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Optimal Extent of Resection for Patients With Stages I or II Breast Cancer Treated With Conservative Surgery and Radiotherapy The

FRANK A. VICINI, M.D.,* TIMOTHY J. EBERLEIN, M.D.,t JAMES L. CONNOLLY, M.D.,4 ABRAM RECHT, M.D.,* ANTHONY ABNER, M.D.,* STUART J. SCHNITT, M.D.,4 WILLIAM SILEN, M.D.,§ and JAY R. HARRIS, M.D.*

The optimal extent of breast resection before irradiation for treatment of early breast cancer has not been defined. Increasing the size of the resection may decrease the risk of local recurrence but will also have an adverse impact on the cosmetic outcome. The 5-year likelihood of a recurrence of the tumor was analyzed in relation to the volume of resected breast tissue in 507 patients with infiltrating ductal carcinoma treated with conservative surgery and radiation therapy between 1968 and 1982. Patients were stratified by clinical T-stage and for each T-stage patients were divided into three groups of equal numbers based on the volume of excised tissue. All patients had at least a gross excision of the tumor and the extent of breast resection was determined at the discretion of the surgeon without knowledge of the histologic features of the tumor. The median follow-up time was 100 months. The 5-year actuarial recurrence rates were analyzed in relation to clinical T-stage (TI or T2) and the presence or absence of an extensive intraductal component (EIC+ or EIC-). For patients with EIC+ tumors, the largest resections were associated with a substantially lower risk of recurrence in the breast than the smallest resections. This effect was seen both for T, tumors (10% versus 29%, p = 0.07) and for T2 tumors (9% versus 36%, p = 0.04). For patients with EIC- tumors, recurrence rates were significantly lower than for EIC+ tumors and were not influenced by the volume of resection to the same degree as EIC+ tumors. In the absence of an EIC, recurrence rates for the largest and smallest resections were 0% and 9% (p = 0.02) for T, tumors and 3% and 6% (p = NS) for T2 tumors. It is concluded that a limited breast resection is acceptable for an EIC- tumor but that a more extensive resection is required for an EIC+ tumor. These results stress the importance of assessing the presence or absence of an EIC in determining the optimal extent of breast resection required before radiation therapy.

A S THE USE of conservative surgery (CS) and radiation therapy (RT) has become an accepted option in the treatment of early-stage breast cancer,' the issue of the optimal extent of breast resection Presented at the 1 1 1th Annual Meeting of the American Surgical Association, April 1 1-13, 1991, Boca Raton, Florida. Address reprint requests to William Silen, M.D., Department of Surgery, Beth Israel Hospital, 330 Brookline Ave., Boston, MA 02215. Accepted for publication April 15, 1991.

From the Department of Radiation Therapy,* Harvard Medical School, and Joint Center for Radiation Therapy, Department of Surgery,t Brigham and Women's Hospital and Harvard Medical School, and Departments of Pathology,f and Surgery,§ Beth Israel Hospital and Harvard Medical School, Boston, Massachusetts

before RT has assumed greater importance. Some studies have shown that increasing the size of the breast resection may diminish the risk of local recurrence,2 but others have shown that this will also have an adverse impact on cosmetic outcome.3'4 Assessing the microscopic margins of a 'lumpectomy' specimen would appear to be the most logical means of ensuring adequate tumor removal before RT without unnecessarily worsening cosmetic outcome in most patients. Unfortunately what constitutes an 'adequate' margin is undefined5' 6 and the impact of involvement of microscopic margins on the risk of local recurrence after CS and RT has not been established.2'7-'0 We have shown previously that assessing infiltrating ductal cancers for the presence or absence of an extensive intraductal component (EIC) can be helpful in judging the adequacy of tumor removal after local excision."' In a study of patients who underwent a re-excision of the primary tumor after an initial gross excision because of positive or close margins of resection, we found that patients with EIC+ tumors had a greater incidence of residual tumor (frequently widespread) in the re-excision specimen than did patients with EIC- tumors (88% versus 44%, p = 0.002). In the present report, we address the issue of the volume of resected breast tissue, its relation to the presence or absence of an EIC, and their combined effect on the likelihood of a local recurrence of the tumor. Our data suggest that a limited breast resection is acceptable for an EIC- tumor but that a more extensive breast resection is required for an EIC+ tumor.

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RESECCTION FOR PATIENTS WITH BREAST CANCER TREATED WITH CS AND RT

Methods From 1968 to 1982, 954 women with unilateral Union Internationale Contre le Cancer/American Joint Committee for Cancer Staging and End-Results Reporting (UICC-AJCC) clinical stage I or II breast cancer were treated at the Joint Center for Radiation Therapy in Boston, Massachusetts. To eliminate the confounding effects of inadequate treatment, 29 patients with less than an excisional biopsy and 116 patients who received a total dose of less than 60 Gy to the region of the primary tumor were excluded from the analysis, leaving 809 clinically eligible patients. Patients with simultaneous bilateral tumors were excluded and, for patients with metachronous opposite breast cancer, only the first tumor was considered for the analysis of failure. Initial biopsy material was reviewed by two of the authors (JL Connolly and SJ Schnitt) for 736 breast tumors (91%). Details of this assessment have been previously described.'2 For this report, analysis was limited to 507 of these 736 cases, in which the histologic type was infiltrating ductal carcinoma, sufficient grossly normal adjacent breast tissue was present for evaluation, and the total volume of excision could be calculated. Pathologic examination assessed the presence and extent of intraductal carcinoma both in the tumor mass and in the adjacent grossly normal breast tissue. As of December 1989, median follow-up time was 100 months for the 366 surviving patients (range, 17 to 219 months). The median follow-up time for all patients was 93 months (range, 5 to 219 months). Six patients were lost to follow-up 17 to 78 months after treatment. The details of treatment have been previously de-

scribed.'3 Surgery consisted of excisional biopsy, defined as gross total removal of the primary tumor, usually without histologic confirmation of pathologic margins. A total of 399 patients (79%) underwent axillary dissection, usually limited to levels I and II.

All patients received whole breast irradiation, typically to a total dose of 45 to 50 Gy during a period of 5 weeks. This was followed by a boost to the original tumor site to at least 60 Gy using either an interstitial implant (Iridium-

192), photons, and/or electrons. Chemotherapy was administered to 125 patients (25%) in various sequencing with radiotherapy. One hundred fourteen of one hundred forty-two patients (80%) with histologically positive axillary lymph nodes received adjuvant chemotherapy. Only 3% (7 of 257) of patients with negative axillary nodes received chemotherapy. The chemotherapy regimens varied substantially during this period, but 90% of patients receiving chemotherapy were treated with cyclosphosphamide, methotrexate, and 5fluorouracil (CMF) or with doxorubicin. Our previous experience has shown that the most important predictor of recurrence in the breast is what we

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have termed an extensive intraductal component (EIC) in the primary excision specimen. This is defined as the simultaneous presence of both a prominent amount of intraductal carcinoma within the primary tumor and intraductal carcinoma clearly extending beyond the infiltrating margin of the tumor or present in grossly normal adjacent breast tissue. It may also denote a tumor that is predominantly noninvasive with focal areas of invasion. The gross volume of excised breast tissue was calculated by multiplying height X width X length, using maximum dimensions of the gross specimen as described by the pathologist. To determine the impact of the extent of breast resection on the risk of recurrence in the breast, the 265 patients with T, tumors were divided into three groups of equal numbers based on the volume of breast tissue resected (less than 13 cm3, 13 to 48 cm3, and more than 48 cm3). The 242 patients with T2 tumors were similarly divided into three groups of equal numbers with volumes less than 35 cm3, 35 to 74 cm3, and more than 74 cm3. Recurrence in the breast ('local recurrence') was defined as the detection of cancer in the parenchyma and/or skin of the treated breast occurring before or simultaneously with the discovery of distant metastases. Recurrences were classified by the location in the breast relative to the primary tumor and boost volume as true recurrence (TR, within the area of the boost), marginal miss (MM, adjacent to the boost), elsewhere (several centimeters from the primary site), and other (skin only and unclassifiable). Because we consider TRs and MMs to be recurrences of the primary tumor (as opposed to a new primary in the ipsilateral breast), only TRs and MMs were used in the calculation of local failure. Failure rates were calculated using two methods: crude 5-year percentages and actuarial curves (by the KaplanMeier method).'4 Patients were censored from the calculation of local recurrence at the time of last follow-up examination, the discovery of metastatic disease, the discovery of regional disease without local recurrence, or death from intercurrent illness. Six patients lost to followup were all without evidence of recurrence and were deleted from calculations at last known follow-up. Patients were censored from calculations of distant failure at the time of death from intercurrent illness or at last followup. Distant failure was scored at the time of first discovery of disease outside of the treatment field (but excluding isolated nodal failure). Cause-specific survival rates were calculated by scoring death from breast cancer and its sequelae, deleting patients who died of other causes at the time of death and those lost to follow-up at last known follow-up. All intervals were calculated from the date of beginning radiotherapy. The statistical significance of the differences between actuarial curves was calculated using the two-tailed log-rank test. Probability values of 0.05 or less were considered statistically significant.

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Results Fifty-five of the five hundred seven patients (1 1%) developed local recurrence of the tumor in the treated breast. Forty of these recurrences occurred within the first 5 years after treatment, for a crude 5-year rate of 8%. The 5- and 10-year actuarial rates of local recurrence were 12% and 17%, respectively, and the 5- and 10-year actuarial rates of distant failure were 21% and 3 1%, respectively. Actuarial survival rates were 86% at 5 years and 75% at 10 years, with 80 patients surviving for more than 10 years. Table shows the association between the extent of breast resection and the 5-year actuarial rate of recurrence in the breast. Overall patients with EIC+ tumors had higher rates of recurrence than patients with EIC- tumors. For patients with clinical stage T, EIC+ tumors, the recurrence rate was 29% for those with resection volumes less than 13 cm3, 22% for those with resection volumes between 13 and 48 cm3, and 10% for those with resection volumes greater than 48 cm3 (29% versus 10%, p = 0.07). For patients with clinical stage T2 EIC+ tumors, the recurrence rate was 36% for those with resection volumes less than 35 cm3, 26% for those with resection volumes between 35 and 74 cm3, and 9% for those with resection volumes greater than 74 cm3. The difference between recurrence rates for patients with the smallest and largest breast resections was statistically significant (36% versus 9%, p = 0.04). The recurrence rates were not significantly different between the intermediate and largest resection groups for patients with T, tumors and for patients with T2 tumors. In patients with EIC- tumors, low rates of local recurrence were obtained for all subgroups. For patients with clinical stage T, EIC- tumors, the recurrence rate was 9% for those with breast resection volumes less than 13 cm3, 2% for those with resection volumes between 13 and 48 cm3, and 0% for those with resection volumes TABLE 1. Five-year Actuarial Rate ofRecurrence of the Tumor in the Breast in Relation to the Extent of Breast Resection and the Presence of EIC

Extent of Breast Resection* Tumor No. of Probability Size Patients Smallest Intermediate Largest Valuet

EIC+

T,

T2 EIC-

T, T2

83 78 182 164

29% 36% 9% 6%

22% 26% 2% 2%

10% 9% 0% 3%

0.07 0.04 0.02 NS

* For patients with T, tumors, the volume of breast resected corresponds to < 13 cm3, 13-48 cm3, and >48 cm3 for smallest, intermediate, and largest resections, respectively. For patients with T2 tumors, the volume of breast resected corresponds to 74 cm3 for smallest, intermediate, and largest resections, respectively. t Probability values compare differences between the largest and smallest breast resections.

Ann. Surg. - September 1991

more than 48 cm3 (9% versus 0%, p = 0.02). For patients with clinical stage T2 EIC- tumors, the recurrence rate was 6% for those with breast resection volumes less than 35 cm3, 2% for those with resection volumes between 35 and 74 cm3, and 3% for those with resection volumes greater than 74 cm3. The differences between these recurrence rates were not statistically significant.

Discussion In this study we examined the association between the extent of breast resection and the risk of a recurrence of the tumor after CS and RT. We found that in patients with an EIC+ tumor, the largest resections were associated with a significantly lower risk of recurrence in the breast than the smallest, both for T1 and T2 tumors. For patients with EIC- tumors, recurrence rates were significantly lower than for EIC+ tumors and were not influenced to the same degree by the volume of resection. Our results suggest that in the absence of an EIC in the primary tumor, a limited excision of the tumor is adequate for patients with stages I and II infiltrating ductal breast cancer. In contrast larger resections are necessary in patients with EIC+ tumors to achieve an acceptable rate of local control. The optimal extent of breast resection necessary to obtain an acceptable rate of tumor control while maintaining good cosmetic results after CS and RT has been widely debated. A critical and as yet unresolved issue is the determination ofwhen an 'adequate' resection ofthe tumor has been achieved. One approach has been to assess the microscopic margins of excision of the resected specimen. Unfortunately there are many problems inherent in defining such margins. Breast specimens are fatty and irregular, making assessment of margins difficult, even with the use of ink to denote surfaces. Routine sectioning by the pathologist does not usually permit examination of the entire surface area of the specimen.6 In addition the intraductal component associated with the tumor has a highly complex, ramifying structure so that in any given section it may not appear continuous. Given these limitations, it has been shown that even in the presence of what appear to be 'negative' margins, approximately one third of breast cancers have additional foci of cancer beyond the limits of the resection.5 6 In addition the clinical significance of 'focally positive' or even 'prominently positive' microscopic margins is not clearly established in patients treated with CS and RT.7-'0 A reproducible and reliable technique for assessing margins remains to be defined. The association between the extent of mammary resection and outcome for patients treated with CS and RT has been examined in several large series.7,15-19 In Table 2 results ofexcisional biopsy (lumpectomy) are compared with those of quadrantectomy (or wide resection). These

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RESECTION FOR PATIENTS WITH BREAST CANCER TREATED WITH CS AND RT

TABLE 2. Local Recurrence Related to the Extent of Breast Resection

Percentage Local Recurrence Series

Retrospective Clarke* Van Limbergent Chu

Noblert NSABP§

Excisional Biopsy

Quadrantectomy

5% (369) 15% (149) 10% (110) 7% (87) 10% (629)

9% (43) 7% (69) 11% (18) 6% (48)

3% (1232)

Veronesill Prospective Veronesi

7% (345)

2.2% (360)

Crude rate of local recurrence-median follow-up 60 months.' rate of local recurrence-median follow-up 80 months.'5 t Crude rate of local recurrence-median follow-up 46 months.'6 § Eight-year actuarial rate of local recurrence-mean follow-up 81 *

t Five-year actuarial

months." 1 Ipsilateral recurrence of the tumor-median follow-up 72 months.'9

retrospective analyses do not establish a consistent advantage for the use of quadrantectomy compared to more limited resections. In 1985,the National Cancer Institute in Milan initiated the only prospective randomized trial comparing 'lumpectomy' followed by RT (including a boost with Iridium- 192) with quadrantectomy and RT in patients with primary tumors smaller than 2.5 cm.2 With 705 cases that could be evaluated, patients treated with lumpectomy had a higher frequency of local recurrence than patients treated with quadrantectomy (7% versus 2.2%). Quadrantectomy in this study (as well as in the retrospective series) clearly resulted in an inferior cosmetic outcome, however. The studies described above do not confirm a consistent advantage for performing larger resections before irradiation for all patients. This in part may be related to the variability in the initial tumor burden in breast cancer patients. As a result some patients may undergo excessive breast resections (with an associated poorer cosmetic result) while others may have inadequate excision of the tumor. Any determination as to the impact of the extent of the surgery on outcome thus becomes difficult .to establish. These studies stress the importance of defining a histopathologic or biologic marker that predicts the extent of breast resection required before RT. Previous studies from our institution suggest that the presence of an EIC may be such a marker.'3 Holland et al.20 performed simulated gross excisions of tumors on mastectomy specimens and then determined the extent and type ofresidual tumor in the remaining breast tissue. Residual disease was found in the breast in 71% of women with EIC+ tumors compared with 28% of those without an EIC (p < 0.0001). Approximately 30% of patients with EIC+ tumors had 'prominent' residual intraductal carcinoma (six or more low-power fields required to encompass the disease) lo-

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cated at least 2 cm beyond the edge of the primary tumor, compared with only 2% of patients with EIC- tumors. In a study of patients who underwent a re-excision of the primary tumor site because of positive or close margins of resection after an initial gross excision, Schnitt et al." similarly found that patients with EIC+ tumors had a greater incidence of 'prominent' residual tumor in the reexcision specimen than did patients with EIC- tumors (44% versus 2%, p < 0.0001). These data helped to generate the hypothesis that the optimal extent of breast resection can be judged on the basis of the presence or absence of an EIC. The results of the present study lend additional support for this hypothesis. The data presented here indicate that a limited breast resection is acceptable for an EIC- tumor but that a more extensive resection is required for an EIC+ tumor. It is worthwhile to note that for EIC- tumors, patients with intermediate volume breast resections had an excellent rate of local control, not substantially different from that of patients with the largest resections. These results have ramifications for cosmetic outcome as well as local control because cosmetic outcome after CS and RT is most adversely affected by the extent of resection.3 4 By assessing the presence or absence of an EIC, the extent of breast resection required before RT can be minimized in the approximately two thirds of all patients with infiltrating ductal carcinomas whose tumors are EIC-, thereby improving the likelihood of a good cosmetic result without decreasing the level of local control. These data also suggest that if patients with EIC+ tumors undergo a wide excision, acceptably low rates of local recurrence can be obtained. We recognize that there are limitations to the practical usefulness of assessing tumors for the presence of an EIC. As always the reproducibility of the diagnosis by the pathologist needs to be considered (i.e., interobserver variability in applying the definition). In addition determining the presence of an EIC requires a more detailed and timeconsuming pathologic assessment than is commonly performed. If the use of pathologic criteria to determine the extent of operation is not deemed feasible, it is likely that either a wide excision will be required in all patients (with poorer cosmetic outcome) or highly restrictive selection criteria will be needed to minimize the risk of recurrence.

Acknowledgment The authors thank Barbara Silver for contributing to the analysis of the data for this study.

References 1. National Institutes of Health (NIH) Consensus Development Conference statement: treatment of early stage breast Cancer. JAMA 199 1; 265(3):39 1-394. 2. Veronesi V, Volterrani F, Luini A, et al. Quadrantectomy versus lumpectomy for small size breast cancer. Eur J Cancer 1990;

26(6):67 1-673.

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3. Olivotto IA, Rose MA, Osteen RT, et al. Late cosmetic outcome after conservative surgery and radiotherapy: analysis of causes of cosmetic failure. Int J Radiat Oncol Biol Phys 1989; 17:747-753. 4. Matery WE Jr, Wertheimer M, Fitzgerald TJ, et al. Aesthetic results following partial mastectomy and radiation therapy. Plastic and Reconstructive Surgery 1990; 85(5):739-746. 5. Frazier TG, Wong RWY, Rose D. Implications of accurate pathologic margins in the treatment of primary breast cancer. Arch Surg 1989; 124:37-38. 6. Carter D. Margins of"lumpectomy" for breast cancer. Human Pathol 1986; 17(4):330-332. 7. Clarke DH, Le MA, Sarrazin D, et al. Analysis of local-regional relapse in patients with early breast cancers treated by excision and radiotherapy. Experience of the Institut Gustave-Roussy. Int J Radiat Oncol Biol Phys 1985; 11: 137-145. 8. Schmidt-Ulrich R, Wazer DE, Tercilla 0, et al. Tumor margin assessment as a guide to optimal conservation surgery and irradiation in early stage breast carcinoma. Int J Radiat Oncol Biol Phys 1989; 17:733-738. 9. Bartelink H, Border JH, van Dongen JA, Peterse JL. The impact of tumor size and histology on local control after breast-conserving therapy. Radiother Oncol 1988; 11:297-303. 10. Solin LU, Fowble B, Martz KL, Goodman RL. Definitive irradiation for early stage breast cancer: the University of Pennsylvania experience. Int J Radiat Oncol Biol Phys 1988; 14:235-242. 11. Schnitt SJ, Connolly JL, Khettry U, et al. Pathologic findings on reexcision of the primary site in breast cancer patients considered for treatment by primary radiation therapy. Cancer 1987; 59: 675-681. 12. Schnitt SJ, Connolly JL, Harris JR, et al. Pathologic predictors of

DISCUSSION

PRESIDENT ROBERT ZEPPA: Thank you, Dr. Silen, and before introducing the discussants who have been asked to discuss this paper, I would like to ask one question. Bill, was there any difference in the backgrounds of the patients who were EIC positive compared with those who were EIC negative with respect to family history of breast cancer, age at first child, etc.? DR. ALEXANDER J. WALT (Detroit, Michigan): To paraphrase a reknowned slogan, "When the Joint Center for Radiation talks, everyone listens," so the recommendations of this group have a profound impact on that sometimes unrecognized world beyond the boundaries of Boston. Bill Silen and Jay Harris, et al, have always been meticulous in their analyses oftheir data, and they have long been proponents of conservation therapy for breast cancer. In this they remain well ahead of current practice in the United States. Despite events such as the June 1990 NIH Consensus Conference, one senses an unfortunate national reluctance to abandon or retreat from mastectomy for T1 and T2 lesions. This is evidenced by the fact that in many states, including the State of Michigan, whose figures I have, conservation therapy for T1 and T2 lesions still remains something under 30%. This is not the time to review all the inhibitory factors that determine this reluctance, but fear of local recurrence is certainly one of themand I think that is what this paper is all about. Surgical life is a series of trade-offs and this is highlighted in the treatment of stage 1 and stage 2 breast cancer. The conflict here lies between maximum local control and optimal cosmesis. In the 11% of women in this and other series who have a local recurrence, three things happen: first, the event is very frightening to the patient and disturbing to her surgeon; second, the mastectomy that we hoped to avoid happens, and inevitably the patient is let down psychologically; third, there may be a small but definite negative impact on ultimate survival. At this point, both surgeons and patient are prone to thinkif not to say-"would all this have been avoided if just half an inch or 1 cm more tissue all around had been taken, and would this cosmetic difference have been an unendurable or a serious disability?" That is the

13.

14. 15.

16. 17.

18.

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early local recurrence in Stage I and II breast cancer treated by primary radiation therapy. Cancer 1984; 53:1049-1057. Harris JR, Botnick LE, Bloomer WD, et al. Primary radiation therapy for early breast cancer: the experience at the Joint Center for Radiation Therapy. Int J Radiat Oncol Biol Phys 1981; 7:15491552. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53:457-48. Van Limbergen E, Van der Bogaert W, Van der Schueren E, Rijnders A. Tumor excision and radiotherapy as primary treatment of breast cancer. Analysis of patient and treatment parameters and local control. Radiother and Oncol 1987; 8:1-9. Nobler MP, Venet L. Prognostic factors in patients undergoing curative irradiation for breast cancer. Int J Radiat Oncol Biol Phys 1985; 11:1323-1331. Fisher B, Redmond C, Poisson R, et al. Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1989; 320:822-828. Chu AM, Cope 0, Russo R, Lew R. Patterns of loco-regional recurrence and results in Stages I and II breast cancer treated by irradiation following limited surgery. Am J Clin Oncol 1984; 7: 221-228. Veronesi U, Salvadori B, Luini A, et al. Conservative treatment of early breast cancer. Long term results of 1232 cases treated with quadrantectomy, axillary dissection and radiation. Ann Surg 1990; 211:250-259. Holland R, Connolly J, Gelman R, et al. The presence of an extensive intraductal component following a limited excision correlates with prominent residual disease in the remainder of the breast. J Clin Oncol 1990; 8(1):113-118.

question. Do you remove a golf-ball-sized or a ping-pong-ball-sized amount of breast tissue? The Boston group are advocating that the extent of any in situ carcinoma present be the determinant of the extent of resection. Let us temporarily accept this argument while recognizing that not everybody, including the NSABP, agrees with it. Ifone views the invasive carcinoma as the bull's-eye of a target, then each concentric ring beyond it has a diminishing incidence of in situ breast cancer. And in case any in situ lesion is left in place, we add radiation therapy in the hope that it will sterilize the area. But to rely on radiation therapy to finish the job carries some danger, and may be analogous, in a sense, to the use of antibiotics to clear a residual abscess. When we look at Bill Silen's T2 EIC-positive group, the recurrence rate was 36% when 3.2 cm3 was removed. When the excision was stepped up to 4.2 cm3, the recurrence rate was only 9%. So it seems that the extra centimeter of excision was of great importance and would lend support to Veronesi's data, in which he had a local recurrence rate of about 2% with generous excision. So we are really much influenced by cosmesis. In this arena, as in so much else in breast cancer today, the patient and the doctor together have to decide about the type and the extent of surgery that one is going to select. Local resection, when carried far enough, ultimately becomes a mastectomy. What has been reported here today helps us to sharpen our decision-making processes. My questions then are as follows: In the period you described to us, 1968 through 1986 or so, I presume that some modified radical mastectomies were done for T 1 and T2 lesions in your institution. Could you tell us what that figure was over that time and what your current figure is? A second question: You have given figures for local recurrence according to your predefined margins. What was the recurrence rate in the rest of the breast? It is important to include that because recurrence elsewhere in the breast obviously adds to the ultimate mastectomy figure. A third question is: EIC positivity is central to your decision-making. Do you rely on frozen sections for determinations of the extent of the in situ component and, if not, in how many did you have to do a second operation after receiving the fixed section? And lastly, is there any improvement in outcome among the 125