Surgery and Radiotherapy for Primary Breast Cancer: What We Have Learned from the Controlled Clinical Trials

Symposium on Breast Cancer

Surgery and Radiotherapy for Primary Breast Cancer What We Have Learned from the Controlled Clinical Trials

RogerS. Foster, Jr., M.D.*

This article reviews the prospective controlled trials relative to the local and regional management of primary carcinoma of the breast. Table 1 lists the varieties of treatments that have been used for treatment of primary cancer in the breast and axillary lymph nodes, as well as the internal mammary and/or supraclavicular nodes. The possible combinations of those treatments number well over 100. Not all of these combinations of alternate treatments have been tested in controlled clinical trials. Yet, most of the important combinations and issues in loco-regional treatment of primary operable breast cancer with surgery and radiotherapy have been or are being studied. The term operable breast cancer is used to refer to cancers that on clinical study appear to be confined to the breast and regional nodes; it implies that all clinically evident cancer can be completely extirpated by the surgical procedure. All physicians recognize that in fact operable breast cancer is all too frequently accompanied by occult metastatic disease that only becomes evident months to years later. Patients with grave signs such as inflammatory skin changes, chest wall fixation of the tumor, fixation of axillary nodes, satellite skin nodulation, or arm edema, which are predictive of almost universal recurrence after resection, are generally excluded from the group of primary operable breast cancers. Moreover, patients with signs of metastases outside the locoregional area do not have primary operable breast cancer. For conceptual purposes, the trials reviewed herein are divided into two groups: those that address the management of the regional nodes, and those that address the issue of total versus partial mastectomy. *Professor of Surgery, Department of Surgery, and Director, Vermont Regional Cancer Center, University ofVermont College of Medicine, Burlington, Vermont

Surgical Clinics of North America-Val. 64, No. 6, December 1984

1125

1126

RoGERS. FosTER,

JR.

Table 1. Treatment Alternatives Used in Local and Regional Management of Patients with Primary Breast Cancer Treated with Surgery andlor Radiotherapy TREATMENT ALTERNATIVES FOR:

Breast Excision of breast and pectoral muscle(s)

Irradiation after axillary dissection

Excision of total breast

Irradiation alone

Excision of gross cancer with margin of "normal" breast (segmental mastectomy or tylectomy)

Axillary dissection, le~els I, II, and III

Excision of gross cancer with margin of "normal" breast (segmental mastectomy or tylectomy) plus irradiation Excision of cancer at apparent junction of cancer and normal tissue (lumpectomy) plus irradiation (usually with boost to tumor site)

Internal Mammary and/or Supraclavicular Nodes

Axillary Nodes

Axillary dissection, levels I and II Axillary sampling (incomplete dissection)

Super-radical mastectomy (radical mastectomy plus dissection of supraclavicular and internal mammary ± mediastinal regions) Irradiation to supraclavicular and internal mammary nodes Extended radical mastectomy (radical mastectomy plus resection of internal mammary nodes) Internal mammary node sampling (as staging procedure)

Axillary sampling plus irradiation Observation (treatment only for progressive disease)

Irradiation alone without tumor excision Excision of cancer at apparent junction of cancer and normal tissue (excisional biopsy)

HISTORICAL OVERVIEW Results of Untreated Cases Before considering the results of local and regional treatment alternatives, the fate of patients who receive no treatment for breast cancer should be considered. The most complete data are from a study by Bloom of 1728 cases from 1800 to the early 1900s. As was common in those times, many of the patients had advanced disease when first seen. The 5~year survival was calculated at 18.5 per cent, while at 10 years the survival rate was less than 5 per cent, and at 15 years the survival rate was less than 1 per cent (Fig. 1). 6 Historic and Anecdotal Reports of Treatment Despite Bloom's large series of untreated cases, the assumption that surgical treatment of breast cancer is new is fallacious. For at least the past two thousand years there have been alternating approaches to the extirpation of breast cancer by total mastectomy or by radical excisions of the

1127

SURGERY AND RADIOTHERAPY FOR PRIMARY BREAST CANCER

2

4

6

8

14

16

18 20 22

YEARS AFTER FIRST SYMPTOM Figure l. Life table for patients with untreated breast cancer at Middlesex Hospital, 1805--1933 (triangles), compared to patients treated by Halsted radical mastectomy at Johns Hopkins Hospital, 1889-1931 (circles). (From Henderson, I. C., and Canellos, G. P.: Cancer of the breast: The past decade. N. Engl. J. Med., 302:79, 1980; with permission.)

breast and axillary nodes, with or without excision of the pectoral muscle, and/or by partial mastectomy. 50 The early Romans performed some form of radical mastectomy for breast cancer that included removal of the pectoral muscles. During the Dark Ages, surgery for management of breast cancer was little used, and at the Council of Tours in 1162, the Church frowned on the use of surgery to treat breast cancer. Forerunners of modern surgeons included Ambroise Pare (1510-1590), who advocated local excision for smaller cancers, as well as the application of topical agents; Andreas Versalius (1514--1564), who treated breast cancer by wide local excision; Marcus Aurelius Severinus (1580-1659), who radically excised the breast and axillary nodes simultaneously; Laurentius Heister (1683-1758), who resected the breast as well as both muscle and ribs in cases where there was invasion; and James Syme (1789-1870), who recommended wide complete excision including removal of the axillary nodes. In the 19th century, apparently most surgeons treated breast cancer by limited resections, with local recurrence the rule. Alexander Monro (1773-1859) found only 4 of 60 treated patients surgically free of disease after 2 years. Sir James Paget (1814--1899), who had an operative mortality rate of 10 per cent in 235 cases, wrote "We may, I think, dismiss that the operation will be the final remedy of the disease." In 1867, Charles Moore discussed the embolic nature of cancer metastases through the blood vessels and lymphatics, and elaborated the basic principles of breast cancer surgery. He wrote that "It is desirable to avoid not only cutting into the tumor but also seeing it ... lest the active microscopic elements in it should be set

1128

RoGERS. FosTER,

JR.

free and lodge in the wound. Diseased axillary glands should be taken away at the same dissection as the breast itself. "54 Routine removal of the axillary nodes in the treatment of breast cancer was practiced as early as 1871 by Kiister44 in Germany and in 1878 by Banks4 in England. Banks had operated on more than 300 patients by 1902 using a technique of en bloc removal of breast and axillary contents without division of the pectoralis major. Under the influence of Halsted, 32 • 33 complete axillary dissection became relatively routine. The classical radical mastectomy became accepted at a time when most patients with breast cancer presented with large and advanced lesions, and metastatic involvement of axillary nodes was common. Three-quarters of Halsted's patients had axillary metastases. In Halsted's own experience, the 10-year survival rate was only 12 per cent (Fig. 1), but his local and regional recurrence rate was far lower than that of his surgical contemporaries who were doing limited resections of advanced cancers. 49 Throughout this century there have been progressive improvements in the results of treatment of breast cancer by radical mastectomy despite little change in the basic surgical technique. At the Massachusetts General Hospital, the disease-free survival rate at 5 years after radical mastectomy was 19 per cent in the period 1894 to 1904, 35 per cent for the years 1921 to 1923, and 50 per cent in the years 1933 to 1941. 68 Haagensen has reported a personal series of highly selected patients operated on between 1935 and 1972, which had a 10-year survival rate of more than 70 per cent. 30 These progressively improving results were doubtless due to a combination of stricter criteria of case selection and the fact that patients presented for treatment with progressively smaller cancers.

ARE PROSPECTIVE TRIALS NECESSARY? Imaginative genius, intuitive insight, and logic based on understanding of biologic principles are important preludes to advances in clinical care. When the new therapy is so effective that it provides a quantum advance, a clinical trial may be unnecessary; unfortunately, there has been no such major advance in the treatment of breast cancer. Retrospective comparisons are fraught with many problems and are highly susceptible to both overt and covert biases. Apparent differences in results may be due to differences in clinical acumen or simply differences in the fashion of recording or the completeness of the data. The genetic constitution of the patient population or the environment (for example, diet) can have a significant impact on prognosis and perhaps on outcome of treatment despite apparently comparable stages of disease. Unless total populations of patients in a geographic area are studied, selection bias based on referral patterns can be profound. Mere designation of a trial as randomized and prospective is not sufficient to assure the value of the data produced and does not permit uncritical acceptance of the conclusions drawn. 65 Many of the smaller trials, while failing to show statistically significant differences, are subject to a large beta- or type 11-statistical error. 29 There may be problems of compliance with treatment according to protocol designation, loss to follow-up,

SURGERY AND RADIOTHERAPY FOR PRIMARY BREAST CANCER

1129

and incompleteness of reporting. The earlier clinical trials of breast cancer management were more commonly plagued by these problems. Progressively increasing sophistication in the methodology of clinical trials has helped move discussions on surgical and radiotherapeutic management of breast cancer from the level of heated and frequently acrimonious debate to the level of scientific inquiry. 21 • 48 This review emphasizes the results of controlled, prospective randomized trials; many of these trials have established that the local and regional therapy alternatives have equal efficacy or lack thereof. Several pioneering retrospective studies are briefly reviewed below for their historical perspectives.

CliNICAL TRIALS RELATIVE TO MANAGEMENT OF REGIONAL NODES Clinical Trials of Irradiation as an Adjunct to Axillary Dissection Roentgen irradiation therapy as a prophylactic adjunct to mastectomy, which was used by Pusey in Chicago in 1901, 19 had, by the middle of this century, become a popular adjunct. The first prospective clinical trials in the management of breast cancer were the Manchester Trials, 20• 58 which addressed the addition of prophylactic radiotherapy to standard radical mastectomy versus an observation policy of treatment only if locoregional recurrence developed (Table 1). A total of 1461 patients entered into two trials of two different types of radiotherapy at 10 years had identical survival rates for both the treated and the observed groups. In the first trial, radiotherapy was directed to the chest wall and axilla, and in the second trial to the axilla and supraclavicular and internal mammary areas. The incidence of local recurrence was reduced by the postoperative radiotherapy, but local control was equal when radiotherapy was given at the time of recurrence. The outcome of the National Surgical Adjuvant Breast Project (NSABP) postoperative radiotherapy trial with 1103 patients was similar24 to the outcome of Manchester Trials. There was no advantage for the prophylactically irradiated group in terms of disease-free status or survival at 5 years; local and regional recurrences were decreased. These two early trials have been criticized on the basis that the modes of irradiation were suboptimal by current standards and because both trials had flaws in their design and execution. 5 • 19 Two more recent trials of postoperative irradiation in Stockholm 74 and Oslo, 39 employing modern radiotherapy techniques and stricter randomization procedures, have confirmed the results of the previous trials (see Table 2). Adjuvant radiotherapy reduces the incidence of locoregional recurrence, but neither improves nor reduces the overall survival rate nor alters the incidence of distant metastases. A policy of observation, in which irradiation is used for therapeutic treatment of recurrence, results in the need to treat a much smaller number of patients. Trials Comparing Alternative Approaches to the Management of Axillary Nodes The untreated axilla can be a site of progressive or recurrent disease following treatment of the primary tumor in the breast. Knowledge of this

1130

ROGERS. FOSTER,

JR.

Table 2. Results of Irradiation Trials to Chest Wall and Regional Node Areas as an Adjunct to Axillary Dissection TRIAL (DATES OF ENTRY)

Manchester"· (1949--1955)* (1952-1955)t

NO. OF PATIENTS

58

720 741

RANDOMIZATION

RESULTS

Radical mastectomy vs. Radical mastectomy plus irradiation

No difference in survival or distant recurrent disease at 10 years; decreased locoregional recurrence

NSABP24 (1961-1968) Protocol B-02

1103

Radical mastectomy vs. Radical mastectomy plus irradiation:!:

No difference in survival or distant recurrent disease at 5 years; decreased locoregional recurrence

Oslo39 (1964-1972)

1089

Radical mastectomy (plus irradiation, castration) vs. Radical mastectomy plus irradiation§ (plus irradiation castration)

No difference in survival or distant recurrent disease at 8 years; decreased locoregional recurrence

Stockholm74 (1971-1976)

960

Radical mastectomy vs. Irradiation§ before radical mastectomy vs. Radical mastectomy plus irradiation§ after mastectomy

No difference in survival or distant recurrent disease at 10 years; decreased locoregional recurrence

*Irradiation tirradiation :j:Irradiation §Irradiation

to to to to

operative area and to axilla. axilla, supraclavicular, and internal mammary areas. apex of axilla, supraclavicular, and internal mammary areas. supraclavicular and internal mammary areas.

possibility, as well as the knowledge that axillary nodes that are normal on clinical examination frequently contain metastases on histologic examination, led to the development of a relatively routine practice of axillary dissection. This was presumed to both prevent further progression of disease in the axilla and to remove a source of secondary metastases. A few observers noted, however, that progression of axillary disease was not as frequent as would be predicted from the histologic findings. In 1922, W. S. Handley34 raised the possibility that some metastases in the nodes could be destroyed by the host. Later, George Crile, Jr., championed the possibility that the regional nodes might play an important immunologic role in systemic resistance to metastases. 17 Sir Geoffrey Keynes, a surgeon at St. Bartholomew's Hospital in London, pioneered the use of interstitial radium implants in both the breast and the axillary node area. 41-43 McWhirter in Scotland provided a major challenge to routine surgical dissection of the axilla when he reported his experience and views on the treatment of breast cancer by simple mastectomy and radiotherapy. 51-53 Crile 14• 15· 17 reported on patients treated by simple mastectomy alone; if axillary recurrence did occur at a later time, delayed axillary dissection

SURGERY AND RADIOTHERAPY FOR PRIMARY BREAST CANCER

1131

was performed, frequently with the addition of radiotherapy. He believed his results were at least as good as, if not superior to, radical mastectomy. The frequently acrimonious controversy generated by proponents and opponents of the above-described treatment alternatives for the axillae of breast cancer patients has only recently begun to be resolved following the availability of data from controlled clinical trials. Three early clinical trials compared radical surgery with simple mastectomy and radiotherapy using the McWhirter regime of 4500 rad over a period of 3 to 4 weeks (Table 3). The Cambridge Trial was limited to patients with palpable axillary nodes. 7 · 8 A Halsted radical mastectomy, followed by radiotherapy, was compared to similar radiotherapy given after a "modified" simple mastectomy, during which surgeons removed accessible nodes but did not perform a formal axillary dissection. There were no differences in survival rates or disease-free survival at 10 years of follow-up time. The Edinburgh or Southeast Scotland Trial, begun in 1964, compared a Halsted radical mastectomy without radiotherapy to a simple mastectomy with radiotherapy. At 5 years, results in 203 patients showed no significant differences in survival. 9 A report of up to 12 years of follow-up of 498 patients, however, showed that survival rate was signficantly better (P<0.05) for the group with radical mastectomy, particularly for those with clinical stage I disease. The authors of the more recent report advise caution in the interpretation of the differences in survival, as there was an excess number of deaths in the simple mastectomy and radiotherapy group, which was attributed to causes other than cancer. 47 The Copenhagen Trial addressed the role of extending the nodal dissection by comparing simple mastectomy and radiotherapy to a superradical mastectomy in which the breast and pectoral muscles, as well as axillary, supraclavicular, and internal mammary nodes were removed (Table 4). 40 There were no significant differences in either survival or loco regional recurrence at 10 years of follow-up. There have been two large clinical trials and one smaller one that addressed the issue of no initial treatment of axillary nodes versus prophylactic treatment with either surgery or radiotherapy. The Southampton Trial compared simple mastectomy and axillary biopsy for staging (node sampling) without radiotherapy to similar surgery, followed by radiotherapy to the chest wall and the axillary, supraclavicular, and internal mammary nodal areas. 70 Short-term follow-up of the 150 patients entered in the study showed no tendency for the irradiated patients to do either better or worse in terms of distant disease recurrence or survival at 3 years, but the number of patients involved in the trial is clearly too small a number to draw conclusions. The Cancer Research Campaign (Kings-Cambridge Trial) has been updated to 8 years of follow-up. 10 The question posed in this trial was, "Does prophylactic radical radiotherapy to the chest wall and regional nodes influence survival when compared to simple mastectomy alone with a waitand-watch policy in which radiotherapy is given only for clinical evidence of progressive disease?" At 8 years, no differences in survival existed between the two groups, although again it was demonstrated that prophy-

Table 3. Results of Surgery Versus Irradiation Trials Compared with Initial Observation Only for Axillary Nodes* NO. OF TRIAL (DATES OF ENTRY)

PATIENTS

RANDOMIZATION

RESULTS

Cambridge7• 8 (1958-1965) All patients: clinically node positive

204

Radical mastectomy plus irradiation vs. "Modified" simple mastectomy plus irradiation

No difference in survival or local failure at 10 years

Edinburgh9• 47 t (SE of Scotland) (1964-1971)

498

Radical mastectomy

Significant (p < 0. 05) survival advantage at 12 years for radical mastectomy group almost entirely accounted for by patients with stage I disease (there was an excess number of deaths, which was attributed to causes other than cancer in the group having simple mastectomy irradiation)

Cancer Research Campaign (King' s/Cambridge )10 (1970--1975) 25% pts: node positive 75% pts: node negative Southampton70 (1973-1975)

NSABP Protocol B-0425 (1971-1974) Clinically node negative

Clinically node positive

vs. Simple mastectomy plus irradiation

2243

150

1079

Simple mastectomy, observation, and therapeutic irradiation when required vs. Simple mastectomy plus irradiation

No difference in survival at 8 years; local recurrence or progression decreased with x-ray

Simple mastectomy and axillary sampling vs. Simple mastectomy and axillary sampling plus irradiation

No difference in survival at 3 years; local recurrence decreased with x-ray

Radical mastectomy

No difference in survival between the three groups at 7 years; only 20% of patients in observation group required delayed axillary dissection

vs. Total mastectomy, observation, and therapeutic dissection of axilla when required vs. Total mastectomy plus irradiation 586

Radical mastectomy vs. Total mastectomy plus irradiation

...... ...... w ~

6'C"l t'l ::ll

en

No difference in survival between the two groups at 7 years

* ± Irradiation of internal mammary and supraclavicular nodes. tPatients in both groups had ovariectomy or radiation of ovaries if they were 60 years or younger.

"'"'t;l' 0

?:1 ..._ ?l

1133

SURGERY AND RADIOTHERAPY FOR PRIMARY BREAST CANCER

Table 4. Results of Trials of Extended Surgical Treatment of Regional Nodes (Internal Mammary and Supraclavicular Nodes) TRIAL (DATES OF ENTRY)

Copenhagen (1951-1957)

40

International Trial of Extended Mastectomy45 · 46 (1963-1968) Milan Cancer Institute Trial72 (included in International Trial, above)

NO. OF PATIENTS

RANDOMIZATION

RESULTS

666

Simple mastectomy plus irradiation vs. Extended radical mastectomy

No difference in survival or local recurrence

1453

Radical mastectomy vs. Extended radical mastectomy

No difference in survival or distant metastases at 10 years; decreased locoregional recurrence in group with extended mastectomy

737

Radical mastectomy vs. Extended radical mastectomy

No difference in survival or distant metastases at 10 years; parasternal recurrence decreased in group with extended radical mastectomy

lactic radiotherapy was capable of decreasing locoregional recurrence. Subset analyses were possible on the 2243 patients. No differences between the watch-and-wait policy and prophylactic radiotherapy were seen on examination of subsets based on tumor size, tumor location in the breast (medial versus lateral), age, and menopausal status. Local recurrence or progression of disease was three times more common in the wait-and-watch grou~O per cent by 5 years, compared to 10 per cent in the group that received immediate irradiation. Progression of axillary disease was not particularly surprising, since one-fourth of the patients had clinically positive nodes. It might be surmised that at least half the patients would have had axillary nodes that were histologically positive for cancer; thus theoretically 50 per cent of the patients not prophylactically treated had the possibility of progressing to clinically evident disease, whereas only 30 per cent did so. In this country, the NSABP Protocol B-04 trial with 1665 patients entered has been underway since 1971. 25• 26 This trial is actually two separate, concurrent trials: one for patients with clinically positive nodes and one for those with clinically negative nodes. For patients whose axillary nodes were positive, the aim of the trial was to compare radical surgical treatment of the axillary nodes to radical regional radiotherapy to the axillary nodes, as well as the supraclavicular and internal mammary nodes and chest wall. It is not anticipated that the 10-year follow-up data will differ from the 7-year data in Figure 2, which shows that both distant treatment failure and survival rates were similar for the treatment alternatives. For patients whose axillary nodes were clinically negative, one-third of the patients were randomized to prophylactic treatment of the axillary nodes by a Halsted-style radical mastectomy; nearly 40 per cent of these

RoGER S. FosTER, JR.

1134

TOTAL MASTECTOMY PLUS RADIATION

RADICAL MASTECTOMY

I-

--

-ANY DISTANT TREATMENT FAILURE-

-SURVIVAL-

'~~

60

40

20

3

4

6

7

0

I

YEARS POST MASTECTOMY

2

3

4

56

7

1;;•_s,~~';;,

Figure 2. NSABP Protocol B-04 trial of relationship of type of regional lymph node management to distant treatment failure and survival for patients with clinically positive axillary nodes. In the group treated by radical mastectomy, approximately 75 per cent had axillary node metastases confirmed histologically; similar involvement would be predicted in the group randomized to total mastectomy plus radiotherapy. From other studies it can be predicted that approximately 33 per cent of the patients in each of the groups with clinically positive nodes had internal mammary node metastases. Internal mammary and supraclavicular lymph nodes were not prophylactically treated in the radical mastectomy group. (From Fisher, B.: A commentary on the role of the surgeon in primary breast cancer. Breast Cancer Res. Treat., 1:17-26, 1981; with permission.)

patients proved to have occult metastases in their axillary nodes identified on routine histologic examination. Another third of the patients with clinically negative nodes were treated by total mastectomy alone, with re-examination at 3-month intervals; only 60 of the 365 patients (16.4 per cent) required a delayed axillary dissection for progressive disease at a mean follow-up of 94 months. Far fewer patients had a delayed axillary dissection than the 40 per cent of patients who might have possibly progressed, based on incidence of metastases in the group having radical mastectomy. Most of the patients requiring a delayed axillary dissection had the procedure within 24 months, but an occasional patient has had progression of axillary disease after 10 years. The final third of patients with negative nodes was treated by total mastectomy and radical regional radiotherapy. As indicated in Figure 3, the curves for distant treatment failure, as well as survival, are similar out to 7 years of follow-up. Moreover, it should be noted that, when the subgroup of patients with central and medial breast cancer in whom the highest incidence of internal mammary metastases would occur was separately examined, there was no survival advantage for the patients treated

1135

SURGERY AND RADIOTHERAPY FOR PRIMARY BREAST CANCER TOTAL MASTECTOMY PLUS RADIATION

RADICAL MASTECTOMY

TOTAL MASTECTOMY 365 PTS

362 PTS

~-\.

\'

I

~% ~~

QO~

0

2

3

4

+

&

/

:

-SURVIVAL-

~

:~


.. +. .. .. 0%

'

-ANY DISTANT TREATMENT FAILURE-

40t

-;

100~ :

56

'1

::r ... ~ 0

I

2

3

YEARS POST MASTECTOMY

4

56

7

-NSABP(12- 31- 79)

Figure 3. NSABP Protocol B-04 trial of relationship of type of regional lymph node management to distant treatment failure and survival for patients with clinically negative axillary nodes. In the group treated by radical mastectomy, approximately 40 per cent had metastases demonstrated histologically; similar involvement would be predicted in the group randomized to total mastectomy plus radiotherapy or total mastectomy and initial observation. From other studies it can be predicted that approximately 20 per cent of each group had internal mammary node metastases. Neither axillary, internal mammary, nor supraclavicular lymph nodes were prophylactically treated in the total mastectomy and initial observation group, and only the axillary nodes were prophylactically treated in the radical mastectomy group. (From Fisher, B.: A commentary on the role of the surgeon in primary breast cancer. Breast Cancer Res. Treat., 1:17-26, 1981; with permission.)

by radiotherapy whether the axillary nodes were clinically positive or negative. 28 Trials of Extended Surgical Treatment of Regional Nodes The trials described above have failed to show an advantage for extended radiotherapy in the supraclavicular and internal mammary nodal areas compared to axillary dissection only or even when compared to no initial treatment of regional nodes. From the clinical trials described below, similar conclusions must be reached relative to the efficacy of extended surgical operations that remove internal mammary nodes as well as axillary nodes. An international trial of radical mastectomy versus radical mastectomy plus internal mammary node dissection (extended mastectomy) was carried out from 1963 to 1968 and involved 1453 patients. 45 • 46 Nearly half the patients in the International Trial were treated at the Milan Cancer Institute and have been separately reported on by Veronesi and Valagussa. 72 Neither treatment group received postoperative radiotherapy. The 10-year report of the International Trial Group showed no differences in survival or relapse-free survival between the two treatment groups. There were more

--------

1136

RoGER S. FosTER, JR.

local recurrences in the radical mastectomy group, but these occurred mainly in patients who also had distant metastases. For the 737 Milan patients in the trial, there was similarly no difference in the 10-year survival. The incidence of internal mammary node metastases in the extended mastectomy group was 20.5 per cent, yet parasternal recurrences appeared in only 3. 7 per cent of the Halsted mastectomy patients who had no prophylactic internal mammary node treatment. Parasternal recurrences occurred in only 0.3 per cent of the extended mastectomy patients. While central and medially located primary tumors were more likely to be associated with internal mammary node metastases than lateral primary tumors (25 per cent versus 18 per cent), the site of tumor location in the breast did not affect survival. The extended mastectomy was no more efficacious as far as survival outcome for medial and central breast cancers than for lateral cancers. The Copenhagen Trial, as noted previously, compared simple mastectomy and radiotherapy to an extended mastectomy that included dissection of internal mammary nodes and supraclavicular nodes as well as axillary nodes. Ten-year survival rates, as well as distant and local recurrence rates, were similar in the two groups. 40 This trial has been criticized because some patients were not managed strictly according to protocol and a portion of "inoperable" cases was included. The exclusion of the "inoperable" patients in further analysis, however, did not affect the results. Conclusions from the Clinical Trials Relative to the Treatment of Regional Nodes Based on the currently available treatment options, the following conclusions related to management of regional nodes can be drawn: 1. Occult metastases are frequently present in patients with breast cancer who have clinically normal axillary nodes. There is a large error in clinical staging, with approximately one-fifth of clinically positive nodes being histologically normal and approximately two-fifths of clinically negative nodes being histologically positive. 2. Progression of occult metastatic disease in clinically negative nodes does occur, albeit much less frequently than might be anticipated from the pathologic findings. Thus, in the NSABP study, fewer than 20 per cent of the patients required a therapeutic axillary dissection after initial treatment by total mastectomy alone, whereas nearly 40 per cent of the control arm having an axillary dissection had histologically positive nodes. In the Milan study of extended radical mastectomy, 20 per cent of the patients were found to have internal mammary node metastases, but subsequent parasternal recurrence occurred in less than 4 per cent of the patients who did not have internal mammary node dissection. 3. Prophylactic therapy of regional nodes by either surgical extirpation or radical radiotherapy does not improve survival versus a policy of therapeutic treatment at a later date. This raises a question as to the importance of nodal metastases in the sequence of generalized metastatic disease. It would appear that nodal metastases are more a sign of generalized disease than instigators of generalized disease. 4. Prophylactic treatment of regional nodes with either surgery or

SURGERY AND RADIOTHERAPY FOR PRIMARY BREAST CANCER

1137

radiotherapy has not increased the incidence of distant metastases nor decreased the survival rate. Thus, the concept that disturbing the regional nodes in breast cancer patients breaches an important immunologic defense seems no more tenable. 13 5. Axillary node dissection of levels I and II currently plays an important role in staging. 27 The role of internal mammary node sampling for staging in selected patients, that is, those patients with no evident axillary node metastases and central or medial primaries, is currently being investigated. 55 Histologic evidence regarding the number of regional nodes involved provides important prognostic information and identifies candidates for systemic adjuvant therapy. 6. Surgical axillary dissection of levels I and II is followed by a low frequency of recurrence in the axilla. 7. The interesting speculation that a combination of systemic therapy and regional radiotherapy might provide a new rationale for regional node and chest wall radiotherapy is yet to be tested in a clinical trial. 5 This concept argues that the mastectomy site may provide an iatrogenic sanctuary due to scarring and poor vascularity that makes cancer cells relatively inaccessible to chemotherapy. This theoretical argument seems inadequate as a basis to promote the use of adjunctive radiotherapy outside of a clinical trial. The role of breast irradiation after partial mastectomy is a completely separate issue that is discussed below.

TRIALS INVOLVING LESS THAN TOTAL MASTECTOMY FOR CASES OF PRIMARY OPERABLE BREAST CANCER Until comparatively recently, it was almost a standard authoritarian opinion in the United States that the entire breast must be removed for the patient with primary operable breast cancer, no matter now small the primary tumor. This policy was based in part on the historic anecdotal reports of the pre-Halstedian era, when local recurrence had been almost universal after local tumor excision (usually incomplete excision of large primary tumors). The policy of complete mastectomy was reinforced by the pathologic observations that demonstrated microfoci of malignancy in areas remote from the presenting primary tumor. u Since the pioneering studies of Sir Geoffrey Keynes, retrospective case reviews by many authors have suggested that, for selected breast cancer patients, there were possible alternatives to treatment by total mastectomy. Table 5 summarizes reports published through 1980. Additional, more rece~t reports appear in the publication of a recent symposium. 35 In most of these reports, partial mastectomy was combined with some form of radiotherapy. A few reports, notably by Crile 17 and colleagues, suggested a possible role in selected patients for wide local excision without radiotherapy. Interpretation of these various reports of less than total mastectomy has been difficult because of the lack of randomized control patients treated by conventional surgery. It is anticipated that the results of the two large and relatively recent major trials described below (the

1138

ROGER

S.

FOSTER,

}R.

Table 5. Retrospective Reports up to 1980 for Selected Patients with Primary Breast Cancer Having Less Than Total Mastectomy AUTHOR/GROUP

NO. OF PATIENTS

DATE

COUNTRY

Adair1

TREATMENT

1943

U.S.A.

72

Mustakallio56

1946, 1954, 1972

Finland

702

Local excision and irradiation

Baclesse3

1949, 1965

France

431

Local excision or biopsy and irradiation

Williams et a!. 75

1953

England

127

Simple excision with or without irradiation

Porritt'52

1964

England

107

Local excision with and without irradiation

Segmental mastectomy and irradiation

CriJe16-1S

1965, 1967

U.S.A.

44

Peters et a!. 12· 59• 60

1967, 1977

Canada

124

Excisional biopsy and irradiation Local excision and irradiation

Quadrant excision with and without irradiation

Rissanen66

1969

Finland

415

Taylor et a!. 69

1971

England

77

Pierquin et a!. 61

1971, 1980

France

134

Wise et a!. 76

1971

England

96

Local excision and irradiation

Nelsen and Montague57

1975

U.S.A.

51

Wedge excision and irradiation

Prosnitz et a!. 64

1975

U.S.A.

293

Excisional biopsy and irradiation

Cope et a!. 13

1976

U.S.A.

121

Local excision and irradiation

Sector mastectomy and irradiation

.

"Simple lumpectomy and irradiation

Milan Trial and the NSABP Protocol B-06 Trial) will provide objective data to compare total mastectomy with partial mastectomy. Before considering the results of these two large trials, the earlier trials involving less than total mastectomy should be discussed (Table 6). Two of the earliest randomized clinical trials attempting to compare partial mastectomy and total mastectomy (simple mastectomy) were conducted at Guy's Hospital. 36• 37 Those trials, Guy's Hospital Trials I and II, were plagued by the problem of inadequate radiotherapy doses and also by the lack of a routine policy of operative salvage in cases in which there was local or regional disease recurrence. The first of these two trials, Guy's I, which began in 1961, was confined to patients older than age 50 who had either clinical stage I or stage II cancers. One group was treated by radical mastectomy followed by supraclavicular and parasternal radiotherapy; the other group was treated by a wide local excision of the primary tumor termed "tylectomy" without axillary dissection, followed by low-dose orthovoltage radiotherapy not exceeding 2700 rad to the axilla or 3800 rad to the breast. The trial was stopped after entry of 370 patients over a 10-year span, when it was felt that there was an excessive incidence of recurrence in the axilla and the breast. Survival was significantly worse for the stage

r

r:Jl

c

::0

Table 6. Results of Trials for Patients with Primary Operable Breast Cancer Having Less Than Total Mastectomy PATIENTS

Guy's Hospital37 1 (clinical stage I and II)

367

Guy's HospitaP 2 (clinical stage I)

Milan71 • 73 (T"N 0 ,M 0) only

7

~

RANDOMIZATION

RESULTS

Radical mastectomy plus irradiation* vs. Wide excision plus irradiation*

No difference in 10-year survival up to 20 years for stage I disease; significantly worse survival for patients with stage II disease treated by wide excision

252

Radical mastectomy plus irradiation vs. Wide excision plus irradiation*

Significantly worse survival of up to 10 years in wide excision group

701

Radical mastectomy

No difference in survival

vs. Quadrantectomy and axillary dissection plus irradiation to residual breast WHO Trial67 (T 1,T2 ,N 0) N 1b,M 0

NSABP Protocol 622 Tumor :s 4 em plus Axillary nodes :s 2 em

179

>2000

t'1

~

NO. OF TRIAL

0

z

Ci

~

Ci

§ :I:

t'1

$:

..,~ 0

::0 "d

2:: :::: ~

Total mastectomy and axillary dissection vs. Tumorectomy and axillary dissection with breast irradiation ± nodal irradiation

No difference in distant relapse or survival

Total mastectomy and axillary dissection vs. Segmental mastectomy and axillary dissection plus irradiation to residual breast vs. Segmental mastectomy and axillary dissection without breast irradiation

Publication of early data pending; both total mastectomy plus axillary dissection and segmental mastectomy and axillary dissection plus irradiation to residual breast now acceptable for entry on NSABP adjuvant systemic therapy trials

~ c:l ::0 t'1 ~

..,

[JJ

*Low-dose orthovoltage irradiation not exceeding 2700 rad to the axilla or 3800 rad to the breast.

(J ~

z

(')

t'1 ::0

,_,. ,_,. ~

<:0

1140

RoGER

S.

FosTER,

JR.

II patients with wide excision in the first trial. The second trial was limited to patients with clinical stage I disease. Again, the radiotherapy doses were low, and the patients in· the group having partial mastectomy fared less well, with a high incidence of local recurrence and poorer survival. Lowdose radiotherapy without a policy of routine secondary surgical treatment proved to be inadequate treatment. The Milan Trial, directed by Professor Umberto Veronesi, compared quandrantectomy, axillary dissection, and radiotherapy to Halsted mastectomy in a highly selected group of patients with clinically negative axillary nodes and with primary tumors smaller than 2 em in size (T 1,N0 ,M 0 ). 71 • 73 The more limited surgical procedure was a very wide local excision of the primary tumor with overlying skin and underlying fascia and complete axillary dissection with removal of the pectoralis minor. Radiotherapy was high-energy external beam opposing tangential field therapy to the breast to a dose of 5000 rad and an additional 1000 rad to the scar area. The comparison group was treated by a classic Halstedian mastectomy. There were 701 patients in the trial, which was carried out between 1973 and 1980. During the early years of the trial, patients in both groups with histologically positive axillary nodes received additional radiotherapy to the homolateral internal mammary and supraclavicular nodes. From 1976 to 1980, lymph node areas were no longer irradiated, and patients with positive nodes were treated with 12 cycles of cyclophosphamide, methotrexate, 5-fluorouracil (CMF) chemotherapy. After up to 9 years of followup (median follow-up, 5.4 years), the number of local and regional recurrences was similar in the two groups. There were no differences in either the disease-free or overall survival between the Halsted mastectomy group and the group with quadrantectomy, axillary dissection, and breast radiotherapy. The NSABP has just completed entry of more than 2000 patients into a major prospective randomized trial comparing total mastectomy to segmental mastectomy (tumor-free margins) and segmental mastectomy with breast irradiation (Fig. 4). Patients in all three areas of the trial had similar axillary dissections performed. Opposing field tangential radiotherapy to 5000 rad was given to the breast only and not to regional nodal areas. Patients with positive nodes received L-phenylalanine mustard (L-PAM) and 5-fluorouracil (5-FU) chemotherapy for 2 years. In contrast to the Milan Trial, patients with clinically positive axillary nodes were accepted into the trial with a tumor size up to 4 em. The preliminary results from this trial are not yet published, but NSABP group members have determined that they will accept into their systemic adjuvant therapy trials those patients who have been treated by either total mastectomy and axillary dissection or by segmental mastectomy, breast irradiation, and axillary dissection. Conclusions from the Clinical Trials Relative to the Amount of Breast Tissue Excised It would appear that the early results of the prospective controlled trials are supporting the concept that for selected patients complete excision of the primary with a tumor-free margin, followed by adequate breast irradiation produces results equivalent to total mastectomy in terms of

1141

SURGERY AND RADIOTHERAPY FOR PRIMARY BREAST CANCER

CLINICAL EXAMINATION

f ELIGIBLE

r AXILLARY DISSECTION

+ TOTAL MASTECTOMY

I

1 FOR PARTIAL MASTECTOMY

1

I 1

AXILLARY DISSECTION

AXILLARY DISSECTION

+

+ PARTIAL MASTECTOMY

PARTIAL MASTECTOMY

+ BREAST RADIOTHERAPY

·---I

ADJUVANT CHEMOTHERAPY WITH L-PAM plus 5-FU IF NODES POSITIVE

ADJUVANT CHEMOTHERAPY WITH L-PAM plus 5-FU IF NODES POSITIVE

·----TOTAL MASTECTOMY IF FURTHER OCCURRENCE OF TUMOR IN IPSILATERAL BREAST

·----I

ADJUVANT CHEMOTHERAPY WITH L-PAM plus 5-FU IF NODES POSITIVE

.--·--TOTAL MASTECTOMY IF FURTHER OCCURRENCE OF TUMOR IN IPSILATERAL BREAST

Figure 4. NSABP Protocol B-06 schema for the randomized clinical trial that compares total mastectomy to partial mastectomy with or without irradiation to the residual breast.

distant recurrence and survival for the first 5 to 9 years. A portion of patients treated by segmental mastectomy will, however, have further occurrence of tumor in the residual breast and will require total mastectomy at a later time. Longer term results must await further follow-up. It is yet to be determined whether there are specific pathologic discriminants that will be predictive for patients who will be least likely to have further occurrence of tumor in the breast following a segmental mastectomy with or without breast irradiation, but presumably such discriminants exist. It should be emphasized that there are important technical details related to both surgical and radiotherapy techniques in breastconserving treatments that may not now be familiar to many surgeons and radiotherapists. Inattention to these details may result in an unfortunate misadventure for the patient.

REFERENCES l. Adair, F. E.: Role of surgery and irradiation in cancer of the breast. }.A.M.A., 121:553-559, 1943. 2. Baclesse, F.: Roentgen therapy as the sole method of treatment of cancer of the breast. Am. J. Roentgenol. Radium Ther., 62:311-319, 1949.

/

1142

RoGER S. FosTER. JR.

3. Baclesse, F.: Five-year results in 431 breast cancers treated solely by roentgen rays. Ann. Surg., 161:103--104, 1965. 4. Banks, W. M.: A brief history of the operations practiced for cancer of the breast. Br. Med. J., 1:5-10, 1902. 5. Bedwinek, J.: Adjuvant irradiation for early breast cancer; An ongoing controversy. Cancer, 53:729-739, 1984. 6. Bloom, H. J. G.: Survival of women with untreated breast cancer-Past and present. In Forrest, A. P. M., and Kunkler, P. B. (eds.): Prognostic Factors in Breast Cancer. Baltimore, Williams & Wilkins Co., 1968. 7. Brinkley, D., and Haybittle, J. L.: Treatment of stage- II carcinoma of the female breast. Lancet, 2:291-295, 1966. 8. Brinkley, D., and Haybittle, J. L.: Treatment of stage- II carcinoma of the female breast. Lancet, 2:1086-1087, 1971. 9. Bruce, J.: Operable cancer of the breast: A controlled clinical trial. Cancer, 28:1443--1452, 1971. 10. Cancer Research Campaign Working Party. Cancer research campaign (King's/Cambridge) trial for early breast cancer. A detailed update at the tenth year. Lancet, 2:55-60, 1980. 11. Cheatle, G. L.: Benign and malignant changes in duct epithelium of the breast. Br. J. Surg., 31:285-306, 1920. 12. Clark, R. M.: Alternatives to mastectomy-The Princess Margaret Hospital experience. In Harris, J. R., Hellman, S., and Silen, W. (eds.): Conservative Management of Breast Cancer. New Surgical and Radiotherapeutic Techniques. Philadelphia, J. B. Lippincott Co., 1983. 13. Cope, 0., Wang, C.-A., Chu, A., et a!.: Limited surgical excision as the basis of a comprehensive therapy for cancer of the breast. Am. J. Surg., 131:400-407, 1976. 14. Crile, G., Jr.: Simplified treatment of cancer of the breast: Early results of a clinical study. Ann. Surg., 153:745-761, 1961. 15. Crile, G., Jr.: Results of simplified treatment of breast cancer. Surg. Gynecol. Obstet., 118:517-523, 1964. 16. Crile, G., Jr.: Treatment of breast cancer by local excision. Am. J. Surg., 109:400-403, 1965. 17. Crile, G., Jr.: A Biologic Consideration of Treatment of Breast Cancer. Springfield, II, Charles C Thomas, 1967. 18. Crile, G., Jr.: The smaller the cancer the bigger the operation? Rationale of small operations for small tumors and large operations for large tumors. J. A.M. A., 199:146-148, 1967. 19. De!Regato, J.: Radiotherapy as a postoperative surgical adjuvant in the management of cancer of the breast. Radiology, 98:695-698, 1971. 20. Easson, E. C.: Postoperative radiotherapy in breast cancer. In Forrest, A. P. M., and Kunkler, P. B. (eds.): Prognostic Factors in Breast Cancer. Baltimore, Williams & Wilkins Co., 1968. 21. Fisher, B.: Cooperative clinical trials in primary breast cancer: A critical appraisal. Cancer, 31:1271-1286, 1973. 22. Fisher, B.: A commentary on the role of the surgeon in primary breast cancer. Breast Cancer Res. Treat., 1:17-26, 1981. 23. Fisher, B.: Surgery and the primary treatment of breast cancer. Breast Cancer Res. Treat., 1:339-348, 1981. 24. Fisher, B., Slack, N.H., Cavanaugh, P. J., eta!.: Postoperative radiotherapy in treatment of breast cancer: Results of the NSABP clinical trial. Ann. Surg., 172:711-730, 1970. 25. Fisher, B., Montague, E., Redmond, C., et a!.: Comparison of radical mastectomy with alternative treatments for primary breast cancer: A first report of results from a prospective randomized clinical trial. Cancer, 39:2827-2839, 1977. 26. Fisher, B., Redmond, C., Fisher, E. R., eta!.: The contribution of recent NSABP clinical trials of primary breast cancer therapy to an understanding of tumor biology: An overview of findings. Cancer, 46:1009-1025, 1980. 27. Fisher, B., Wolmark, N., Bauer, M., et a!.: The accuracy of clinical nodal staging of limited axillary dissection as a determinant of histologic nodal status in carcinoma of the breast. Surg. Gynecol. Obstet., 152:765-772, 1981. 28. Fisher, B., Wolmark, N., Redmond, C., eta!.: Findings from NSABP protocol No. B04: Comparison of radical mastectomy with alternative treatments. II. The clinical and biologic significance of medial-central breast cancers. Cancer, 48:1863--1872, 1981.

SURGERY AND RADIOTHERAPY FOR PRIMARY BREAST CANCER

1143

29. Freiman, J. A., Chalmers, T. C., Smith, H., et al.: The importance of Beta, the type II error and sample size in the design and interpretation of the randomized control trial. N. Engl. J. Med., 299:690--694, 1978. 30. Haagensen, C. D., and Bodian, C.: A personal experience with Halsted's radical mastectomy. Ann. Surg., 199:143--150, 1984. 31. Halnan, K. E.: Postoperative radiotherapy and breast cancer. Lancet, 1:1401, 1976. 32. Halsted, W. S.: The results of operations for the cure of cancer of the breast performed at the Johns Hopkins Hospitals. Ann. Surg., 20:497-555, 1894. 33. Halsted, W. S.: The results of radical operations for the cure of carcinoma of the breast. Ann. Surg., 46:1-19, 1907. 34. Handley, W. S.: Cancer of the Breast and Its Treatment. Edition 2. New York, Paul B. Roeber, 1922. 35. Harris, J. R., Hellman, S., and Silen, W. (eds.): Conservative Management of Breast Cancer: New Surgical and Radiotherapeutic Techniques. Philadelphia, J. B. Lippincott Co., 1983. 36. Hayward, J. L.: The Guy's trial of treatments of "early" breast cancer. World J. Surg., 1:314-316, 1977. 37. Hayward, J. L.: The Guy's Hospital trials on breast conservation. In Harris, J. R., Hellman, S., and Silen, W. (eds.): Conservative Management of Breast Cancer: New Surgical and Radiotherapeutic Techniques. Philadelphia, J. B. Lippincott Co., 1983. 38. Henderson, I. C., and Canellos, G. P.: Cancer of the breast: The past decade. N. Engl. J. Med., 302:17--30, 1980. 39. Host, H., and Brennhovd, I. 0.: The effect of postoperative radiotherapy in breast cancer. Int. J. Radiat. Oncol. Biol. Phys., 2:1061-1067, 1977. 40. Kaae, S., and Johansen, H.: Simple versus radical mastectomy in primary breast cancer. In Forrest, A. P. M., and Kunkler, P. B. (eds.): Prognostic Factors in Breast Cancer. Baltimore, Williams & Wilkins Co., 1968. 41. Keynes, G.: Treatment of primary carcinoma of the breast with radium. Acta Radiol., 10:393--401, 1929. 42. Keynes, G.: Conservative treatment of cancer of the breast. Br. Med. J., 2:643--647, 1937. 43. Keynes, G.: Place of radium in the treatment of carcinoma of the breast. Ann. Surg., 106:619--630, 1937. 44. Kiister, E.: Zur Behandlung des Brustkrebses: Arch. F. Clin. Chirg., 29:723--753, 1883. 45. Lacour, J., Bucalossi, P., Caceres, E., eta!.: Radical mastectomy versus radical mastectomy plus internal mammary dissection. Cancer, 37:206-214, 1976. 46. Lacour, J., Monique, L. E., Caceres, E., et al.: Radical mastectomy versus radical mastectomy plus internal mammary dissection: Ten year results of an international cooperative trial in breast cancer. Cancer, 51:1941-1943, 1983. 47. Langlands, A. 0., Prescott, R. J., and Hamilton, T.: A clinical trial in the management of operable cancer of the breast. Br. J. Surg., 67:170-174, 1980. 48. Levitt, S. H., and McHugh, R. B.: Radiotherapy in the postoperative treatment of operable cancer of the breast. Pt. l. Critique of the clinical and biometric aspects of the trials. Cancer, 39:924--932, 1977. 49. Lewis, D., and Rienhoff, W. F.: A study of results-Johns Hopkins Hospital, 188~1931. Ann. Surg., 25:336-400, 1932. 50. Mansfield, C. M.: Early breast cancer. Its history and results of treatment. Exp. Biol. Med., 5:1-121, 1976. 51. McWhirter, R.: Treatment of cancer of the breast by simple mastectomy and roentgen therapy. Arch. Surg., 59:830-842, 1949. 52. McWhirter, R.: Principles of treatment by radiotherapy for breast cancer. Br. J. Cancer, 4:368--371, 1950. 53. McWhirter, R.: Simple mastectomy and radiotherapy in the treatment of breast cancer. Br. J. Radiol., 28:128-139, 1955. 54. Moore, C. H.: On the influence of inadequate operations on the theory of cancer. R. Chir. Soc., 1:244--280, 1867. 55. Morrow, M., and Foster, R. S., Jr.: Staging of breast cancer; A new rationale for internal mammary node biopsy. Arch. Surg., 116:748-751, 1981. 56. Mustakallio, S.: Conservative treatment of breast carcinoma-Review of 25 years' follow up. Clin. Radiol., 23:110-116, 1972.

1144

ROGERS. FOSTER,

JR.

57. Nelson, A. J., and Montague, E. D.: Resectable localized breast cancer: The rationale for combined surgery and irradiation. }.A.M.A., 231:189-191, 1975. 58. Patterson, R., and Russell, M.: Clinical trials in malignant disease: Ill. Breast cancer: Evaluation of postoperative radiotherapy. J. Fac. Radiol., 10:175-180, 1959. 59. Peters, M. V.: Wedge resection and irradiation: An effective treatment in early breast cancer. J.A.M.A., 200:144-145, 1967. 60. Peters, M. V.: Wedge resection with or without radiation in early breast cancer. Int. J. Radiat. Oncol. Bioi. Phys., 2:1151-1156, 1977. 61. Pierquin, B., Owen, R., Maylin, C., et al.: Radical radiation therapy of breast cancer. Int. J. Radiat. Oncol. Bioi. Phys., 6:17-24, 1980. 62. Porritt, A.: Early carcinoma of the breast. Br. J. Surg., 51:214-216, 1964. 63. Prosnitz, L. R., and Goldenberg, I. S.: Radiation therapy as previous treatment for early stage carcinoma of the breast. Cancer, 35:1587-1596, 1975. 64. Prosnitz, L. R., Goldenberg, I. S., Harris, F. R., et al.: Primary radiotherapy for stage I and II breast cancer: A follow-up report from four East Coast university hospitals. Int. J. Radiat. Oncol. Bioi. Phys., 6:1339-1340, 1980. 65. Raventos, A.: Clinical trials of adjuvant radiation therapy for breast cancer. Cancer, 39:941-944, 1977. 66. Rissanen, P. M.: A comparison of conservative and radical surgery combined with radiotherapy in the treatment of stage I carcinoma of the breast. Br. J. Radiol., 42:423-426, 1969. 67. Sarrazin, D., Monique, L. E., Montaine, M. F., et al.: Conservative treatment versus mastectomy in T 1 or small T 2 breast cancer-A randomized clinical trial. In Harris, J. R., Hellman, S., and Silen, W. (eds.): Conservative Management of Breast Cancer: New Surgical and Radiotherapeutic Techniques. Philadelphia, J. B. Lippincott Co., 1983. 68. Taylor, G. W., and Wallace, R. H.: Carcinoma of the breast. Fifty years experience at the Massachusetts General Hospital. Ann. Surg., 132:833-843, 1950. 69. Taylor, H., Baker, R., Fortt, R. W., et al.: Sector mastectomy in selected cases of breast cancer. Br. J. Surg., 58:161-163, 1971. 70. Turnbull, A. R., Chant, A. D. B., and Buchanan, R. B.: Treatment of early breast cancer. Lancet, 2:7-9, 1978. 71. Veronesi, V., Saccozi, R., DelVecchio, M., et al.: 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. 72. Veronesi, V., and Valagussa, P.: Inefficacy of internal mammary nodes dissection in breast cancer surgery. Cancer, 47:170-175: 1981. 73. Veronesi, V., DelVecchio, M., and Greco, M.: Results of quadrantectomy, axillary dissections, and radiotherapy (quart) in T 1N0 patients. In Harris, J. R., Hellman, S., and Silen, W. (eds.): Conservative Management of Breast Cancer: New Surgical and Radiotherapeutic Techniques. Philadelphia, J. B. Lippincott Co., 1983. 74. Wallgren, A., Glas, U., Strender, L.-E., et al.: Adjunctive therapy in breast cancer: The Stockholm experience. In Ames, F. C. (ed.): Current Controversies in Breast Cancer. M.D. Anderson Clinical Conferences in Cancer Series, Austin, University of Texas Press, 1984. 75. Williams, I. G., Murley, R. S., and Curwen, M. P.: Carcinoma of the female breast: Conservative and radical surgery. Br. Med. J., 2:787-796, 1953. 76. Wise, L., Mason, A. Y., Ackerman, L. V.: Local excision and irradiation: An alternative method for the treatment of early mammary cancer. Ann. Surg., 174:392-401, 1971. Vermont Regional Cancer Center 1 South Prospect Street University of Vermont College of Medicine Burlington, Vermont 05401