have been only partially satisfactory in management of the condition. Injections
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of hyaluronidase, as suggested by Habif, have been of value in some patients. 2o A more satisfactory procedure for control of this complication when it arises is needed, but the prevention of this complication by careful protection of the axillary vein during operation, by the use of hand and arm exercise (squeezing a rubber ball) following surgery, and elevation of the extremity with the first appearance of edema are each of considerable importance. CARCINOMA OF THE BREAST IN PREGNANCY
For many years, the prognosis of carcinoma of the breast developing during pregnancy was considered to be so serious that it was considered inoperable and incurable. More recently, reports appearing in the literature have indicated that, although it is true that the survival rate of patients with breast cancer in association with pregnancy is lower after radical mastectomy than in nonpregnant patients, some of these cases may be cured by operation. The coexistence of breast cancer and pregnancy is uncommon, estimated to be 2 per cent of all patients with breast cancer. 46 Several studies have shown that patients who develop carcinoma during pregnancy have a higher incidence of axillary node metastasis at the time of operation than do nonpregnant females with cancer. This probably represents a delay in diagnosis due to the fact that the breast is engorged and more difficult to examine than in the nonpregnant female. In a group of 78 patients who underwent radical mastectomy for treatment of carcinoma during pregnancy with axillary node metastasis, the five-year survival was 5 per cent. 25 In 14 additional patients in whom lymph node metastasis was not present, the five-year survival was 61 per cent and the ten-year survival was 40 per cent. There is now general agreement that a radical mastectomy should be performed immediately upon the establishment of a definite diagnosis of mammary cancer, when the condition is found during pregnancy or lactation. Further, studies have indicated that abortion cannot be clearly shown to have a favorable effect on the course of the disease. A follow-up of patients who have had a radical mastectomy for carcinoma of the breast and thereafter become pregnant shows a survival rate equivalent to that of patients who do not become pregnant after their operation. 26 On the basis of these findings, it would seem that patients who have been operated upon for carcinoma of the breast may become pregnant after their treatment without influencing their expected survivalY SUMMARY
Both interest and controversy continue to characterize the status of therapy for carcinoma of the breast. There is general agreement that removal of the breast constitutes the basic principle upon which proper
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management is based. While some observers prefer superradical techniques and others modified or simple mastectomy with or without postoperative irradiation therapy, a distinct majority continue to prefer the standard radical mastectomy of the Halsted type. More investigation is being done in the development of adjuvants to surgical therapy. The use of chemotherapy is being evaluated in a national cooperative study, and the early results support its usefulness in slowing the rate of recurrences, especially in premenopausal patients. It is firmly recognized that more work with carefully controlled statistical studies is necessary before further conclusions can be drawn in this field. These approaches, in conjunction with surgical therapy, offer considerable optimism for the future.
REFERENCES l. Ackerman, L. V.: Evaluation of treatment of cancer of breast at University of
Edinburgh (Scotland) under direction of Dr. Robert McWhirter. Cancer 8: 883, 1955. 2. Adair, F. E.: Role of surgery and irradiation in cancer of breast. J.A.M.A. 121: 553, 1943. 3. Arons, M. S., Smith, R. R. and Myers, M. H.: Significance of cancer cells in operative wounds. Cancer 14: 1041, 1961. 4. Auchincloss, H.: Significance of location and number of axillary metastases in carcinoma of the breast: A justification for a conservative operation. Ann. Surg. 158: 37, 1963. 5. Baclesse, F.: Five-year results in 431 breast cancers treated solely by roentgen rays. Ann. Surg. 161: 103,1965. 6. Block, G. E., Vial, A. B. and Pullen, F. W.: Estrogen excretion following operative and irradiation castration in cases of mammary cancer. A preliminary report. Surgery 43: 415, 1958. 7. Bloom, H. J., Richardson, W. W. and Harries, E. J.: Natural history of untreated breast cancer (1805-1933). Brit. M. J. 5299: 213, 1962. 8. Butcher, H. R., Jr.: Radical mastectomy for mammary carcinoma. Ann. Surg. 157: 165, 1963. 9. Clagett, O. T.: Proc. Staff Meet. Mayo Clin. 32: 662, 1957. 10. Crile, G., Jr.: Treatment of breast cancer by local excision. Am. J. Surg. 109: 400, 1965. 11. Cutler, M.: Tumors of the Breast., Philadelphia, J. B. Lippincott Co., 1962, p. 300. 12. Dahl-Iversen, E. and Tobiassen, T.: Radical mastectomy with parasternal and supraclavicular dissection for mammary carcinoma. Ann. Surg. 157: 170, 1963. 13. Daland, C. M.: Untreated cancer of the breast. Surg. Gynec. & Obst. 44: 264, 1927. 14. Danese, Callisto, and Howard, J. M.: Postmastectomy lymphedema. Surg. Gynec. & Obst. 120: 797, 1965. 15. Dao, T. L. and Kovaric, J.: Incidence of pulmonary and skin metastases in women with breast cancer who received postoperative irradiation. Surgery 52: 203, 1962. 16. Foote, F. W., Jr. and Stewart, F. W.: Comparative studies of cancerous versus non-cancerous breasts. 1. Basic morphologic characters. II. Role of so-called chronic cystic mastitis in mammary carcinogenesis. Influence of certain hormones on human breast structures. Ann. Surg. 21: 6, 197, 1945. 17. Gilbertsen, V. A.: Survival of asymptomatic breast cancer patients. Surg. Gynec. & Obst. 122: 81, 1966. 18. Haagensen, C. D. and Cooley, E.: Radical mastectomy for mammary carcinoma. Ann. Surg. 157: 166, 1963. 19. Haagensen, C. D. and Cooley, E.: Treatment of early mammary carcinoma. A cooperative international study. Ann. Surg. 157: 157, 1963.
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20. Habif, D. Y.: Cited by Haagensen, C. D.: Diiieases of the Breast. Philadelphia, W. B. Saunders Co., 1959, p. 652. 21. Halsted, W. S.: The swelling of the arm after operations for cancer of the breast. Bull. Johns Hopkins Hosp. 32: 309, 1921. 22. Halsted, W. S.: Results of operations for the cure of cancer of the breast performed at Johns Hopkins Hospital from June 1889-January 1894. Ann. Surg. 20: 497, 1894. 23. Handley, R.: Some observations and reflections on breast cancer. J. Roy. ColI. Surgeons, Edinburgh,6: 1, 1960. 24. Handley, R. S. and Thackray, A. C.: Conservative radical mastectomy (Patey's operation). Ann. Surg. 157: 162, 1963. 25. Harrington, S. W.: Carcinoma of the breast. Results of treatment when the carcinoma occurred in the course of pregnancy or lactation and when pregnancy occurred subsequent to operation (1910-1933). Ann. Surg. 106: 690, 1937. 26. Holleb, A. 1. and Farrow, J. H.: Relation of carcinoma of the breast and pregnancy in 283 patients. Surg. Gynec. & Obst. 115: 65, 1962. 27. Horsley, J. S. and Horsley, G. W.: Twenty years' experience with prophylactic bilateral oophorectomy in the treatment of carcinoma of the breast. Ann. Surg. 155: 935, 1962. 28. Kaae, S. and Johansen, H.: Simple mastectomy plus postoperative irradiation by the method of McWhirter for mammary carcinoma. Ann. Surg. 157: 175,1963. 29. Kennedy, B. J., Mielke, P. W. and Fortuny, 1. E. Therapeutic castration versus prophylactic castration in breast cancer. Surg. Gynec. & Obst. 118: 524, 1964. 30. Kennedy, C. S. and Miller, E.: Simple mastectomy for mammary carcinoma. Ann. Surg. 157: 161, 1963. 31. McDivitt, R. W. and Stewart, F. W.: Breast carcinoma in children. J.A.M.A. 195: 388, 1966. 32. McWhirter, R.: Simple mastectomy and radiotherapy in the treatment of breast cancer. Brit. J. Radiol. 28: 128, 1955. 33. Madden, J. L.: Modified radical mastectomy. Surg. Gynec. & Obst.121: 1221, 1965. 34. Moore, S. W. and Lewis, R. J.: Carcinoma of the breast in women 30 years of age and under. Surg. Gynec. & Obst. 119: 1253, 1964. 35. Newman, W.: In situ lobular carcinoma of the breast: Report of 26 women with 32 cancers. Ann. Surg. 157: 591, 1963. 36. Papadrianos, E., Cooley, E. and Haagensen, C. D.: Mammary carcinoma in old age. Ann. Surg. 161: 189,1965. 37. Patey, D. H. and Dyson, W. H.: Prognosis of carcinoma of the breast in relation to type of operation performed. Brit. J. Surg. 2: 7, 1948. 38. Pickren, J. W.: Lymph node metastases in carcinoma of female mammary gland. Roswell Park Memorial Inst. Bull. 1: 79, 1956. 39. Porritt, A.: Early carcinoma of the breast. Brit. J. Surg. 51: 214, 1964. 40. Shimkin, M. D.: Duration of life in untreated cancer. Cancer 4: 1, 1951. 41. Thomas, G. C. and Brown, B. C.: Studies on the prevention of surgical implantation of cancer. Ann. Surg. 151: 581, 1960. 42. Treves, N.: An evaluation of prophylactic castration in the treatment of mammary carcinoma. An analysis of 152 patients. Cancer 10: 393, 1957. 43. Urban, J. A.: Clinical experience and results of excision of the internal mammary lymph node chain in primary operable breast cancer. Cancer 12: 14, 1959. 44. Wangensteen, O. H.: Super-radical operation for breast cancer in the patient with lymph-node involvement. Proc. 2nd Nat. Congress, 1952, p. 230. 45. White, E. C., Fletcher, G. H. and Clark, R. L.: A report of experience with preoperative irradiation for carcinoma of the breast. Ann. Surg. 155: 948, 1962. 46. White, T. T. and White, W. C.: Breast cancer and pregnancy: Report of 49 cases followed 5 years. Ann. Surg. 144: 384, 1956. 47. Williams, 1. G. and Curwen, M. P.: Total mastectomy with axillary dissection and irradiation for mammary carcinoma. Ann. Surg. 157: 174, 1963. Duke University Medical Center Durham, North Carolina 27706