Breast conservation therapy for invasive carcinoma of the breast

Current Problems in Surgery ~ Volume XXXII Number 3 March 1995 BREAST CONSERVATION THERAPY FOR INVASIVE CARCINOMA OF THE BBF, AST Patrick I. Borgen, MD Assistant Professor of Surgery Cornell University Medical College Chief of the Breast Service Memorial Sloan-Kettering Cancer Center New York, New York Michael P. Moore, MD, PhD Assistant Professor of Surgery Columbia University New York, New York Alexandra S imkovich Heerdt, MD Clinical Instructor Cornell University Medical College Director, Special Surveillance Breast Program Memorial Sloan-Kettering Cancer Center New York, New York J eanne A. Petrek, MD Assistant Professor of Surgery Cornel University Medical College Associate Attending Surgeon Memorial Sloan-Kettering Cancer Center New York, New York [~v/[ Mosby A Times Mirror Company Current Problems in Surgery ~ Volume XXXII Number 3 March 1995 BREAST CONSERVATION THERAPY FOR INVASIVE CARCINOMA OF THE BBi~,AST TABLE OF CONTENTS 193 Foreword 194 In Brief 198 199 200 203 Introduction Historical Perspective Evolution of Radiation Therapy in Breast Cancer The Multifocality of Breast Cancer 204 Retrospective Trials 206 211 Prospective, Randomized Trials of Breast Conservation Therapy Patient Selection Criteria for Breast Conservation Therapy 212 213 213 214 215 215 216 218 Factors Associated With Recurrence Tumor Size Multicentricity Histopathology Lymph Node Status Controversial Issues Extensive Intraductal Component Operative Considerations Curr Probl Surg, March 1995 191 223 223 224 228 233 236 Radiation Therapy in Breast Conservation Patients Introduction Practical Aspects Adjuvant Systemic Therapy for Early Breast Cancer Management of Local-Regional Relapse After Breast Conservation Therapy References 19~ CurrProbl Surg, March 1995 FOREWORD Carcinoma of the breast is a major public health problem and has increasingly attracted the interest of clinicians and the lay public for the past 25 years. During this period, there have been many highly significant advances in the management of patients with this disease such as the proven benefit of chemotherapy adjuvant to mastectomy; the establishment of breast conservation therapy as a primary thera- peutic procedure; and, most recently, the discovery of the molecular genetic basis for the origin of breast carcinoma in certain patients. This issue of CURRENT PROBLEMS IN SURGERY is written by a distinguished group of surgeons: Drs. Patrick Borgen, Alexandra Heerdt, and Jeanne Petrek from the Memorial Sloan-Kettering Cancer Center and Dr. Michael Moore from Columbia University in New York. The mono- graph is especially noteworthy because it not only addresses the topic of breast conservation therapy in an exhaustive way but it also. deals with the topics of adjuvant chemotherapy and radiation therapy as well. All clinicians, regardless of their specialty, who care for patients with carcinoma of the breast will benefit from reading this excellent contribution. Samuel A. Wells, Jr., MD Editor-in-Chief Curt Probl Sur~ March 1995 193 BREAST CONSERVATION THERAPY FOR INVASIVE CARCINOMA OF THE BREAST IN BR IEF Breast cancer remains one of the most significant health threats to women in America today. It has been estimated that 1 woman in 10 will have breast cancer develop during her lifetime in this country, and 20% to 30% of those will go on to die from their disease. The history of treatment of breast cancer is a rich and interesting one. Before the second half of this century, treatment approaches to this disease were monolithic. However, in the past four decades treatment approaches have been the subject of much controversy and debate. At the center of this struggle lies the fact that physicians are still try- ing to identify the ideal therapy for carcinoma of the breast. This therapy should represent the best compromise between the least mu- tilating and the most efficacious form of treatment. Currently,. for most patients with early stage breast cancer that therapy is breast conservation therapy. As it is currently defined, this includes com- plete removal of the tumor from the breast, a thorough axillary lymph node dissection on the ipsilateral side, and finally radiotherapy to the affected breast. A growing number of prospective studies and ret- rospective reviews have established the safety and efficacy of this form of treatment. A recent consensus conference sponsored by the Na- tional Cancer Institute reported that breast conservation therapy was equal to mastectomy for patients with Stage I and Stage II breast can- cer and was preferable to mastectomy because it is less disfiguring. Nevertheless, controversy continues surrounding a number of com- ponents of this breast-preserving approach. The greatest controversy surrounds patient selection criteria. Controversial issues include tu- mor size limitations, patient age, the presence of an extensive intra- ductal component, the location of the tumor in the breast, and the implications of microscopically involved surgical margins. The man- agement of the axilla continues to be the center of much controversy as well. Debate exists concerning whether the axillary lymph node dissection is purely diagnostic or whether in fact it has therapeutic value. Even radiotherapy issues remain controversial, including treat- 194 Curr Probi Surg, March 1995 ment fields, dosing fractions, and the value of a boost dose to the tumor bed. At least one of the natural sequelae to the existence of these areas of confusion is that breast conservation therapy is underused in this country. Other explanations for this underuse include cost concerns, geographic limitations, and fear of radiation therapy on the part of the patient. In this treatise we review and comment on the available data concerning these controversial issues. We hope that this mono- graph will be useful to the physician who is endeavoring to treat the patient with breast carcinoma and yet is faced with a morass of con- flicting data concerning breast conservation therapy. Curr Probl Surg, March 1995 19~ Patrick L Borgen, MD, is Chief of the Breast Service, De- partment of Surgery, Memorial Sloan-Kettering Cancer Center and Assistant Professor of Surgery at Cornell Uni- versity Medical College. Dr. Borgen received his medical de- gree from Louisiana State University Medical School and trained in general surgery at the Ochsner Clinic. After the completion of his general surgery residency, he completed a fellowship in surgical oncology of the breast at Memorial Sloan-Kettering Cancer Center. His laboratory interests in- clude mitogenic signal transduction, genetic alterations, and the progression of genetic abnormalities that occur in the transition from benign breast epithelium to adenocar- cinoma. His areas of clinical interest include management of the high-risk patient, management of local recurrence after breast conservation therapy, and breast cancer in men. Alexandra Simkovich Heerdt, MD, is Clinical Instructor on the Breast Service, Department of Surgery, Memorial Sloan- Kettering Cancer Center and Director of the Special Sur- veillance Breast Program at Memorial Sloan-Kettering Can- cer Center. Dr. Heerdt obtained her medical degree from Jefferson Medical College in Philadelphia and completed her general surgical residency at the New York Hospital- Cornell Medical Center in New York. She completed a re- search fellowship in molecular oncology in the breast can- cer research laboratory at Memorial SloamKettering Can- cer Center. Dr. Heerdt' s academic interests include the role of growth factors in breast cancer, the chemoprevention of breast cancer, and the controversy surrounding infiltrat- ing lobular carcinoma of the breast. 196 Curr Probl Surg, March 1995 Michael P. Moore, MD, PhD, is an Assistant Professor of Sur- gery at Columbia University. Dr. Moore received his medi- cal degree from Loyola Stritch School of Medicine in Chi- cago and his PhD from Loyola University of Chicago. He completed his residency in general surgery at the New York Hospital-Cornell University Medical College in New York and completed a fellowship in clinical oncology at Memo- rial Sloan-Kettering Cancer Center. Dr. Moore's academic interests include management of inflammatory breast can- cer, management of occult breast cancer presenting as ax- illary metastasis, management of ductal carcinoma in situ, and breast conservation therapy. Jeanne A. Petrek, MD, is Associate Attending Surgeon on the Breast Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center and Assistant Professor of Surgery at Cornell University Medical College. Dr. Petrek completed her internship and residency in general sur- gery at the Peter Bent Brigham Hospital after graduating from Case Western Reserve University School of Medicine. She then served a 2-year surgical oncology fellowship at Memorial Sloan-Kettering Cancer Center in New York City. Her research interests concern the interaction of endog- enous hormones and breast cancer. Her research related to axillary dissection includes three randomized trials of surgeon-controlled variables. Currently she is conducting a government-funded study concerning the etiology of lymphedema. Curr Probl Surr March 1995 197 BREAST CONSERVATION THERAPY FOR INVASIVE CARCINOMA OF THE BREAST INTRODUCTION Physicians endeavoring to treat patients with malignant disease have long struggled to strike a balance between the efficacy of a par- ticular treatment and the quality of life after that treatment. Nowhere has this struggle had a more varied and tortuous course or been more controversial than in the treatment of patients with breast cancer. In less than a century, the prevailing wisdom has swung from a phi- losophy of surgical avoidance to various forms of radical mastectomy and now to refining the concept of breast conservation therapy (BCT). Breast conservation therapy has emerged as an appropriate treat- ment for a wide range of patients with early stage breast cancer. This monograph focuses on BCT for invasive adenocarcinoma only. We de- fine BCT as total excision of the tumor (with clear surgical margins), axillary lymph node dissection, and radiation therapy to the breast. A myriad of lesser treatment plans have been described that ignore the available data and place the patient at increased risk for local or regional recurrence. In 1990, to clearly evaluate the available data on BCT, the National Cancer Institute held a Consensus Development Conference on the Treatment of Early-Stage Breast Cancer. At that time, the conclusion was reached that ~breast conservation therapy is an appropriate method of primary therapy for the majority of women with stage I and II breast cancer and is preferable because it provides survival rates equivalent to those of total mastectomy and axillary dissection while preserving the breast. "1' 2 This statement represents the culmi- nation of an exhaustive analysis of data from retroSpective and pro- spective trials comparing BCT with the more extensive procedures of either modified radical or radical mastectomy. Several important comments can be made based on these trials. First, it is clear that, although this form of therapy is ~preferable' in most cases, it is by no means the best option for all patients: We will address patient selection criteria, surgical technique, a critical com- ponent in obtaining the best oncologic and cosmetic results, and the 198 Curr Probl Surg, March 1995 role of chemotherapy. Finally, we will consider the problem of recur- rence in the patient population undergoing BCT. Through an under- standing of these factors, the rationale for performing BCT and the necessary caveats and concerns become clear. HISTORICAL PERSPECTIVE The first known mention of breast cancer appeared in the Edwin Smith Papyrus written in approximately 3000 ac. a The author cau- tioned that no form of therapy was appropriate because of the in- curable nature of the disease process. This mentality persisted for a long time, with only isolated reports of attempts to eradicate the dis- ease through local excision. It was not until the eighteenth century that the concept of an op- erative approach to breast cancer emerged. At that time, Jean Louis Petit, the first director of the French Surgical Academy, advocated the removal of the breast, pectoral muscles, and the axillary lymph nodes to treat the disease. 4 Although this can be considered the first radi- cal mastectomy, it would take many more years for this procedure to become the accepted form of therapy. In Germany, in the latter half of the nineteenth century, Richard von Volkmann and Theodor Billroth began to use similar surgical procedures for the treatment of breast cancer. In the United States of America (USA), it was William Stewart Halsted of The Johns Hopkins Hospital who championed the rationale for and the technique of what is now commonly known as the radical mastectomy. Halsted published his results in 1894 and documented a dramatic drop in local recurrence rates from 60% to 70% to a remarkable 6% .5 This established the radical mastectomy as the "gold standard" of therapy for three quarters of a century. It was not until 50 years later that Patey of the Middlesex Hospital in London proposed preserving the pectoralis major muscle, e In a long-term follow-up of patients undergoing this procedure, Patey 7 was able to demonstrate that the local relapse rate and the overall survival were equivalent to patients treated with the standard radical mastectomy. Subsequent reports have also served to confirm the equivalent efficacy of these two procedures, a-14 While the debate continued regarding the extent of mastectomy in- dicated, a second debate emerged in the scientific and the surgical community. This controversy centered around the innate biology of the disease. Halsted had argued that breast cancer was primarily a local-regional disease and spread in an orderly centripetal fashion. 1~-1a Thus the extent of the procedure would appear to be relevant. The strongest argument against this alternative hypothesis came from a large series of patients with breast cancer who were fol- lowed up for long periods after mastectomy. 19"2~ In all of the series Curt Probl Surg, March 1995 199 there were long-term survivors who were treated by local means only. A second compelling line of evidence came from these same trials and showed that some patients with node-negative disease already had systemic spread. We believe that breast cancer begins as a local- regional disease and at some point in time becomes systemic. With the results of the modified radical mastectomy of Patey being equivalent to that of the radical mastectomy of Halsted, and with the growing sentiment that breast carcinoma may be a systemic disease from its inception, it logically followed that even more conservative surgery, in the form of partial mastectomy or even "tumorectomy," would evolve. One of the earliest attempts at BCT came from Guy's Hospital in London. zz' za This trial almost became the death knell of breast conservation because the local recurrence rates were unac- ceptably high and the radiation doses used were not tumoricidal. The retrospective and prospective trials of BCT are summarized in Tables 1 and 2. These trials document the safety and efficacy of BCT and secured its central position in the treatment of patients with carci- noma of the breast. EVOLUTION OF RADIATION THERAPY IN BREAST CANCER Concurrent with these developments in the operative management of breast cancer, however, was the consideration of radiation therapy alone as tre.atment of breast cancer. Shortly after Halsted had re- ported his results with the radical mastectomy, Francis Williams at Boston City Hospital reported that radiation was being used success- fully as the sole treatment for patients with breast carcinoma. 24 Al- though the author cautioned that his anecdotal experience with ra- diation therapy was not proof of its effectiveness, his report provided the impetus for a further examination of the role of radiation in this disease. Scattered reports of the usefulness of radiation alone, by both surgeons and radiation therapists, were found in the literature over the following 50 years. 25-al In 1937, Keynes presented a series of more than 200 patients treated with local excision and radium needle im- plantation who subsequently, at 5 years, had a survival equivalent to that of patients undergoing mastectomy. 2a A subsequent report of ra- diation alone in the management of patients with carcinoma of the breast came from Helsinki, Finland. Mustakallio 29' ao treated more than 700 such patients with external beam radiation therapy and ob- tained a 10-year suwival rate of 61%. Local recurrence rates, however, were 25%. Mustakallio, as were all of the early radiation therapists, was limited by both the use of orthovoltage equipment and a lack of knowledge concerning the proper radiation dosage. However, by the early 1960s, improved equipment for external beam radiotherapy was available. The older orthovoltage devices were un- Curt Probl Sur~, March 1995 c~ c~ U 2 t~ Q~ 0 ~ o o 0 ~ 0 o ~ o 0 0 0 0 e~ e~ ,,,,ill e~ q q e~ e,l ~1 �9 ~ 0 o able to deliver adequate dosages to deeper tissues and produced poor cosmetic results and complications resulting from high doses to the skin. The newer megavoltage linear accelerator equipment and cobalt-60 machines allowed a more uniform distribution of radiation to the breast and draining lymph nodes with relative sparing of the overlying skin. In addition, the correct dosages of radiation delivered for tumor control were being defined. These advances helped estab- lish radiotherapy as an important component of modem-day breast cancer therapy. Adequate radiotherapy is vital to reducing local re- currence rates after BCT. 3z THE MULTIFOCALITY OF BREAST CANCER Multiple pathologic studies have demonstrated that breast cancer is a multifocal disease, aa-4z One method of demonstrating this is by "simulating ~ a partial mastectomy in patients subsequently undergo- ing a mastectomy. Residual tumor within the mastectomy specimen can be identified after the local excision has been performed. In the late 1960s and the early 1970s, two groups of patients underwent this type of simulation at Memorial Sloan-Kettering Cancer Center (MSKCC). In the first series, 508 patients underwent excision of an area that was at least twice the size of the tumor itself, although the exact amount of resected tissue was variable.aa The percentage of pa- tients who were found to have residual carcinoma in the subsequent mastectomy specimen varied with respect to the size of the primary tumor but was never less than 50% (Table 3). In the second study, a benchtop quadrantectomy was performed on the mastectomy specimen, and the remaining three quadrants were studied for the presence of carcinoma. ~4 In these patients, tu- mors less than 2 cm were associated with a 20% incidence of multi- locality. A study performed at Nijmegen in the Netherlands correlated the amount of tumor remaining in the specimen with both size of the primary tumor and distance from the tumor. 35 In an elegant study, serial subsectioning and radiography of 399 mastectomy specimens was performed. On dissection of the specimen, the presence of re- sidual tumor and its distance from the primary, index tumor were noted. In three tumor size categories analyzed, the incidence of mul- tifocal disease was approximately 60% (Table 4). Of note, in all cases, most of the residual tumor was greater than 2 cm from the primary index lesion. In addition, residual tumor was found to be primarily noninvasive. These studies performed on mastectomy specimens have now been corroborated by the analysis of specimens of patients undergo- ing BCT. ~9"43 In patients who have undergone a reexcision of a pre- Curr Probl Surg, March 1995 203 TABLE 3. "Simulated" mastectomy series Res idual Invasive Noninvasive Number of carcinoma carc inoma carc inoma Study pat ients Tumor size (%) (%) (%) Shah, 1973 a2 508 Rosen, 1973 aa Microscopic 73 (2 cm 50 2.1-4 cm 52 ~4 cm 83 203 100 (2 cm 20 103 ~2 cm 10 NS NS 9 11 5 5 NS, Not specified. TABLE 4. Inc idence of mul t i foca l i ty in breast cancer D is tance from pr imary tumor Multffocal d isease >2 cm Tumor s ize (%) -->2 cm (%) Total (%) Invasive (%) Noninvasive (%) -----2 cm 59 17 42 14 28 -- TABLE 5. Differences in series of patients managed by breast conservation therapy Patient selection criteria Extent of operation Axillary dissection Radiation dosage and schedule Presence or absence of boost Chemotherapy Confirmation of margins period. Wherever possible, significant differences from study to study and within a single series have been noted. Much of the early work with radiation therapy in the treatment of breast cancer was performed at the Princess Margaret Hospital in Toronto, Ontario. Thus, this form of therapy became fairly accepted over a number of years at that institution and a retrospective analy- sis evaluated a large number of patients. 5~ Between 1958 and 1978, 680 patients underwent partial mastectomy, with or without postop- erative radiation therapy. Overall survival in both of these groups of patients was not statistically different. However, at both 5 and 10 years of follow-up, breast relapse was much higher in patients not under- going postoperative radiation (16.3% compared with 7.6%). The re- port does not define the extent of "partial" mastectomy performed. In addition, the radiation dosages administered to these patients would be considered suboptimal by today's standards. Longer term follow-up continued to demonstrate equivalent survival in both groups of patients despite the increased rate of local recurrence within the group of patients treated by partial mastectomy alone. 7z During a similar time period, a second large series of patients was treated with BCT in Marseille, France. Between 1961 and 1974, more than 1100 patients had this form of therapy. 69 Tumors were less than 5 cm in size (T 1 to Tz). However, in a few very select cases, patients with tumors greater than 5 cm were eligible to undergo partial mas- tectomy and radiation therapy. These patients were therefore in- cluded in the results. The presence of clinically positive lymph nodes did not exclude a patient from participation in the study. In the early years of this form of therapy, the operation was often l imited to an incisional biopsy to confirm the diagnosis of breast carcinoma. How- ever, in later years, wide excision with a 1-cm to 2-cm margin of nor- real surrounding breast tissue was used. The overall analysis consists of a combination of both operative groups. Radiation was given to a dose of 5000 cGy with a 2500 cGy boost to the area of the tumor bed. Disease-free survival at 5, 10, and 15 years of follow-up was 86%, 80%, and 62%, respectively. Breast carcinoma recurrences occurred in a total of 13.2% of patients over the time course of the study. Unfortu- Curt Probl Sur~ March 1995 nately, although many patients had an extremely long period of follow-up, it is not clear what the mean and median follow-up time for all patients in the study were and, therefore, conclusions concern- ing breast carcinoma recurrence rates and overall survival are some- what limited. Two other institutions in France, the Institut Curie and the Institut Gustave-Roussy, also reported their experience with BCT.46, 54, 65, 67, 68, rz However, once again, there were wide variations in the operations performed and also in the method and dosage of radiation to the breast. Despite these limitations these studies em- phasize that breast conservation is safe and appropriate for a subset of patients. Two centers within the USA, the Joint Center for Radiation Therapy (JCRT) in Boston and the University of Pennsylvania in Philadelphia, have treated large numbers of patients with conservative breast sur- gery and postoperative radiation therapy. From 1968 until 1981, the JCRT treated 607 clinical stage I and II patients with limited resec- tion and axillary lymph node dissection followed by radiation. Ra- diation dose was 4500 to 5000 cGy over a 5-week period, followed in some patients by a boost of 1500 to 2500 cGy with either an intersti- tial implant or with external electron beam. Patients in this series had an actuarial local recurrence rate of 10% at 5 years and 16% at 10 years after treatment. Similar results were obtained in the 697 patients treated at the Uni- versity of Pennsylvania between 1977 and 1985. s3 These patients had T 1 and T 2 tumors and underwent local excision with an attempt to obtain negative margins, as well as axillary dissection, before initia- tion of radiation therapy. Radiation doses in this series again were 4500 to 5000 cGy to the entire breast with a boost of 1400 to 2000 cGy to the tumor bed with electrons or iridium-192 interstitial implant. In these patients, the overall survival rate was 83% at 10 years. Local recurrence occurred in 6% at 5 years and in 16% at 10 years. PROSPECTIVEp RANDOMIZED TRIALS OF BREAST CONSERVATION THEHAPY Since 1960, there have been seven randomized, prospective trials of breast conservation therapy. A brief synopsis of each trial will be presented, and a summary of the findings of all but one of these tri- als is presented in Table 2. As with the retrospective studies, it is im- portant to note the differences in extent of the operation, patient se- lection criteria, and dosage and administration of radiation. The trial that does not appear in the table has been omitted be- cause of the inadequacy of both the operative procedure and the ra- diation therapy. The Guy's Hospital trial, began in 1960 and random- Curr Probl Sur~ March i995 ized patients to receive either radical mastectomy or wide excision of approximately 3 cm of normal breast tissue in addition to the in- dex tumor. One hundred ninety-two patients were treated by radical mastectomy and 184 were treated with local excision and postopera- tive radiation. However, those who underwent a wide local excision did not have dissection of their axillary contents, even if N1 disease was present. In addition, both groups of patients received radiation therapy, but this was to a suboptimal dose of 3800 cGy over a 3-week period. The results of this trial demonstrated the inadequacy of the treatment in the second group of patients. 22' 2a At 10 years of follow- up, there was already a 30% incidence of local recurrence among those patients undergoing conservative therapy. With longer term follow-up, recurrence was well over 50%, if axillary recurrences were included. Had there not been further randomized trials of BCT, it most certainly would have been abandoned. However, the findings from the six modern randomized, prospective trials of BCT are mark- edly different from these results. The first reports from a modern prospective, randomized trial came from the National Tumor Institute in Milan in 1981. a7 Between 1973 and 1980, 701 patients were randomized to undergo either a Halsted radical mastectomy or breast-conserving therapy with a ~quadrantec- tomy." This operative approach involved the removal of the entire quadrant in which the tumor was found. All patients with tumors of 2 cm or less in maximal diameter and clinically negative axillary lymph nodes were eligible for inclusion in the study. Postoperatively, patients who had been randomized to quadrantectomy underwent radiation of the breast to a dose of 5000 cGy with either a 6 MeV lin- ear accelerator or a cobalt unit, as well as a boost of 1000 cGy to the area overlying excision of the tumor. In addition, those who were found to have positive lymph nodes on pathologic examination (ap- proximately 25% in each group) had further therapy. Before 1976, this consisted of adjuvant radiotherapy with 4000 to 4500 cGy to the ip- silateral internal mammary and supraclavicular nodes. From 1976 un- til 1980, additional radiation was no longer used but was replaced by the administration of chemotherapy with 12 cycles of a cytotoxic che- motherapeutic regimen. Patients undergoing chemotherapy received this concurrently with radiation therapy. The results of this study indicate that the patient groups were simi- lar with respect to tumor size, age, and menopausal status. Three hundred forty-nine patients were treated with radical mastectomy, and 352 patients were treated with quadrantectomy and radiation therapy. Local recurrence occurred in three patients undergoing radical mastectomy and in one patient undergoing quadrantectomy. In addition to the one local recurrence, there were four more new primary carcinomas within the ipsilateral breast in patients under- going quadrantectomy. If these are considered to be local failures, Curr Probl Surg, March 1995 ~.,07 the total number of local failures is slightly higher in the population undergoing quadrantectomy (five versus three). Actuarial disease-free and overall survival were essentially equivalent in both groups of pa- tients at 7 years of follow-up. Further reports from the same institution regarding this group of patients have continued to demonstrate equivalence of the two treat- ment methods. 98' 99 At a mean follow-up of 103 months, disease-free survival was 77% in patients treated with a Halsted radical mastec- tomy and 80% in those treated with quadrantectomy, whereas the overall survival was 83% and 85% for the respective groups of patients. Local recurrences at this time numbered seven in both groups of pa- tients, with an additional seven patients having new ipsilateral breast carcinomas after having undergone quadrantectorny. In 1989, a larger series of patients treated by BCT, including the 352 treated by quadrantectomy in the original series, was reported by the National Tumor Institute of Milan. 9~ From 1970 to 1983, a total of 1232 patients were treated conservatively at that institution. In the later years, from 1980 to 1983, patients with clinically palpable N1 dis- ease of the axilla were permitted to undergo quadrantectomy, al- though the largest allowable tumor size remained 2 cm. The median follow-up was 72 months, with a range of I to 202 months. Thirty- five (2.8%) patients had a local recurrence develop and 19 (1.6%) had a new primary, tumor develop within the ipsilateral breast. Overall survival at 5 and 10 years after diagnosis was 91% and 78%, respec- tively. Concurrent with the prospective, randomized trial performed in Milan was another European trial carried out under the auspices of the World Health Organization and performed at the Institut Gustave- Roussy in Villejuif, France. The preliminary results of this trial, con- ducted between October 1972 and December 1980, were reported in 1984. 91 Selection criteria were similar to that of the Italian study, with only tumors 2 cm or less included in the population. UTumorectomy," rather than quadrantectomy, was the procedure used for removal of the cancer in the conservative cases and a modified radical mastec- tomy rather than a radical mastectomy was performed in patients randomized to undergo mastectomy. The tumorectomy consisted of removal of the gross tumor with a 2-cm margin of normal glandular tissue. Radiation was delivered to a dose of 4500 cGy with a cobalt 60 unit, and a boost to the tumor bed of 1500 eGy was given. Patients with pathologically positive lymph nodes were further randomized to undergo, or not to undergo, nodal radiation to the supraelavicular and axillary regions. No patients received chemotherapy. One hundred seventy-nine patients were randomized during the period of the study; 88 were treated with mastectomy, and 91 were treated with conservative treatment. As in the Milan trial, patients were stratified equally by age, tumor size, and axillary lymph node 2.0S Curr Probi Surg, March 1995 disease. Actuarial disease-free and overall survival were essentially equivalent in both groups with a median follow-up of 4.5 years. Lo- cal recurrence developed in 12% of patients undergoing mastectomy and in 5% of patients undergoing tumorectomy, a difference that was not statistically different. At 10 years of follow-up in this group of patients, the survival in both groups of patients was 80%. Disease-free survival was also simi- lar, with 42% in the mastectomy group relapsing and 34% of the tu- morectomy group relapsing, aa Local recurrence within the breast or on the chest wall was encountered in 9% of patients who underwent mastectomy and in 7% of patients who underwent tumorectomy. While these two trials were underway in Europe, another large, ran- domized, prospective trial comparing conservative treatment with mastectomy was begun in the USA. This study, directed by the Na- tional Surgical Adjuvant Breast Project (NSABP), compared not only modified radical mastectomy with segmental resection and axillary lymph node dissection but also included a third arm of patients who underwent segmental mastectomy alone that was not followed by ra- diation therapy. Unlike the other two studies, patients were recruited and treated at multiple institutions throughout the USA and Canada instead of at one institution. Eligibility criteria were also somewhat different, with tumor sizes up to 4 cm being acceptable. In addition, patients with clinically involved axillary lymph nodes were eligible for participation. Segmental mastectomy was defined as removal of the tumor and enough surrounding breast tissue to ensure patho- logically negative margins. There was no necessity for gross sur- rounding normal tissue. Radiation was given to a minimum dose of 5000 cGy at a rate of 1000 cGy/week. No boost doses were given to the tumor site. Patients found to have positive axillary lymph nodes on histologic examination underwent adjuvant cytotoxic chemo- therapy. Five-year results of this NSABP Protocol B-06 were made available in 1985. sa'a5 Between 1976 and 1984, 1843 patients had been enrolled and were included in the comparisons. Five hundred eighty-six were in the mastectomy arm, 632 were in the segmental resection alone arm, and 625 were in the segmental resection plus radiation therapy arm. As in previous series, there was no statistical difference in the ages, size of tumors, or nodal status of the patients enrolled .in each arm. Any patient in either of the segmental mastectomy arms not found to have histologically negative margins subsequently under- went mastectomy. This occurred in approximately 10% of patients in each group. The 5-year actuarial incidence of recurrence within the ipsilateral breast was 7.7% in patients treated by segmental mas- tectomy and radiation therapy, but it was 27.9% in patients treated by segmental mastectomy alone (p < 0.001). Disease-free survival, dis- tant disease-free survival, and overall survival were similar when com- Curr Probl Surg, March 1995 2,09 paring patients undergoing modified radical mastectomy with those undergoing segmental mastectomy. Patients undergoing mastectomy had a 5-year overall survival of 76%, a disease-free survival of 66%, and a distant disease-free survival of 72%. Patients undergoing seg- mental mastectomy had a similar 5-year overall survival of 85%, a disease-free survival of 72%, and a distant disease-free survival of 76%. At 8 years of follow-up, the results continued to be similar. 44 Ten percent of patients who had segmental mastectomy (now referred to simply as "lumpectomy") and radiation therapy had ipsilateral breast tumors develop, whereas 39% of patients who had undergone lumpectomy alone had a recurrence within the ipsilateral breast. The disease-free, distant disease-free, and overall survival in the group with lumpectomy and radiation was still equivalent to the group un- dergoing modified radical mastectomy. Recently, a great deal of controversy surrounding this NSABP B-06 trial has arisen because it has become apparent that data from St. Luc Hospital in Montreal, Canada, were falsified. A recent update of the information, with consideration of the falsified data and unpub- lished at the time of preparation of this manuscript, has just been completed by an outside organization (personal communication with B. Fisher, MD, re: a reanalysis of NSABP Protocol B-06, March 30, 1994.) 96 Excluding the data from the St. Luc Hospital, 1527 patients remain evaluable. The reanalysis demonstrates that there are no sig- nificant differences in overall survival, disease-free surcival, or distant disease-free survival among patients undergoing modified radical mastectomy or lumpectomy with radiation therapy. Local recurrence in the ipsilateral breast at 10 years has occurred in 12.2% of patients undergoing lumpectomy with radiation therapy and in 38.2% of pa- tients undergoing lumpectomy alone. In effect, the removal of the data from St. Luc Hospital did not change the original conclusions (personal communication, B. Fisher, MD). A second, single-institution, prospective randomized trial was ini- tiated by the United States National Cancer Institute in 1979. In this randomized, prospective trial, 237 patients were randomized to un- dergo either modified radical mastectomy or "lumpectomy" followed by radiation therapy. 9~ The lumpectomy in this series consisted of removal of all gross tumor, although microscopic negative margins were not a necessity. Radiation was performed to a total dose of 4860 cGy. Patients with positive axillary lymph nodes also had a small su- praclavicular field treated, and all patients had a boost of 1500 to 2000 cGy to the tumor bed with either iridium-192 implants or an elec- tron beam. Any patient with positive lymph nodes had postoperative chemotherapy with doxorubicin and cyclophosphamide. As in other studies, both overall suivival and disease-free survival were very simi- lar between the two groups. The actuarial rate of local recurrence at 210 Curr Probi Surg, March 1995 5 and 8 years was 12% and 20%, respectively. The follow-up period has been too short for longer term data analysis. Two other European randomized, prospective trials were under- way during the same period as the United States National Cancer In- stitute trial. The first of these was a multicenter trial organized by the European Organization for Research and Treatment of Cancer (EORTC) that accrued 903 patients between 1980 and 1986. aa Of the evaluable patients, 422 were treated with modified radical mastec- tomy and 452 were treated with a wide excision incorporating a 1-cm margin of normal breast tissue surrounding the tumor. Radiation therapy was given to a dose of 5000 cGy with a boost of 2500 cGy to the tumor site with iridium implants. All stage I and I! patients with breast carcinoma were eligible for participation in the trial. As in the other studies, overall survival and distant disease-free sur- vival were virtually identical in both groups of patients. Although the follow-up period has been short, the actuarial 5-year survival in both groups was 85%. The actuarial incidence of local recurrence at 8 years was 13% in patients treated by local excision and radiation therapy and 9% in those patients undergoing mastectomy. The last randomized, prospective trial was performed by the Dan- ish Breast Cancer Cooperative Group (DBCG) between 1983 and 1989. Nine hundred fifty patients were entered into the study for random- ization, with 859 eventually evaluable. Of these, 429 underwent a modified radical mastectomy and 430 underwent a wide excision fol- lowed by radiation therapy. All patients with stage I and II breast car- cinoma were eligible for participation in this trial. The excision in the group undergoing conservative therapy consisted of gross removal of the tumor. However, the specimen was analyzed for the presence of negative margins. Breast radiation was performed to a dose of 4800 to 5000 cGy, with a subsequent boost to the scar area of 1000 to 2500 cGy. Overall, the results were again very similar to those of the other trials, although the follow-up period in this group of patients had a mean of only 40 months. 99' loo Both recurrence-free survival and over- all survival were once again comparable. Moreover, although the study has had a relatively short period of follow-up, the incidence of recurrence in the breast has been approximately 3%. PATIENT SELECTION CPtlTEHIA FOR BHEAST CONSERVATION THEHAPY The local-regional failure rate associated with breast conservation at MSKCC is among the lowest reported. TM Those factors thought to contribute to excellent local-regional control include a fastidious op- Curr Probl Surg, March 1995 2.11 TABL I~ 6. Contraindications to breast conservation Absolute Relative Controversial Multicentric disease Pregnancy Postradiation cancers Collagen vascular disease Tumor size/breast size Subareolar location Young age Extensive intraductal component Microscopically involved margins erative approach to the primary tumor and axillary lymph nodes, ra- diotherapy to the breast with a boost to the primary site, and finally, perhaps most importantly, patient selection. There are few absolute contraindications to breast conservation, and the commonly ac- cepted contraindications in stage I and stage II breast cancer are listed in Table 6. Steroid-dependent collagen vascular disease re- mains an absolute contraindication because of the universally poor cosmetic results after radiation. 1~ Diffuse residual microcalcitica- tions remain a contraindication to breast conservation because this may connote residual intraductal or invasive carcinoma and make routine follow-up difficult. Pregnancy mitigates against breast conser- vation in that definitive radiotherapy to the breast postoperatively cannot be delivered in the presence of a developing fetus. Delay of radiotherapy until the end of gestation may have untoward ef- fects.lO3, 104 The goal of BCT is twofold. First, the goal is to achieve effective local-regional control of the tumor, thereby maximizing cure. Second, a cosmetically and functionally acceptable breast should be pre- served. FACTORS ASSOCIATED WITH HECUHRENCE It is important to determine factors associated with an increased risk of local-regional failure after BCT because local-regional failure is a poor prognostic event, with approximately one half of patients dying of their disease. 1~ The disease-free survival at 5 years after ipsilateral breast tumor recurrence after breast conservation is ap- proximately 50% to 60%. As the use of BCT has increased over the last several decades, so has the knowledge of factors associated with increased risk of local regional failure, rz' rs, 106,110,112,113,118-130 The most common factors are tumor size, histology, the age of the pa- 212 Curr Probi Surg, March 1995 tient at diagnosis, the presence or absence of extensive intraductal component (EIC), involved margins, lymphatic vessel invasion, and metastases to regional lymph nodes. TUMOR SIZE Conventional Wisdom in the past had held that the larger the tu- mor the greater the chance of local-regional failure after breast con- servation. This is not the case because local control rates are the same in patients with large tumors compared With patients With small tumors.~la' ~9, ~a~-laa The Institut Gustave-Roussy reported on 783 pa- tients treated With breast conservation with a local-regional failure rate of 13% in the T1 group and 12% in the T z group. ~a Quantitation of tumor size and local regional failure came from Veronesi. He dem- onstrated that the recurrence rate in his series for tumors less than 1 cm in diameter was 7.5%. In larger tumors, with diameters ranging from 1.6 to 2,5 cm, the recurrence rate was 7.6% .~3a Patients With large tumors or patients With an inappropriate tumor- to-breast size ratio have not been included in the randomized stud- ies. Therefore it cannot be stated with certainty that patients with tumors greater than 4.5 cm have an equal alternative in the therapy of early breast cancer. The randomized studies of BCT arbitrarily de- fined the greatest diameter that would be included in each of the six studies. Recently, several studies have reported on the use of induc- tion chemotherapy to convert previously poor candidates for breast conservation, based on tumor size, to acceptable patients for conser- vation. The most widely recognized study is that from Bonadonna who reported on 165 patients with tumors larger than 3 cm in great- est diameter. TM The patients were all treated With induction chemo- therapy, and 157 of 161 patients demonstrated shrinkage of the tu- mor. Ninety'five percent of the patients who were previously ineli- gible for breast conservation (according to their protocol standards in Milan) were subsequently defined as eligible. What has not been demonstrated is that the survival in these patients is equal to that of the untreated patient having breast conservation. It would seem that until further data are available, patients treated with neoadjuvant chemotherapy to convert ineligible candidates for breast conserva- tion to eligible candidates should be undertaken in a research pro- tocol setting. MULTICENTRICITY Multiple primary carcinomas are reportedly associated with a marked increased risk of local-regional failure after breast conservation. 124'1~5"137 Leopold TM reported 10 such patients with Curr Probl Surg, March 1995 213 multiple lesions, and 4 of the 10 had tumor recurrences. By contrast, 707 patients with a solitary lesion had a recurrence rate of 11%. The authors concluded that the use of BCT for patients with more than one primary breast carcinoma should be considered with caution. Additional information was gained from the study of Kurtz la~ who reported that 4 of 16 (25%) patients with multiple tumors had local recurrences develop, whereas in 525 patients with a single tumor, 56 (11%) had local failure. Additionally, another small series of multiple lesions was reported from Yale University with a 6-year actuarial re- currence rate of 25% for patients with multiple lesions compared with 12% for patients with a single lesion. 124 HISTOPATHOLOGY The conventional wisdom held for many years that tumor histo- logic type and histologic grade were associated with increased risk of local-regional failure.lZZ' 122,127, lZa, 1as This has proven not to be the case, inasmuch as patients with infiltrating lobular carcinoma have no increased risk of local-regional failure compared with patients with infiltrating ductal cancer . 114' 119 ,122,127,128,138-140 This finding might be somewhat misleading in that patients with infiltrating lobu- lar carcinoma, because of the growth characteristics of lobular dis- ease, have complete excision with negative margins less frequently than patients with ductal carcinoma. So although patients are offered breast conservation, a certain percentage are unable to have complete resection with appropriate cosmesis and therefore are not good can- didates for conservation. Histologic grade of the lesion has not been associated with an in- creased risk of local-regional failure, although the presence of lym- phatic vessel invasion may be associated with increased failure rates.lal, 141 There are several series that have linked lymphatic ves- sel invasion with increased local-regional failure. The issue of histologic margins remains unclear and continues to spark lively debate. There are at least four large retrospective reviews demonstrating that resection margins involved with tumor, in fact, lead to an increased local-regional recurrence. 112' 121,142-148 Several studies have demonstrated no relationship. Veronesi reported that in- volved margins were associated with a slightly greater than twofold risk of local-regional failure in 6 (13%) 0f46 patients with positive mar- gins compared with 13 (5.5%) of 237 patients with negative margins in their series} 42 Ghossein TM demonstrated that if a small resection (tumorectomy) was done, positive margins were present 41% of the time and the local failure rate was 15%. If a wide local excision was performed, the positive margin rate was one third that of the smaller resection and the local failure rate dropped another 50%. A quadran- 214 Curr Probl Surg, March 1995 tectomy generated positive margins in 7% with a diminution in the local-regional failure rate to 5%. It would therefore seem that with larger resection one is able to assure negative margins with greater certainty and that local-regional failure follows accordingly. Similar information was generated from the Joint Center of Radiation. Vicini 14s demonstrated for small lesions with a small resection that the local recurrence rate was 29%. The recurrence rate fell to 10% for patients with a larger resection. Therefore, larger resections with wider margins have a significant impact on local failure rates. The data on the impact of margins and local regional control re- main somewhat controversial. Solin 14r has suggested that perhaps the issue of margins was more an issue for the radiation therapist than the surgeon. He reported 257 patients who had negative mar- gins (arbitrarily defined as greater than a 2-ram rim of normal tissue) and received 6000 cGy radiation. A second group of 57 patients had a positive margin and were treated with 6500 cGy (37 of these pa- tients with a close margin [arbitrarily defined as less than 2 ram] were treated with 6400 cGy). A third group of 346 patients with unknown margins were treated with 6240 cGy. ~47 He demonstrated no signifi- cant difference among the groups in 5-year disease-free survival, over- all survival, or actuarial local-regional control. Although this is not a randomized prospective study, the use of such a boost to the pri- mary site is gaining favor. Numerous centers including MSKCC in- clude a boost to the primary site in virtually all patients. ~16' ~47 LYMPH NODE STATUS It was often said in the early days of breast conservation that pa- tients with clinically involved lymph nodes were perhaps better treated with a more definitive procedure such as a modified radical mastectomy rather than breast conservation. In fact, the data suggest that the opposite may be true. From the Milan trial it was demon- strated that in patients with positive lymph nodes treated with ei- ther BCT or a Halsted mastectomy, the disease-free survival and over- all survival was better in the BCT group. 86 Similar information was reported from Yale University suggesting the possibility of a synergis- tic effect between the radiation therapy of breast conservation and adjuvant chemotherapy. 125 Clearly, a clinically involved axflla is not a contraindication to BCT. CONTROVERSIAL ISSUES The controversial issues regarding increased risk of local-regional failure after breast conservation include both the age of the patient at the time of diagnosis and the presence or absence of extensive in- Curr Probl Sur~ March 1995 21~ traductal disease. Several series have reported the impact of age on the increased local-regional failure rate seen in younger patients.110' lzo, lz2,12a. 149-15a Young age has been arbitrarily defined in these series and can range from less than 35 years up to and includ- ing less than 50 years of age. Nonetheless, the young patients uni- formly have an increased local-regional failure rate when compared with older patients treated in a similar fashion in the same institu- tion. Reich 149 from the Joint Center of Radiation Therapy in Boston reported 597 patients with early stage breast carcinoma. Forty-seven of the patients were 35 years or younger and their local-regional re- currence rate after breast conservation was 26%. In the older patients, the recurrence rate was 10%. Similar. findings were reported from M.D. Anderson, where young age was defined as less than 50 years of age. The 10-year local-regional failure rate was 26% in the younger patients and 12% in the older patients. TM The data from Europe are similar. Kurtz defined young age as 40 years old. In patients younger than 40 years, the local-regional failure rate was 21% (13 of 62) com- pared with a failure rate of 11% in 434 patients older than 40 years of age. ~a Combining the European experience, Kurtz reported on 1382 patients with stage [ and stage II breast carcinoma. A 19% local- regional failure rate was observed in the group less than 40 years old. A 9% local-regional failure rate was observed in patients older than 40 years. ~5~ In an attempt to explain the propensity toward increased local- regional failure in the younger patients after conservation, Kurtz dem- onstrated that lymphatic stromal reaction was higher in the younger group.~52 Patients of a young age, compared with older patients, more commonly had a high histologic grade of tumor (42% versus 38% ). An extensive intraductal component was far more common in the young patient compared with an older patient 121% versus 6% ). Al- though this does not completely explain the increased rate of local failure in the young, it does lend histologic credence to the differ- ences observed. EXTENSIVE INTRADUCTAL COMPONENT Extensive intraductal component (EIC) is commonly defined as in- traductal carcinoma comprising 25% of the index lesion and present in noninvolved adjacent breast tissue. The first study defining the in- creased risk of local failure in patients who have EIC came from the Joint Center of Radiation Therapy. In a group of 597 patients with early stage breast carcinoma, 28% were defined as EIC positive and had a local-regional failure rate of 25%. Most of the group were EIC negative and had a local failure rate of only 5% .~5 It was also found that EIC was more commonly seen in younger compared with older ~16 Cur:" Probl Surg, March 1995 patients (44% versus 31%). This alone, however, did not account for the difference in recur rence . Kur tz 151 reported 496 patients. Of 106 who were EIC positive the local failure rate was 18% compared with most of the patients who were EIC negative and had a 7.9% local failo ure rate. Lindley and colleagues 12z reported 293 patients treated with breast conservation and demonstrated similar fndings. Patients who were EIC positive had a marked increased rate of local failure (22%) compared with patients who were EIC negative (10%). In an attempt to define the biologic significance of EIC, Hol- land35, ls5 in conjunction with the Joint Center of Radiation Therapy reported the histologic findings in mastectomy specimens in patients who were EIC positive compared with those who were EIC negative. The analysis examined the amount of carcinoma that was anatomi- cally distant from the index lesion and its distance from the index lesion. In the 66 patients defined as EIC positive, residual carcinoma was present within 2 cm in 59%. In the EIC-negative group residual carcinoma was present in only 29% 15s This differential persisted in a statistically significant fashion up to and including patients with tumors 6 cm, where the incidence of residual carcinoma was 21% in the EIC-positive group compared with 8% in the EIC-negative group. It is therefore questioned whether EIC positivity and surgical mar- gins are interrelated and, perhaps, whether wider margins of resec- tion affect local control in EIC-positive patients. An interesting corollary can be drawn from the Joint Center of Ra- diation study, which examined the size of the resection specimen and the presence or abs.ence of EIC and local recurrence. In patients who were EIC positive a small resection was associated with a recurrence rate of 29% compared with a 10% local failure rate among patients with a larger resection. Similar results were seen in patients with larger tumors in that patients with EIC-positive T 2 lesions had a 36% local failure rate if a small resection was performed. If a larger resec- tion was performed, the local failure rate was 9%. Extensive intraduc- tal component, therefore, is independently predictive of increased lo- cal failure. Patients with EIC may require wider resection or a boost to the primary site. Patient selection plays a pivotal role in obtaining excellent local- regional control. Although it would seem that most early stage breast carcinomas are amenable to treatment with either mastectomy or breast conservation, there is a subset of patients where further con- sideration is warranted. The presence of EIC would seemingly dictate a larger resection. *4s Both histologically negative and mammographically negative margins of resection should be obtained. Mammographic negative margins are achieved when the mammogram taken after resection is free of mi- crocalcifications. If one is unable to generate negative margins of re- Curr Probl Sur~j March 1995 217 section histologically or mammographically, the patient is best treated by modified radical masteetomy. A most difficult consideration is the treatment of the young patient with early stage breast cancer. It would appear that patients treated with BCT have an increased risk of local-regional failure. The age at which this increased risk occurs is difficult to discern. It is, nonethe- less, appropriate to inform younger patients of the increased risk of local-regional failure after BCT. A combination of several of these fac- tors, such as the presence of EIC and young age, should perhaps shift the emphasis away from breast conservation. There are evolving data that suggest that the use of adjuvant che- motherapy or adjuvant hormonal manipulation decreases the risk of local-regional failure in BCT. 156' 157 In the future, use of adjuvant therapy may prove valuable in decreasing local failure rates in pa- tients at high risk for recurrence, thereby providing an additional in- dication for adjuvant therapy. OPERATIVE CONSIDERATIONS The operative approach to the patient with breast carcinoma is no longer as simple as it once was. Placement and extent of the surgical biopsy significantly impact the ease with which either breast conser- vation or mastectomy can be completed in the future. Histologic or cytologic diagnosis must be obtained before discussion of treatment options with the patient and her family. A pretreatment or preexcision mammogram is necessary in any pa- tient suspected of having breast carcinoma. This will help to deter- mine the size and extent of the lesion, the presence of multicentric lesions within the ipsilateral breast, and the extent of EIC. Mammog- raphy may also provide valuable information regarding the contralat- eral breast. Occasionally at this stage it becomes apparent that a pa- tient is not a candidate for breast conservation because of the pres- ence of diffuse microcalcifications or obvious multicentric tumors. Cytologic diagnosis through fine needle aspiration (FNA) or core biopsy is often helpful in treatment planning and the discussion of the potential options with the patient. Fine needle aspiration is as- sociated with a small percentage of both false-positive and false- negative results, and the outcomes are highly dependent on the ex- pertise of both the surgeon obtaining the aspiration sample and the pathologist interpreting the specimen. 158 Preparation of the specimen is of utmost importance and can significantly alter the interpretation of the cytologic architecture. Any lesion suspicious for a breast car- cinoma, in which a negative FNA is obtained, should be excised. The initial approach to breast conservation involves the resection of the index lesion within the breast. The lesion may either be pal- 218 Curr Probl Sur~ March 1995 pable and approached directly or the lesion may be nonpalpable, identified and localized by mammography. Often the approach of the radiologist for localization is a needle and hookwire. The surgical in- cision must be placed directly over the lesion, thereby eliminating tunneling and the unnecessary disruption of breast tissue. This be- comes an important issue if unsuspected positive margins of resec- tion are obtained and reexcision is required. This would mandate re- excision not only of the biopsy cavity but the entire tunneled area. Such massive tissue disruption may translate into a poor cosmetic result. In addition, inappropriately large areas of excision may have a deleterious impact on radiation treatment planning. A curvilinear excision along Langer's lines of tension is preferred and should not be placed in the circumareolar position unless the mass falls directly under the circumareolar plane. Radial incisions are used almost ex- clusively for lesions in the inferior pole of the breast, specifically at the 6 o'clock axis. The radial incision at this point affords cosmetic results equal to the usual curvilinear incision. It is customary that the incision be separate from the axillary dissection incision. The only exception to this would include lesions high in the axillary tail of Spence, where it would be impossible to encompass both the lesion and the axillary dissection through separate incisions. Hemostasis must be meticulous, decreasing the potential for a postoperative hematoma. Such hematoma formation often delays the delivery of either cytotoxic chemotherapy or radiotherapy to the breast. Metallic clips are placed at the biopsy site to define the tu- mor bed for subsequent radiotherapy boost. The breast parenchyma surrounding the biopsy site is rarely reapproximated. The area fills postoperatively with a seroma and eventually reorganizes. This has not proven to be a problem for either interpretation of postoperative mammograms or delivery of radiation to the tumor-bearing site. If the lesion is large enough to require quadrantectomy, approximation of the breast tissue becomes appropriate. The subcutaneous tissue is then reapproximated with a buried absorbable suture to reduce ten- sion on the skin closure. The skin is then closed with a running sub- cuticular horizontal mattress absorbable suture. Adhesive strips are often applied to further remove tension from the cutaneous closure. Drainage of the biopsy cavity is rarely indicated. Lesions in the axillary tail of Spence or in the upper outer quad- rant overlying level I of the axilla provide an additional clinical chal- lenge. Excision of the lesion with noninvolved margins often neces- sitates violation of the regions thought to be lower axilla. For this rea- son excision of the index lesion and the axillary lymph nodes can be performed through a single radial incision. The index lesion is re- moved with noninvolved margins. It is important to place clips at the site of this tumor bed, facilitating a boost and avoiding radiating the lymph node-bear ing portion of the axilla. It is helpful to use a dif- Curl" probi Surg, March 1995 219 ferent size clip in the tumor bed to help distinguish it from axillary clips. After excision of the lesion, axillary dissection to the appropri- ate level can then be completed. The specimen is delivered from the wound and is marked appro- priately for analysis of the resection margins. A histopathologic diag- nosis must also be established. A silk stitch is placed in the superior axis of the specimen and cut short, and a second stitch is placed in the lateral aspect of the specimen and cut long to denote the lateral axis of the specimen. The specimen is then sent to the histopathol- ogy laboratory, where it is inked and the margins are assessed. Ana- tomic orientation is helpful in patients who have an unsuspected in- volvement of the margins so that the area in question can be ad- dressed specifically, thus not requiring complete re-resection of the tumor bed. Inking of the margins provides the only accurate assess- ment of margin identity. Margin assessment is not as accurate as one would hope but may predict local-regional failure. Several studies, including a study by Veronesi and colleagues, 159 demonstrated that histopathologically defined negative margins may in fact be involved microscopically if more refined techniques such as monoclonal antibody evaluation are used. At present, the significance of such microscopic involvement remains unclear. Analysis of the margins with the usual inking and the requisite number of representative sections taken of the speci- men appears to define adequate biologic significance. The axilla remains an area of some controversy. The trend in the treatment of invasive breast carcinoma has been toward less and less aggressive operative therapy. The trend has been from the radical mastectomy to the modified radical mastectomy to breast conserva- tion. It has been suggested that we continue this extrapolation and eliminate or minimize the axillary lymph node dissection. We believe that this would constitute a significant error. The goals and expecta- tions of axillary lymph node dissection are straightforward. Axillary lymph node dissection is both a diagnostic and therapeutic proce- dure. The expectation is that axiUary dissection yields clearance of all axillary disease, prevents axillary recurrence, and accurately stages the axflla. There is little controversy that axillary nodal involvement remains the most important prognostic indicator in patients with breast car- cinoma. Survival is markedly impacted by involvement of axillary lymph nodes. The involvement of a single axiUary lymph node in pa- tients with T 1 lesions results in a significant decrease in overall disease-free survival by the end of the first decade. The therapeutic options for axillary treatment include primary ir- radiation, axiUary lymph node biopsy, axillary sampling, and com- plete or partial axillary lymph node dissection. We advocate treat- ment of the axilla in all patients with invasive breast carcinoma. The ~24) Curr Probl Surg, March 1995 extent of axillary dissection may be tailored to the size of the tumor. Multiple series have suggested that involvement of axillary lymph nodes and the number of involved lymph nodes is a linear function of tumor size. 1s~ The smallest invasive tumors would include duc- tal carcinoma in situ with microinvasion. It is quite difficult to dis- cern the probability of axillary involvement in such patients. An analy- sis of the 644 patients with T1 tumors treated at our institution be- tween 1964 and 1970 showed that, of all lesions equal to or less than 1 cm, 13% of the patients were axillary node positive and less than 5% of the total had more than four lymph nodes involved. This is in contradistinction to a recent report of a small number of patients, suggesting a very low incidence of nodal involvement in patients with TIA lesions. ~a9 Axfllary nodal involvement remains moderately predictable not only in the relationship between tumor size and involvement of lymph nodes but also as to the level of involved lymph nodes. Levels I and II incorporate approximately 70% to 80% of the total nodal- bearing tissue of the axilla, with the remaining 20% to 30% of lymph nodes found at level III. Skipped metastases to level III are quite un- common and have been reported in 0.5% to slightly less than 2% of cases. In the complete axillary dissections advocated by Veronesi, skipped metastases were present in 0.4% of the to ta l . ~88 The distribution of involved lymph nodes in a study from Veronesi demonstrated that level I nodes only were involved in 58% of the pa- tients, level I and II nodes were involved in 22% of patients, and all three levels were involved in 16.3% of patients. ~66 It is interesting to note that if level I and II nodes were involved with a T 1 tumor, there was a 46% risk of involvement of level III nodes and a 40% risk with a T z lesion. Similarly, the T 3 lesions were associated with a 53% risk of involvement on level III if the lower two levels were involved. It is for this reason that if any suspicious axillary lymph nodes are encoun- tered either preoperatively or intraoperatively, a complete axi]lary dis- section is advocated. Axillary sampling is a procedure that has recently been advocated by several authors. This concept seems to be at odds with the extant data. A mathematical model was created evaluating 1446 complete axillary dissections performed at the National Tumor Institute in Mi- lan between 1983 and 1986.167 The purpose of the study Was to de- termine the sample size from level I that would be predictive, at a 90% level, of certainty of a total N O status in the remaining lymph nodes. The minimum number of axilIary nodes needed to be sampled to be predictive of N O status with at least a 90% certainty was 10 lymph nodes for T 1 tumors and 11 lymph nodes for Tz and T a tumors. If 11 negative lymph nodes were sampled from level I, the probability of an N O status was 93% for T~ lesions and 92% for T z lesions. In a similar fashion, the total number of lymph nodes removed was Curr Probl Sur~ March 1995 2.gl also demonstrated to be associated with axillary recurrence. A study from Europe demonstrated that in patients in whom an axillary sam- pling was performed in which one to two lymph nodes were removed there was a 5-year probability of axillary recurrence of 10% .1~8 If three to four lymph nodes were removed, a 5% risk of axillary recurrence was noted. In addition, a significant decrease in survival was noted if less than five lymph nodes were removed. A randomized prospective study evaluating the value of axillary lymph node dissection was per- formed in which 658 clinical N o patients were randomized to undergo axillary lymph node dissection or axillary observation. 169 A statisti- cally significant difference was seen in the 5-year survival rate and the axillary recurrence rate between the two groups. The conclusion of this study was that axillary dissection yielded a sulvival benefit with less frequent axillary recurrence, visceral metastases, or supra- clavicular metastases. The NSABP B-04 trial randomized patients to undergo total mas- tectomy with or without axillary dissection. This trial is often dis- cussed but is poorly understood. The trial set out to address the fun- damental question of the necessity for axfllary dissection in the man- agement of patients with breast carcinoma. The study appeared to provide two lines of evidence that axillary treatment was not thera- peutic, which had a significant impact on the philosophy of perform- ing axillary lymph node dissections. However, further analysis of the data from the NSABP B-04 trial suggests that the negative result might have been confounded by surgeons' deviation from the protocol and subject to a beta (type II) error because of a small patient population subset. In this study, 35% of patients assigned to the group receiving total mastectomy alone had axillary nodes removed. 161 More than four nodes were examined in approximately one third of patients, and more than nine nodes were removed in 20% of this subset. The significance of this is apparent when one notes that the frequency with which the patients receiving total mastectomy in this trial re- quired subsequent axillary dissection for palpable disease was related to the extent of the initial, incidental axillary lymph node dissection. No palpable axillary metastases developed if at least six nodes were removed initially, whereas axillary disease developed in 12% of pa- tients if one to five nodes were removed initially and in 21% of pa- tients if no nodes were removed. These data suggest that a signifi- cant percentage of the patients in this group could have benefitted from axillary dissection 162 and that in most patients treated by total mastectomy, occult axillary breast cancer progresses. The issue of patient population size and the potential for a beta statistical error must also be considered. 162 Although 365 patients were randomized to each treatment arm, the value of axillary treat- ment was restricted to patients with positive axillary nodes. On the basis of the node-positivity rate in the group randomized to radical ~1,22 Curr Probi Surg, March 1995 mastectomy (whose nodes were examined), the target population is reduced to 137 patients (38% of 360) who may be assumed to have involved axillary nodes. It is also clear that patients with occult dis- tant metastatic disease at the time of treatment will not benefit from axillary treatment. Again, from the data in the radical mastectomy arm, the population in question is reduced by 75% to 34 patients who had positive nodes and no occult distant spread. In addition, it is important to consider the salvage potential of delayed axillary treat- ment. It has been estimated that 25% of patients treated by total mas- tectomy alone who subsequently develop axillary adenopathy are curable.162 This reduces the number of patients cured by delayed ax- illary treatment by eight, bringing the total to 26 patients who could have benefitted from initial axillary treatment: 7% of the initial popu- lation, Statistical analysis indicates that to have a 90% chance of de- tecting a 7% difference between two treatment arms of a clinical trial at a statistical significance level ofp = 0.05, 2000 patients are required. Such analysis suggests that the negative result obtained in the NSABP B-04 trial fails to prove that axillary treatment is of no value but rather suggests that the number of patients who might benefit is relatively small. A level I and II lymph node dissection is advocated for patients with a T 1 lesion and negative clinical nodes. Any patient with suspi- cious nodes or a larger lesion is treated with complete axillary lymph node dissection. The axillary lymph node dissection is best per- formed through a curvilinear incision from the mid belly of the pec- toralis major muscle to the inferior portion of the hair-bearing axilla to the anterior border of the latissimus dorsi muscle. Thin flaps are created in the usual fashion to facilitate evaluation and completeness of the dissection after therapy. Radiation therapy remains an important part of the multimodality approach in breast conservation. Several selective studies have dem- onstrated that radiation therapy may, in fact, not be needed in all patients, but these series are quite selective. 14z' 17o-172 A very interest- ing subset of patients was identified by Veronesi, in which he dem- onstrated that according to patient age more senior patients had a very low risk of recurrence after wide local excision without radia- tion therapy. 142 This is not comparable to the excisions performed in the USA, however, because a quadrantectomy is performed rou- tinely in Milan. RADIATION THERAPY IN BREAST CONSERVATION PATIENTS INTROD UCTION Radiation therapy has played a continuous but evolving role in the management of patients with breast cancer since shortly after the dis- Curr Probl Sur~ March 1995 2~ covery of radium and the x-ray tube late in the nineteenth century) 73 Palliative, curative, and adjuvant radiotherapy have all been applied to this disease over the last century. These usages led to the devel- opment of modern breast conservation, which consists of a breast- preserving operation combined with radiotherapy to the residual breast tissue to eradicate any residual microscopic disease at the site of the primary tumor or spread through the duct system. PRACTICAL ASPECTS Consultation at Time of Diagnosis For Discussion of Options The role of the radiation oncologist can begin at the time that posi- tive biopsy is obtained. For many reasons, the patient often does not have an initial consultation until after excision and axillary lymph- adenectomy. As with any multimodality treatment program, the pa- tient is then able to obtain another physician's viewpoint. The pa- tient also is given an overview of the 6-week course of radiation, in- cluding what to expect in terms of outcome and side effects, as well as time involved, anticipated changes in her energy level, and treat- ment details. Severe complications occur infrequently I~1% of pa- tientsJ. These include carcinogenesis, brachial plexopathy, radiation- related heart disease, soft tissue necrosis, and rib fractures. Some pa- tients present to the radiation oncologist with a large fund of knowl- edge; for others, this serves as the time to question, reexamine their treatment options, and begin the final decision-making process. Preradiotherapy Mammography All patients need good quality mammography to exclude the pos- sibility of multicentric and bilateral disease. Patients bring their most recent mammogram. Films from outside the hospital are submitted for review or are repeated if necessary, especially with special views such as "cone" views or magnification of excision areas or any ques- tionable areas. For patients whose disease was identifiable only by mammography, films taken after excision are essential to ensure that all mammographic evidence of the carcinoma has been removed op- eratively before initiating treatment planning. Assessment of the Margins of the Surgical Specimen Margin assessment with India ink provides a guideline to judge both the adequacy of the operative procedure and the multifocal po- tential of the tumor, The pathologists' comments on the margins rep- resent the interpretation of the sampling that has been reviewed. Not every portion of the specimen surface can be sampled. We reported a group of patients at MSKCC with "involved margins" after limited resection who returned to the operating room for further surgery. Of 224 Curr Probl Sur~ March 1995 the 15 who opted for mastectomy, residual carcinoma was identified in 73%. Of the six patients who opted for a wider reexcision, only one (17%) had identifiable residual disease in the additional speci- mens.4a These two patient subsets were similar in all respects except for the operative procedure. The differences in the final pathologic findings are probably attributable to the volumes of breast tissue re- moved for study. The radiotherapist first reviews the pathologist's report. In patients in whom the final inked margins are assessed to be "close" or "in- volved" with tumor, all slides from that procedure are requested and reviewed with an attending pathologist to quantitate the volume of tumor at the margins and to assess the multifocal spread beyond the tissue studied. As an example, a margin may be classified as "posi- tive" but on review shows only one or two small areas of noncomedo in situ carcinoma cells at or near the margin in one of the slides. In this case, no further operation may be recommended depending on the size of the patient's breast and her interest in further surgery. This finding would help decide, however, the final dose used for the "boost" after whole breast radiation. As a second example, ff carci- noma cells are observed at multiple areas along the margin and ff multiple margins exhibit involvement, further resection is strongly recommended. For patients with close or involved margins, if EIC is observed as well, further resection is advised. 174 We believe that consistent use of margin information in treatment planning is important for local control. Schmidt-Ullrich and col- leagues 175 reported 108 patients treated with breast-conserving sur- gery and radiation who were followed for a median of 5 years. Mar- gins were classified as negative, close, or positive, and the boost doses after whole breast radiation were prescribed on the basis of that clas- sification. Patients with negative margins receive a boost dose of 1000 cGy; those with close margins, 1500 cGy; and those with positive mar- gins, 2000 cGy. Excellent local control was achieved and no differ- ences in recurrence were noted between the three subsets. In a sec- ond study, by Pezner and colleagues, 116 patients were treated with whole breast radiation but no boost if resection margins were as- sessed with India ink and classified as negative. In patients in whom the specimen margins were unknown, a boost was used after comple- tion of whole breast radiation. The difference in local control between the two groups of patients was very similar. Technical Planning Technical planning, or simulation, is carried out 3 to 4 weeks after axillary lymph node dissection when the patient has resolution of. seroma formation noted after the procedure. In the initial simulation step, an alpha cradle (Smithers Medical Products, Inc., Hudson, OH) is molded to the patient to support her in the supine position with Curr probl Sur~ March 1995 225 her arm abducted to 90 ~ at the shoulder. All patients receive whole breast radiation after breast-conserving surgery. In patients with sev- eral involved axillary lymph nodes, the paraclavicular area is also in- cluded in the treatment fields, although every attempt is made to shield the region of the axillary lymph node dissection. This is im- portant because operation and radiation to the axilla are synergistic in the development of lymphedema. A clip placed by the surgeon at the highest or medial extent of the surgical dissection is most useful in this regard. The extent laterally along the axillary vein (toward the arm) need not be marked nor the extent of dissection inferiorly near the tail of the breast. For patients who have a complete level I and II lymph node dissection with all nodes negative, the apex of the axilla and the paraclavicular areas are generally not irradiated. Internal mammary lymph node irradiation is not routinely used, although it is considered in patients with extreme medial lesions. 176 The pro- tractor method is used whenever the paraclavicular area is irradiated to minimize any "matching fibrosis" between the junction of the beams of the tangent fields and the paraclavicular area. 177 Although it is beyond the scope of this paper to describe the de- tails of simulation for this group of patients, several points are note~ worthy. Clips placed in the medial, lateral, inferior, superior, and deep margins of the breast resection at time of operation are ex- tremely important for accuracy in the boost dose delivery. The latter is particularly true for extreme medial, lateral, and deep lesions (i.e., ones in which the operative excision may not be directly beneath the surgical scar). The palpable edge of the breast tissue is outlined on the patient's skin and then soft lead wires are placed over these markings. Fields tangent to the circle described by the rib cage are used in most pa- tients, and the MSKCC radiation oncologists accept a maximum of approximately 3 cm of lung volume during treatment. When this vol- ume of lung is exceeded, the patient in a decubitus position is then treated, with the breast posit ioned on a thin slab of flat Styrofoam, and is simulated with a technique used more commonly by the French .46 Both cobalt and 6-MeV accelerator beams have been used over the past 10 years to treat patients with primary breast carcinoma. In small women, the anticipated skin reaction and final cosmetic outcome ap- pear similar with each, although this is a point of further study. In large and heavy patients, the isodose distribution is much improved with the 6-MeV photon beam. Doses prescribed to the whole breast have consistently been 4600 cGy for patients with invasive carcinoma. In the past, both electron beam and iridium implants have been used as boost techniques. At present, primarily on the basis of availability of multiple electron beam energies in our department, the electron beam boost is used 2,2A~ Curr Probl Surg, March 1995 in nearly all patients. Boost doses for patients with invasive carcinoma and negative margins generally consist of seven fractions of 200 cGy each, for a total dose within the tumor bed of 6000 cGy. For patients with minimally involved margins, 1800 to 2000 cGy boosts are gener- ally prescribed, in 9 to 10 fractions. For those patients who had their initial limited resection outside MSKCC and were reexcised by our surgical staff and found to have no residual carcinoma in the entire specimen, the boost dose is limited to 600 cGy in three fractions. For patients with ductal carcinoma in situ, a quadrant boost of 1000 cGy is often prescribed. There are radiotherapy factors, some of which may not be avoid- able, which decrease cosmetic outcome, as noted in a recent review article. 17a These include whole breast doses of more than 50 Gy, daily fraction sizes greater than 200 cGy, overlapping treatment fields, in~ homogeneity of radiation dose greater than 10%, larger area boosts, and simultaneous administration of chemotherapy. Follow-up Patient Care During a 6-week course of treatment, all patients are examined at least once a week for acute side effects by the radiation oncologist. Our experience indicates that the treatment is well tolerated by most patients, with side effects confined to minimal edema, skin erythema or tanning, and dry desquamation. The one patient subgroup with a predictably higher incidence of more severe moist desquamation is that categorized as qarge breasted" or ~heavy2179 Despite the prophy- lactic use of skin care products, severe skin reactions invariably oc- cur acutely in all areas of skinfolds. Large-breasted women also received lower overall cosmetic scores, using our I to 10 linear analog scale, compared with women of aver- age size. 179 Similarly, heavy women were more likely to have arm edema develop on the treated side than women of average height and weight, la~ No differences have been found in an analysis of local con- trol or distant failure. In addition to close clinical follow-up, mammography has been ex- tremely useful in the continuing evaluation of these patients. The first postradiation mammogram is obtained as soon as the radiation edema subsides and then at least at loyear intervals, if not sooner. Localization clips again serve as useful markers to the diagnostic ra- diologist when evaluating these radiographs. A physical examination is scheduled every 3 to 4 months for the first 3 years, alternating be- tween the radiation oncologist and the surgeon. The use of breast-conserving surgery without postoperative radia- tion implies that local recurrence is never detrimental to the patient's overall survival. Uncontrolled disease in the breast can ulcerate and can progress to cancer en cuirasse. The small amount of published data suggests that cancer relapse causes at least as much anxiety and Curr Probl Surg, March 1995 227 distress as the initial diagnosis. ~sl We recommend that doctors and patients consider participation in randomized trials that test for a group of patients that do not need breast radiation after limited sur- gery. In the meantime, virtually all patients not entered into trials should be offered and encouraged to undergo breast radiation after conservation surgery. ADJUVANT SYSTEMIC THERAPY FOR EARLY BREAST CANCER The main objective of BCT or mastectomy is to eradicate local dis- ease and prevent local-regional recurrence. In patients without sys- temic metastases, operation may lead to cure; however, most women presenting with apparently localized breast carcinoma have occult metastases (micrometastases) despite negative staging investigations. Before the introduction, during the 1890s, of aggressive local opera- tive treatment for primary breast cancer, all patients eventually had metastatic disease develop. 18z Long-term follow-up of patients treated by radical mastectomy, in contrast, has indicated that approximately one third of unselected patients do not have recurrence develop, 21 implying that they did not have clinically meaningful dissemination. For the remaining two thirds, however, cells have already metasta- sized before the time of primary treatment. Hence, even if local con- trol were to be totally effective, these patients could not be cured without systemic-therapy. Patients undergoing limited breast resection and axillary resection will be advised to have the same systemic adjuvant program as if they were undergoing mastectomy because the recommendations are based on the likelihood of micrometastases. Systemic treatment can be hormonal or can be chemotherapy with cytotoxic drugs that alter the mitotic processes of cancer cells and, incidentally, normal host cells, laa Both forms of systemic treatment have been evaluated as ad- juvants to local control in the management of primary disease. TM Node-Posit ive Breast Cancer Axillary lymph node involvement has long been and continues to be recognized as the most important prognostic factor in primary op- erable breast cancer. Without additional treatment, one third of all patients with negative axillary lymph nodes will have metastases de- velop by 10 years compared with two thirds of those with one to three positive nodes and 85% of patients with four or more involved nodes.la The first trials of adjuvant chemotherapy were limited to pa- tients with positive nodes. Two early trials of adjuvant chemotherapy have been particularly influential. In 1972 the National Surgical Adjuvant Breast Project ini- tiated a randomized comparison of 2 years of L-phenylalanine mus- 228 Curt Probl Surg, March 1995 tard compared with no systemic therapy for patients found to be node positive at mastectomy, la5 In 1973, the Italian National Tumor Institute in Milan started a comparison of no systemic therapy com- pared with 1 year of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). aa6 Both trials demonstrated that chemotherapy improved disease-free survival by approximately 10%, with particular activity in premenopausal patients for whom there was also a sur- vival advantage. Extensive subsequent experience has confirmed the survival ben- efit of chemotherapy in premenopausal patients with positive lymph nodes. It cannot be stated unequivocally whether this result is due to increased "cure" or profoundly delayed recurrence, but the effect is maintained over at least 14 years of observation and is substantial, with an improvement in median survival in excess of 6 years in the Milan trial, ls7 A major meta-analysis of all randomized trials of adju- vant therapy of patients with early breast carcinoma was presented in 1985 and published in 1988.1SSThis study documented that, on average, multiagent cytotoxic chemotherapy (largely 6 months of CMF) decreased 5-year mortality by 25%. A comparison of 6 months of CMF to 1 year of the same regimen found no advantage to the longer administration, a result that has generally been corroborated. 1~9 Although a regimen containing oral cyclophosphamide was superior to the "all IV" regimen in patients with metastatic breast carcinoma, 19~ no prospective trials have been carried out to compare the various CMF schedules in the adjuvant setting and, in overview, no one CMF protocol appears to be mark- edly superior to any other. The establishment of doxorubicin as the most active single agent in metastatic breast cancer has led to its inclusion in adjuvant therapy trials. The Cancer and Leukemia Group B (CALGB) per- formed a prospective, randomized trial of CMF regimen for 1 year compared with the same regimen for one half year followed by one half year of a doxorubicin combination. These investigators reported an advantage in disease-free survival for patients with more than three involved lymph nodes who received doxorubicin. 19~ Mathe and colleagues ~gz found an advantage in disease-free and overall survival for premenopausal patients and in disease-free st/rvival in postmenopausal patients with more than three positive nodes for a doxorubicin-containing regimen compared with CMF. The Milan group randomized patients with one to three involved lymph nodes to receive doxorubicin after CMF or CMF alone. They found no advantage from the addition of the anthracycline. ~9~ It has been suggested that the negative trials using doxorubicin failed because of suboptimal doses and schedules. TM Because doxorubicin is perceived as being more toxic than the components of CMF, its use in adjuvant programs in patients with small numbers of positive Curr Probi Surg, March 1995 2~9 lymph nodes requires demonstration of therapeutic superior- ity195,196 and that has not occurred. For patients at highest risk, those with 10 or more involved nodes, regimens applying ultrahigh-dose chemotherapy with bone marrow reinfusion and cytokine hematopoietic support have been investi- gated. 197 Uncontrolled data suggest that such treatments may indeed be beneficial in selected cases, but a prospective, randomized trial currently under way must be watched carefully. Medical oncologists now routinely use doxorubicin in regimens of moderate to high-dose intensity in premenopausal patients at high- est risk (i.e., those with higher degrees of nodal involvement). On the basis of available data, this would seem to be a reasonable approach, but the critical ongoing trials must be observed carefully. For patients with a small number of positive nodes, there are insufficient data to recommend treatment other than 6 months of CMF, although the NSABP regimen of doxorubicin and cyclophosphamide does merit fa- vorable consideration in selected cases. Endocr ine Therapy. The major interest has been in the "antiestro- gen" tamoxifen, which is particularly active in postmenopausal pa- tients with hormone-responsive stage IV disease. Large trials in En- gland lga and Scotland 199 and meta-analysis of tens of thousands of treated patients have demonstrated unequivocally that postmeno- pausal patients, particularly those with estrogen receptor-posit ive tumors, experience a 20% reduction in their rate of mortality by use of the drug for at least 2 years after the primary mastectomy. Some premenopausal patients, however, respond to tamoxifen by experi- encing an estrogen surge, 2~176 possibly because of blockade at the hy- pothalamic level by tamoxifen, which may decrease the efficacy of the drug and may also have independent adverse consequences. Ex- traordinarily high estrogen levels in the range of thousands of pico- grams may develop in young patients receiving tamoxifen. Although benefit has been noted in tamoxifen trials for premenopausal pa- tients, 2~ we do not know whether this is limited to individuals older than age 40 or to those who do not have hyperestrogenemia develop. Therefore administering tamoxifen to premenopausal women is con- troversial and rarely performed at the current time at MSKCC. Concerning duration of tamoxifen use, comparative data suggest that 5 years are superior to 2 years, and randomized trials are in progress comparing 10 years with 5 years, z~ However, there are many examples now in experimental laboratories of breast carcinoma cell lines that are tamoxifen-dependent and will grow preferentially in the face of tamoxifen so that lengthy duration of tamoxifen deserves care- ful study. 2~ A slightly increased risk of thromboembolic phenomena has been reported for patients receiving tamoxifen. Tamoxifen does not cause, 230 Curr Probl Sur~ March 1995 and may actually protect against, osteoporosis. Lipid profiles are fa- vorably altered, z~ Hot flashes and mood swings are common side effects. These effects suggest that tamoxifen has estrogen agonist properties in tissues other than breast carcinoma. Excess noncancer deaths were not reported in the British laa or Scottish 1as experience. An increased incidence of uterine cancer and consequent deaths was noted in a recent NSABP report. TM The relatively slight toxicity of tamoxifen compared with conven- tional chemotherapy has raised the issue of opt imum treatment of postmenopausal patients who are candidates for hormonal treat- ment. That is, ff tamoxifen is effective, should patients be subject to the rigors of chemotherapy? In fact, the safety of tamoxifen is such that the true question is not tamoxifen compared with chemotherapy but tamoxifen compared with tamoxifen plus chemotherapy. Node-Negative Breast Cancer Without additional treatment, approximately 70% of patients whose tumors do not involve the axillary lymph nodes at mastectomy remain disease-free at 5 years. As adjuvant treatment became estab- l ished in the node-positive population, it became evident that there might be a role for systemic therapy for these patients with a rela- tively good prognosis. Reticence about exposing patients with espe- cially favorable prognoses to potentially toxic treatments resulted in eligibility limitations in several trials and generally restricted the therapies used to those with acceptable, low-morbidity profiles. In June 1990, data on 10 studies were reviewed in depth at a National Consensus Development Conference held in Bethesda, Maryland. 1 The data demonstrated that adjuvant chemotherapy, largely CMF and variants, decreased the relapse rate by at least one third, with a broad range. The Milan group studied 8 months of intravenous CMF in patients with estrogen receptor-negative tumors, finding a signifi- cant survival advantage over the control group. 2~ Node-negative patients have also participated in trials of adjuvant tamoxifen. Tamoxifen, largely in postmenopausal patients with estro- gen receptor-posit ive tumors, decreases the relapse rate by at least one fourth. 199' 2o6 In addition, several of these studies suggest that pa- tients with estrogen receptor-negative disease may also respond, but this is at variance with other studies and also with the general expe- rience in patients with node-positive disease and therefore awaits fur- ther scrutiny and confirmation. The most effective means of improving the success of any treat- ment modality is by identifying patients most likely to benefit. If ad- juvant treatment decreases the rate of relapse by approximately one third and if an unselected population of node-negative patients is treated, the relapse rate will decrease from 30% to 20%. If a patient population can be defined with only a 9% chance of relapse, therapy Curr Probl Sur~ March 1995 231 will lower that risk to 6%, for a very small net gain. In such a popu- lation adjuvant treatment may not be indicated. Hence, prognostic factors are important in advising patients and guiding physicians. The most important prognostic factor in node-negative patients is the size of the primary tumor. Rosen and colleagues 2~ followed node-negative patients for more than 20 years after mastectomy. They found that those with the most common histologic types of infiltrat- ing ductal or lobular cancer less than 1 cm in diameter or the rare histologic types of mucinous, papillary, medullary, or tubular varie- ties less than 3 cm had a 13% overall recurrence rate. Nuclear grade, hormone receptor status, flow cytometry, and other factors are being evaluated in patients with node-negative disease in an attempt to de- fine factors that do not correlate with classic histopatholo~y. 2~ The HER-2/neu oncogene is now not known to be a prognostic factor in patients with node-negative disease. 2~ Toxicity of Chemotherapy Acute toxicities of conventional chemotherapy include nausea, alo- pecia, and complications of myelosuppression. With modem man- agement, toxic mortality with CMF will be less than 1%. Excess leu- kemia has been demonstrated in programs that include melphalan. For cyclophosphamide-based regimens without extensive radio- therapy, large series have not revealed excess risk, 21~ although a few reported cases have raised the question. 211 Amenorrhea is common and is likely to be permanent in patients older than 40. 212 Thrombo- embolic phenomena are increased with both chemotherapy and ta- moxifen. Investigators in the CALGB found arterial thrombosis (in- cluding stroke) in 7 of 901 patients with stage II breast carcinoma. The risk appears to normalize with cessation of therapy. 21a Anthracycline-induced cardiomyopathy is rare in patients treated with less than 400 mg/m 2 of doxorubicin and thus has not been a problem in the adjuvant setting. 214 The Sequence of Adjuvant Chemotherapy and Primary Radiation Although an early report suggested that patients treated with ra- diation as part of breast-conserving surgery tolerated subsequent chemotherapy less well than nonirradiated mastectomy patients, 215 a prospective randomized trial comparing early with late radio- therapy has so far found no difference in the administered chemo- therapy dose. 216 The optimal timing of radiation after breast- conserving operation and adjuvant chemotherapy for the patients in whom it is indicated has recently been reviewed and is still contro- versial, z17 Concomitant delivery would be ideal from the medical standpoint; however, in these cases, increases in the acute skin reac- tions were observed, often necessitating an interruption of the radia- tion treatment, Curr Probl Surg, March 1995 Some clinicians advocate a "sandwich technique." Part of the che- motherapy is delivered, the patient's chemotherapy is then withheld while she undergoes a 6-week course of radiation, and then the re- maining planned chemotherapy is delivered. Other clinicians advo- cate elimination of the most radiosensitive chemotherapeutic agent (methotrexate) and a continuation of the course of cyclophospha- mide and 5-fluorouracil. For opt imum delivery of adjuvant chemotherapy, the "sandwich technique" is not ideal. Many centers prefer to administer the che- motherapy first if both radiation and chemotherapy are indicated. Be- cause the endpoint of chemotherapy is to prevent systemic disease compared with primary radiation with its endpoint of local control, the adjuvant chemotherapy is delivered first, using optimal doses, timing, and drug combinations. The radiation then follows the completion of chemotherapy when the patient's blood cell counts show recovery. However, there is no evidence that reasonable delays in substituting chemotherapy are detrimental to control of microme- tastases, 21a so the administration of radiotherapy first is also a ratio- nal option. If no adjuvant chemotherapy is indicated, the patient pro- ceeds to radiation within 3 to 4 weeks of the axillary surgery. MANAGEMENT OF LOCAL-HEGIONAL RELAPSE AFTER BREAST CONSERVATION THERAPY The frequency with which local-regional recurrence occurs after BCT and radiation therapy varies from 8% to 22% (Table 7) .44, 57, 112, 113, 125, 154, 219-223 Patient selection criteria, as well as im- proved operative and radiotherapeutic techniques, have led to reduc- tions in local relapse rates in recent years. Local-regional recurrence rates increase over time after BCT at a steady rate and, in most long- term studies, the 5-year recurrence rates double by the 10th year.5r, 113, 219 Studies of breast-conserving surgery without radiation therapy have uniformly reported high local recurrence rates in the range of 14% to 46% .lrl, 224, 225 The current standard of treatment for local relapse after BCT is salvage mastectomy. Most patients relapsing locally after BCT have no evidence of dis- tant metastasis and therefore have operable disease. The inoperabfl- ity rate caused by extensive local-regional disease ranges from. 5% to 12.5% (Table 8).113' 220-222, 226 Patients relapsing within 5 years of BCT have a much higher inoperability rate than those patients relapsing after 5 years from BCT: 17% versus 1.4%, p = 0.005.1~ Prior or syn- chronous distant metastases are detected in approximately 5% of the patients at the time of local relapse. 113' 22o These data suggest that full preoperative staging is required before salvage mastectomy. The extent of the salvage operation depends on the extent of re- currence and the specific details concerning the breast conservation. Curr Probl Surg, March 1995 233 TABLE 7. Local-regional recurrence rate after breast-conserving surgery and radiatit)n therapy Local-regional Years of Number of Median recurrence Institution study patients follow-up (%) Royal Marsden 5~ 1954-1969 211 120 22.0 M.D. Anderson TM 1955-1985 525 64 10.3 Multi- institutional ~2 1958-1965 158 160 22.0 Institut Curie 21a 1960-1980 518 172 18.0 Yale New Haven ~z5 1960-1982 278 90 17.0 Marseilles 11a 1963-1982 1593 132 12.9 Harvard ~a 1968-1981 733 76 13.3 University of 1970-1986 1030 40 9.3 Pennsylvania 2z~ Tours 22~ 1976-1986 202 42 13.5 NSABP 44 1976-1984 629 81 14.5 Westminster ~2 1979-1985 356 60 13.5 TABLE 8. Inoperabfl ity rate of local-regional recurrence after breast-conserving operation and radiation therapy Number of Inoperable Inst itut ion patients (%) Marseil les l~a 178 11.0 HaIvard 219 90 12.0 University of 52 5.0 Pennsylvania 220 Tours 221 16 12.5 Cretie1225 51 10.0 In the presence of recurrent breast carcinoma that is fixed to the pec- toralis major muscle or recurrent, bulky axillary disease, radical mas- tectomy may be indicated. If the axilla has not previously been dis- sected, salvage mastectomy is most commonly a modified radical mastectomy. The recurrent tumor close to the pectoral fascia may require resection of the anterior layer of the pectoralis major muscle fibers. Extensive tumor recurrence may necessitate wide skin resec- tion and closure by autogenous tissue transfer. If the axilla has been fully dissected as part of a BCT approach, salvage mastectomy may be achieved by total mastectomy. Postoperative complications are unusual and occur in 3% to 7% of cases.22o, 227, 22a The complication rates in patients who have been ir- radiated are comparable to complication rates in nonirradiated pa- tients undergoing mastectomy. This fact emphasizes the point that Curr Probi Surg, March 1995 current radiation techniques rarely cause skin changes that result in flap necrosis. Breast reconstruction after salvage mastectomy is an important is- sue for patients with a local relapse after BCT. Autogenous tissue transfer should be the standard method used because subpectoral tissue expansion often fails because of inelasticity of the skin after radiation therapy. The best methods of autogenous reconstruction are transabdomina] myocutaneous (TRAM) flap or a free flap (TRAM or gluteal) with microvascular anastomosis. Salvage mastectomy offers excellent local-regional control. Local- regional relapse rates after salvage range from 4% to 15% .lO8, 220, 227, 22s A recent report from MSKCC reported a 15% local relapse rate in 46 patients who underwent salvage mastectomy. 227'22a In an ex- tended study of 128 patients carried out by the New York Metropoli- tan Breast Cancer Group, 0.5% had local-regional relapse after salvage.lla, lO6, 227-229 Local-regional relapse after salvage mastectomy is less frequent in patients who have a prolonged disease-free inter- val between BCT and local-regional failure. 1~ 113, 227-229 Patients with a disease-free interval of greater than 5 years had a local-regional re- currence of 4% after salvage compared with a 12% relapse rate of pa- tients with a disease-free interval of less than 5 years. 1~ 113 Virtually all series reporting overall survival after salvage mastec- tomy report a 50% breast cancer-free survival at 5 years. 57' 112 There- fore, strong consideration should be given to adjuvant systemic therapy after salvage mastectomy. Predicting outcome after salvage surgery has been problematic. The most frequently reported predic- tive factor is the disease-free interval from the time of initial breast- conserving therapy to the first local regional relapse. 1~ 113, 227-229 Not all studies have been able to corroborate these findings. 112' 22o The original T-stage and axillary lymph node status were not found to be prognostic factors uniformlyXla; however, some studies do suggest that the status of the lymph nodes at the time of conservation was highly predictive of relapse rates after salvage mastec- tomy.lOS, 11s, 227, z2a Evaluating the patients who relapse after salvage mastectomy at MSKCC considering the lymph node status at breast conservation showed a median time to relapse of 39 months in the node-positive group; the node-negative group had not yet reached their median relapse time. 22a There are few viable alternatives to salvage mastectomy. If adequate radiation therapy was given initially, further irradiation of the breast is ill-advised. Attempts to reconserve the breast by local excision of a breast recurrence have been reported for small recurrent tumors. 23~ A 12% local relapse rate at 5 years for salvage mastectomy is far su- perior to the 36% local relapse rate reported for conservative salvage surgery.lOS, 2ao In patients who experience local relapse more than 5 years after breast conservation, the local-regional relapse rate after Curr Probl Surg, March 1995 ~,,~5 salvage surgery was 4% for salvage mastectomy and 22% for conser- vative salvage surgery) ~ z3o In conclusion, salvage mastectomy provides excellent local- regional control for most patients with local-regional relapse after BCT. Survival rates after salvage surgery suggest that strong consid- eration should be given to adjuvant therapy in these patients. 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