The Actual Extent of Mastectomy: A Key to Survival

PERSPECTIVES IN BIOLOGY AND MEDICINE Volume 30 ¦ Number 3 ¦ Spring 1987 THE ACTUAL EXTENT OF MASTECTOMY: A KEY TO SURVIVAL DONALDJ. FERGUSON* During the past 3 decades, surgery for breast cancer has been gradually attenuated by a turn of thought that began in the United Kingdom and has spread worldwide, holding that efforts to excise all the local and regional disease do not improve results. It is now widely taught that "dissemination rates are unaffected by the type of primary treatment" [1], "operable breast cancer is a systemic disease" [2], and "local treatment does not influence survival" [3]. One basis for these beliefs is the appearance of disseminated cancer many years after treatment that is locally effective. Another reason is the similarity in rates of survival after nominally different types of mastectomy. If, on the other hand, it may be observed by a more careful scrutiny of the evidence that the actual extent of mastectomy can affect survival and that a significant proportion of mastectomy patients are cured—in the sense that they live a normal life span without recurrent cancer—the quoted generalizations are seen to apply only to a certain fraction of operable patients. Members of this doomed subgroup cannot be individually recognized at the time of mastectomy and therefore cannot safely be treated differently from the others. It may, of course, be postulated that all cancer patients, or all human beings for that matter, have dormant cancer cells that never proliferate, but this theory has no apparent usefulness. The purpose of this essay is to review the evidence for and against mastectomy, by showing that the present, generally disparaging opinion *Department of Surgery, University of Chicago, 5841 Maryland Avenue, Chicago, Illinois 60637.© 1987 by The University of Chicago. All rights reserved. 003 1-5982/87/3003-054 1$01 .00 Perspectives in Biology and Medicine, 30,3 ¦ Spring 1987 | 311 TABLE 1 Ten-year Survival in Randomized Comparisons of the Extent of Mastectomy Project Types of Mastectomy Survival Local Recurrence P (%) Cases (N) 1st series 2d series Total vs. I—III extendedI— III TotalII vs. radicalII—III Total vs. radical Partial vs. radical Partial vs. radical Partial vs. radical Radical vs. extended Total vs. radical Total vs. radical Total vs. radical Quadrant vs. radical I—III I—III I I II II I—III I—III I I II II II II I (<2 cm) I (<2 cm) 44 48 46 49 52 61 57 52 59 68 35 49 53 56 54 58 39 38 31 35 79 78 NS <.05 NS <.002 <.05 .40 .50 NS 21 24 Not NSgiven 23 15 34 16 33 8 63 26 24 14 10 8 16 Not .90given NS Not given <.003 <.001 <.001 <.05 NS NS NS NS 199 183 113 91 242 256 112 108 122 130 70 80 746 697 365 362 294 292 159 148 352 349 312 Nodes Found (N) Adjuvants Internal Axillary Mammary Randomization X-ray Rads EndoDrugcrineMethodExclusions (9i ) Not described Not described Not described Not described 12 15 15 15 15 15 2-4 Not described Not described 4300 0 3300 3300 4500 0 3800 3000 3800 3000 3800 3000 Yes Yes Yes Yes 6000 0 4000 0 6000 0 Yes Yes Yes Yes Case40 no. 45 OK3 deaths OK OK OK OK Not given Not given 15 0.3 2 5.7 11 Kaae [9, 10] Brinkley[ll, 12] Bruce [5, 13] Atkins [6, 7] Lacour [14, 15] Fisher [16, 17] Lythgoe [3, 18] Veronesi [19, 20] 313 is not well founded and by demonstrating that not only the extent but the detailed care applied to the resection determines survival. To relate extent to survival, we need a randomized comparison of defined variations in resection with adequate follow-up. Results up to 5 years have been shown to mislead in part because of the often slow progression of breast cancer (4 vs. 5, 6, 6 vs. 7). Patients who remain well for 15—20 years after radical mastectomy have little further risk of recurrence , and their average life expectancy is then the same as that of a matched control population [8]. There is only one randomized study carried to 20 years [7]. If we compromise by accepting 10 years, only seven other projects meet these minimum requirements. We can briefly examine all of this evidence; the studies and their references are listed in table 1. Descriptions of the Surgery Names of the various types of mastectomy are listed in table 1 . The actual resections performed are found to vary within study groups as well as between studies that are nominally of the same procedure. Insofar as such variations may affect survival, they obviously impair the validity of any conclusions that are drawn, and they are therefore described here in more detail. The smallest operation was partial mastectomy. In project 4, it was called "extended tylectomy" and defined as "wide excision of the lump together with the surrounding breast tissue within 3 cm of palpable or visible growth" [6]. Deep and peripheral tumors obviously could not have such a margin. Patients with medial tumors were excluded from the study, perhaps for this reason. Another variation of partial mastectomy called "quadrantectomy" was studied in project 8, in which only patients with no palpable nodes and cancers less than 2 cm in diameter, as measured by the pathologist after excision, were included; 45 percent of the tumors were less than 1 cm in diameter [19]. The involved segment of the breast was removed, including skin and fascia, with at least 2 cm of tissue surrounding the cancer. Through the same or a separate incision, the axillary nodes (numbers not given) were dissected out, with removal of part of the minor pectoral muscle. Cosmetic results were thought to be good in "more than 70 percent of the cases." Total (simple) mastectomy was evaluated in projects 1, 2, 3, 6, and 7. In project 2, 79 percent of total mastectomies included axillary lymph nodes, and, in 42 percent of these patients, there were nodal metastases. Probably the most prominent nodes were removed, and this may have altered survival [21]. In project 6, total mastectomy included an average of 15 nodes, the same number as this group found in their radical 314 I DonaldJ. Ferguson ¦ Mastectomy and Survival mastectomies [22]. In their hands, these nominally different procedures are in an important respect exactly alike. That the results are also similar might have been anticipated. Total mastectomy with lymphadenectomy does not differ in basic concept from modified radical mastectomy, the most-used operation in recent years, for which there are no 10-year randomized comparisons. Radical mastectomy, included in all the projects except the first, has this name because of the myectomy. Resection of the sternal part of pectoralis major and the pectoralis minor continues to be advocated by some surgeons because it increases the margin of normal tissue beneath the cancer, resects lymphatic vessels traversing the muscle, and facilitates complete nodal dissection [23]. The posterior margin of total mastectomies , or modified radical resections, is commonly within 0—10 mm of the tumor or biopsy cavity. (In 126 patients, our pathologist noted the margin in 39, of which 31 were SlO mm.) In the radical mastectomies of project 7, myectomy was optional. In its absence, the distinction from the total mastectomies of the comparison group is diminished. The radical mastectomies of project 2 could be supplemented ad lib. by removal of internal mammary nodes. These variations were not enumerated or distinguished in the survival data. The radical mastectomies of project 6, performed by various surgeons in 34 institutions, removed on the average about half as many nodes as can be obtained [8]. In 20 percent of patients undergoing radical mastectomy in project 2, healing was delayed more than 2 months. The percentage of patients who had local first recurrences after radical operations was high in all these studies (table 1). In our institution among all patients eligible for randomization at stages I and II and treated by radical surgery from 1960 to 1978, the local recurrence rate is 3 percent (17/513). The incidence of local recurrence , like the incidence of delayed healing and the count of lymph nodes removed, is an indication of the care and thoroughness with which the operation was done. Extended radical mastectomy, performed as described by Urban [24], aims to remove both of the primary lymph node drainage areas en bloc with the breast and intervening tissues. About 40 percent of patients at combined clinical stages I and II have axillary nodal metastases and roughly 20 percent have internal mammary involvement. The good reasons there are for removing axillary nodes therefore should apply also to the internal mammary nodes, but these reasons f^e not applied, probably because complete removal of the latter is surgically difficult and, if not done properly, dangerous. To obtain practically all of the internal mammary nodes, it is necessary to resect part of the sternum, costal cartilages 2-5, and pleura and to dissect out the vessels and adjacent tissues above the first interspace. The resulting defect in the chest wall is at least 4.5 cm in width. It must be closed, preferably with Cortex®, Perspectives in Biology and Medicine, 30, 3 ¦ Spring 1987 \ 315 under strong tension to prevent pain, deformity, and paradoxical respiratory motion. There is no visible or palpable postoperative defect apparent to the patient when this has been done properly. The need for removing pleura en bloc is clearly shown in figure 7 of McDonald, Haagensen, and Stout [25], a photomicrograph showing metastases adjacent to this membrane. Apparently, few surgeons are trained to handle this resection expertly: most of the extended operations in studies 1 and 5 were not en bloc; after the radical mastectomy was finished, some nodes were dissected extrapleurally from the intercostal spaces [14, 26]. About half the extended radical operations in project 5 were said to be en bloc, a procedure pictured as a narrow parasternal excision filled in by a strip of denervated and devascularized muscle that could not hold any tension [27]. The average number of internal mammary nodes removed in our experience with extended radical mastectomy [28] has been six. No number is given for project 1. The averages for the various groups of project 5 were two to four. Veronesi [29] published his part in project 5 separately, showing results that cannot be numerically reconciled with data in the parent study. We have tabulated only the latter. Neither of the two studies nominally about extended radical mastectomy used the Urban operation, and their resections were evidently not complete. The Quality of Surgery—Effect on Survival By a combination ofchance and design, in project 4, survival following radical mastectomy done by trainees was compared with that following nominally the same procedure performed by specialists in breast surgery (table 1; compare the two paired groups at stage I). (See fig. 1.) The difference in survival favored the specialists by 16 percent at 10 years, P < .0007 [7]. Although the quality of partial mastectomy in the second group was presumably also improved, survival remained equally poor. None of the other studies dealt overtly with quality of surgery, and yet, on the basis of the evidence cited of incompleteness of both radical and extended operations, this is probably the factor that explains their small differences in survival results, exactly as it did in the first group of stage I patients in the Guy's trial. The quality of surgery in our institution, where fully trained surgeons have always scrubbed in, underwent change when a blood bank and well-developed anesthesia service allowed the duration of radical mastectomy to increase from an average of 1.6 hours from 1927 through 1944 to 3.7 hours from 1945 through 1978. While survival of patients at pathologic stage I remained the same (74 and 73 percent) at 10 years in the two eras, survival at pathologic stages II and III, in which the better care in dissection now possible would likely make the most difference, 316 I DonaldJ. Ferguson ¦ Mastectomy and Survival ----- 1st Series ------ 2nd Series Significance P<.0007 —i--------1--------1--------1--------r--------1--------r--------1-------1--------r-------1 ? t~ 84 96 108 120 U2 14a 156 168 100 19? 204 216 2:8 Months Fig. 1.—Survival of patients at stage I in project 4 after radical mastectomy performed by surgical trainees (first series) compared to that following the same operation performed by specialists in breast surgery (second series). Reprinted from [7] with permission. increased from 29 to 47 percent and from 8 to 26 percent, respectively [8]. It may also be pertinent to the quality of mastectomy that survival of black patients at 5 years at each stage is 4 to 14 percent lower than that of Caucasians in a widely based sample from this country [30]. Black patients , mostly in a lower socioeconomic group, are more often operated on by trainees with only nominal supervision. In our institution, survival in the two races is the same [28]. Survival rates would be the ultimate test of the quality of resection if they could be reliably compared between one project and another. Such comparisons are not appropriate because of uncontrolled variations in patient selection and clinical staging, both of which are partly subjective, and because of unique restrictions to entry such as found in project 8. Nevertheless it can be noted that survivals are unusually low after radical mastectomy in projects 6 and 7 and the first series of project 4 compared to other experience in project 4, project 2, and elsewhere [8]. Survival and Recurrences: The End Results The objective of the Guy's Hospital trial, project 4, was, according to Atkins, to test "the hypothesis that radical mastectomy was no more effective in preserving life in cases ofearly cancer ofthe breast than such restricted surgery as simple removal of the lump" [6]. The results at 10 Perspectives in Biology and Medicine, 30, 3 ¦ Spring 1987 \ 317 ____ Radical ------ W.E. Significance P<002 40 Months 80 96 104 Fig. 2.—Survival of patients at clinical stage I up to 10 years after radical mastectomy, compared to that after partial mastectomy (Wide Excision, W.E.) in project 4. Reprinted from [7] with permission. and 20 years show that the smaller procedure failed for both clinical stages I and II (table 1, figs. 2 and 3). Adjuvant radiotherapy, given to both treatment groups, has been criticized as being inadequate for the smaller procedure. To prove equal to radical mastectomy, it would have to reduce mammary and axillary recurrences to zero without causing appreciable morbidity, an unlikely possibility [21]. Whether or not radiotherapy was at the optimum dosage in project 4, the basic question pertained to the extent of surgery, and it was given a clear answer. The Bruce trial, project 3, also significantly favors radical mastectomy over a smaller operation for patients at stage I, though not for those at stages II and III. Only half the patients had been followed for 10 years at last report. No significant differences were found in the other studies, except that local recurrence was higher in project 5 after the smaller operation (table 1). In this study at 5 years, patients at stage II with medial-central cancers had a significantly higher survival after extended, compared to radical, mastectomy; this comparison of subgroups was not reported at 10 years. (We also observed higher survival for medial-central tumors, 62 percent of the total in our series, after extended radical mastectomy 3 18 I DonaldJ. Ferguson ¦ Mastectomy and Survival ------ Radical ----- WE Significance P< .05 —?-------1-------1-------1-------t------t-------1-------1-------1-------1-------1-------1-------1-------1-------1-------1-------1 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 FiG. 3.—Survival of patients at clinical stage II up to 20 years after radical mastectomy, compared to that after partial mastectomy (Wide Excision, W.E.) in project 4. Reprinted from [7] with permission. at 5 years [28] and will report on this randomization, in which the survival difference continues, at 10 years.) The nonsignificant differences in survival in the table also are mainly in favor of the larger procedure. Postoperative Radiotherapy Radiotherapy was used to supplement only the smaller of the two procedures in projects 1, 3, 6 (stage II), 7, and 8. Assuming that it may have affected survival, both the extent of surgery and the radiation are without controls in these protocols. Another group of total mastectomies in project 6 who received radiotherapy is not listed in the table because it is not relevant to the surgical comparison; their survival was 6 percent higher than that Ofcontrols who had total mastectomy without radiation, a difference not statistically significant. No indication of late (8 + years) toxicity of radiotherapy was given in these studies. (Serious complications have been observed at 8 to 40 years in 1 1 percent of patients who had adjuvant radiation after radical mastectomy [31], and, to date, there has been a 4 percent mortality directly attributable to radiation in this series.) The basic problem with any adjuvant is that some cancer cells are Perspectives in Biology and Medicine, 30, 3 ¦ Spring 1987 \ 3 19 resistant to it. The chance that adjuvant chemotherapy, endocrine treatment , or radiation can eliminate all remaining cancer cells after mastectomy is therefore better if there are fewer of them and should be maximal following the most complete operations. No controlled trial of any adjuvant has been carried out in groups of patients each of whom had a demonstrably careful and complete operation. The Changing Faces of the Data It is instructive to compare sequential reports on the same projects. The Guy's trial (partial vs. radical mastectomy) has often been cited as evidence that smaller operations are "just as good," viz. Atkins 1972 (referring to all the data): "No significant difference between the results of the two operations can be detected at any time up to 10 years after treatment." But later: "in stage 2 cases radical mastectomy gives significantly better survival ... at 10 years but not at 5 years" [6]. Hayward , in 1977, stated, "There was no significant difference between the two operations in 5- and 10-year survival" (referring to patients in both stages). And, after tylectomy at stage I, "In almost all cases, local recurrence can be treated successfully by further surgery or radiotherapy and it does not appear to affect distant recurrence or survival" [32]. Hayward stated in 1980, ". . . there is no firm evidence that local control of disease can be achieved by any treatment other than mastectomy" [33]. Hayward , in 1981, stated, "If the primary complex is treated inadequately, the tumour recurs locally, the distant metastatic rate increases and survival is diminished" [34]. (Halsted may have wafted this thought from the empyrean.) The most recent report, published in a book mainly about radiotherapy—not in our library or bookstore and not indexed by Medline—documents significantly higher survival at 10-20 years for both stages I and II after radical mastectomy [7]. It is as if this result, not what was expected and wanted, although honestly reported, was laid to rest. In 1986, this project continues to be referred to as supporting the avoidance of mastectomy [35]. The Bruce trial similarly was, for many years, cited as evidence that the radical procedure was no better (viz. Bruce 1971). There is "no statistically significant difference in survival data." (The 5-year survival for radical mastectomy was 76 percent, for total mastectomy 66 percent) [13]. Hamilton stated in 1974, "There is no significant difference in survival between patients randomly allocated to simple mastectomy plus radical radiotherapy or standard radical mastectomy" at 5 years [36]. Hamilton statec' in 1977 that the difference was 3 percent at 10 years [37]. Three years later, the latest report [5] gives radical mastectomy a 9.5 percent advantage at 10 years, P < .05 (table 1). This paper contains a fairly complete statistical analysis. 320 I DonaldJ. Ferguson ¦ Mastectomy and Survival Earlier Diagnosis, Smaller Cancers, and Cosmesis Preclinical or minimal breast cancer, usually discovered by mammography , includes noninvasive proliferations and microscopic cancers, or those up to 5 mm in diameter. Survival after total mastectomy has been close to 100 percent, and there is no need for more surgery. Partial mastectomy is not adequate because such tumors are commonly multicentric . In project 8, for example, there have already been a number of recurrences and "new" cancers in the breasts so treated. Cancers over 5 mm in diameter have appreciable risk of adenopathy, and the safest treatment is a complete operation. Given the clear choice that exists between preservation of mammary tissues and a reduced risk of recurrent cancer, the great majority of patients chooses the latter. Differences in appearance or function in postmastectomy patients who have had total, radical, or extended radical mastectomy are not recognized by most patients, nurses, or surgical residents who follow them in the clinic, assuming that the procedures have been properly performed. Replacement of muscle by shifting the origin of the latissimus dorsi at the time of mastectomy without alteration of the incision leaves the patient ready to receive a prosthesis under local anesthesia. Thus complete surgery need not be more deforming than total mastectomy (or modified radical mastectomy), and the patient who receives only the latter is subjected to increased risk for no good reason. Conclusions Analysis of the eight randomized comparisons of different types of mastectomy that have been carried to at least 10 years reveals some basic deficiencies. In four of the studies, radiotherapy was added only to the smaller procedure, thus clouding the surgical comparison. Nevertheless, in three of the four, the nonirradiated patients with the larger operations had the higher survival. Numbers of lymph nodes removed and examined were not given in six projects. In the other two, they were about half the number expected with careful surgery. In one study, the small number of nodes obtained was the same for radical as for simple or partial mastectomy, indicating that there was not much difference in the procedures. The only two studies of "extended radical" operations documented inadequate margins of resection. The two studies with significant differences in survival both favored the larger operation. Survival following mastectomies performed by surgical trainees was inferior to that following more thorough and careful operations performed by surgical specialists. The available data support the reasonable assumption that survival of breast cancer patients is proportional both to the nominal extent of the mastectomy and to the competence with which it is carried out. Perspectives in Biology and Medicine, 30, 3 ¦ Spring 1987 \ 32 1 REFERENCES 1.Forrest, A. P. M. Conservative management of breast cancer: a review of British controlled trials. Ann. R. Coll. Surg. Engl. 62:41-43, 1980. 2.Fisher, B. Laboratory and clinical research in breast cancer—a personal adventure. Cancer Res. 40:3863-3874, 1980. 3.Lvthgoe, P. J., and Palmer, M. K. Manchester regional breast study—5 and 10 year results. Br. J. Surg. 69:693-696, 1982. 4.Hamilton, T.; Langlands, A. O.; and Prescott, R. P. The treatment of operable cancer of the breast. Br. J. Surg. 61:758-761, 1974. 5.Langlands, A. O.; Prescott, R. J.; and Hamilton, T. A clinical trial in the management of operable cancer ofthe breast. Br.J. Surg. 67:170-174, 1980. 6.Atkins, H.; Hayward, J. L.; Klugman, D. J.; and Wayte, A. B. Treatment of early breast cancer: a report after 10 years of a clinical trial. Br. Med. J. 2:423-429, 1972. 7.Hayward, J. L. The Guy's Hospital trials on breast conservation. In Conservative Management ofBreast Cancer, edited by J. R. Harris, S. Hellman, and W. Silen. Philadelphia: Lippincott, 1983. 8.Ferguson, D. J.; Meier, P.; Karrison, T.; et al. Staging ofbreast cancer and survival rates. An assessment based on 50 years of experience with radical mastectomy. JAMA 248:1337-1341, 1982. 9.Kaae, S., and Johansen, H. Breast cancer: five year results: two random series of simple mastectomy with postoperative irradiation versus extended radical mastectomy. Am. J. Roentgenol. 87:82-88, 1962. 10.Kaae, S., and Johansen, H. Simple mastectomy plus postoperative irradiation by the method of McWhirter for mammary carcinoma. Ann. Surg. 170:895-899, 1969. 1 1 . Brinkley, D., and Haybittle, J. L. Treatment of stage-II carcinoma of the female breast. Lancet 2:291-295, 1966. 12.Brinkley, D., and Haybittle, J. L. Letter to the editor: Treatment of stageII carcinoma of the female breast. Lancet 2:1086-1087, 1971. 13.Bruce, J. Operable cancer of the breast: a controlled clinical trial. Cancer 28:1443-1452, 1971. 14.Lacour, J.; Bucalossi, P.; Cacares, E.; et al. Radical mastectomy versus radical mastectomy plus internal mammary dissection. Cancer 37:206-214, 1976. 15.Lacour, J.; Le, M.; Cacares, E.; et al. Radical mastectomy versus radical mastectomy plus internal mammary dissection. Cancer 51 : 1941-1943, 1983. 16.Fisher, B.; Montague, E. D.; Redmond, C; and Barton, B. Comparison of radical mastectomy with alternative treatments for primary breast cancer. Cancer 39:2827-2839, 1977. 17.Fisher, B.; Redmond, C; Fisher, E. R.; et al. Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation. N. Engl. J. Med. 312:674-681, 1985. 18.Lythgoe, J. P.; Leck, L; and Swindell, R. Manchester regional breast study. Lancet 1:744-747, 1978. 19.Veronesi, U.; Saccozzi, R.; and Vecchio, M.D. Comparing radical mastectomy with quadrantectomy, axillary dissection, and radiotherapy in patients with small cancers of the breast. N. Engl. J. Med. 305:6-11, 1981. 20.Veronesi, U.; Zucali, R.; and Luini, A. Local control and survival in early breast cancer: the Milan trial. Int. J. Radial Oncol. Biol. Phys. 12:717-720, 1986. 322 I DonaldJ. Ferguson ¦ Mastectomy and Survival 21.Hayward, J. L. The conservative treatment of early breast cancer. Cancer 33:593-599, 1974. 22.Fisher, B.; Bauer, M.; Margolese, R.; et al. Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. N. Engl. J. Med. 312:665-673, 1985. 23.Hulthorn, A.; Hulton, L.; Roos, B.; et al. Effectiveness of axillary lymph node dissection in modified radical mastectomy with preservation of pectoral muscles. Ann. Surg. 179:269-277, 1974. 24.Urban, J. A. Radical mastectomy with en bloc in continuity resection of the internal mammary lymph node chain. Surg. Clin. North Am. 36:1-18, 1956. 25.McDonald, J. J.; Haagensen, C. D.; and Stout, A. P. Metastasis from mammary carcinoma to the supraclavicular and internal mammary lymph nodes. Surgery 34:521-542, 1953. 26.Dahl-Iversen, E., and Tobiassen, T. Radical mastectomy with parasternal and supraclavicular dissection for mammary carcinoma. Ann. Surg. 170:889-891, 1969. 27.Veronesi, U., and Zingo, L. Extended mastectomy for cancer of the breast. Cancer 20:677-680, 1967. 28.Meier, P.; Ferguson, D. J.; and Karrison, T. A controlled trial of extended radical mastectomy. Cancer 55:880-891, 1985. 29.Veronesi, U., and Valagussa, P. Inefficacy of internal mammary nodes dissection in breast cancer surgery. Cancer 47:170—175, 1981. 30.Young, J. L.; Ries, L. G.; and Pollock, E. S. Cancer patient survival among ethnic groups in the United States./. Nat. Cancer Inst. 73:341-352, 1984. 31.Ferguson, D. J.; Sutton, H. G, Jr.; and Dawson, P. J. Late effects of adjuvant radiotherapy for breast cancer. Cancer 54:2319—2323, 1984. 32.Hayward, J. L. The Guy's trial of treatments of "early" breast cancer. World J. Surg. 1:314-316, 1977. 33.Hayward, J. L. Radical breast surgery. Ann. R. Coll. Surg. Engl. 62:43-45, 1980. 34.Hayward, J. The surgeon's role in primary breast cancer. Breast Cancer Res. Treat. 1:27-32, 1981. 35.Bluming, A. Z.; Dosik, G; Lowitz, B.; et al. Treatment of primary breast cancer without mastectomy. Ann. Surg. 204:136—147, 1986. 36.Hamilton, T.; Langlands, A. O.; and Prescott, R. J. The treatment of operable cancer of the breast. Br. J. Surg. 61:758—761, 1974. 37.Hamilton, T., and Langlands, A. O. A clinical trial in the management of operable cancer of the breast./. R. Coll. Surg. Edinb. 22:52-55, 1977. Perspectives in Biology and Medicine, 30,3 ¦ Spring 1987 | 323 ...