W ITH THE INCREASING USE of mammography,

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1 Outcome After Invasive Local Recurrence in Patients With Ductal Carcinoma In Situ of the Breast By Melvin J. Silverstein, Michael D. Lagios, Silvana Martino, Bernard S. Lewinsky, Pamela H. Craig, Philip J. Beron, Parvis Gamagami, and James R. Waisman Purpose: To detail the outcome, in terms of local recurrence, local invasive recurrence, distant recurrence, and breast cancer mortality for patients previously treated for ductal carcinoma in situ (DCIS). Patients and Methods: Clinical, pathologic, and outcome data were collected prospectively for 707 patients with DCIS accrued from 1972 through June Results: There were 74 local recurrences; 39 were noninvasive (DCIS) and were invasive. Fifty-one percent of patients with invasive recurrences presented with stage 1 disease; the remainder presented with more advanced disease. Invasive local recurrence after mastectomy was a rare event that occurred in 0.8% of patients. Invasive recurrence after breast preservation was more common and occurred in 7.4% of patients. The 8-year probability of breast cancer mortality after breast preservation was 2.1 %, a number that is likely to W ITH THE INCREASING USE of mammography, ductal carcinoma in situ (DCIS) has become a more common diagnosis. In the early 1980s, most cases of DCIS were treated with mastectomy and local recurrence rates were low, generally around 1% to 2%.1-4 With the acceptance of breast-conservation therapy for invasive breast cancer, 5-7 an increased number of cases of DCIS have been treated with breast conservation with or without radiation therapy. Breast conservation, for most patients, results in a better cosmetic result when compared with mastectomy, even when state-of-the-art skin-sparing mastectomy and autologous tissue reconstruction are used. But to achieve the generally superior cosmetic result of breast preservation, patients must be willing to accept a higher risk of local recurrence, with rates that range from 10% to 40%, depending on a variety of factors. 3, 4, 8-13 Local recurrence after conservative treatment for DCIS is demoralizing and, if invasive, as approximately one half of recurrences are,3,4,8-10,14,15 it is also a potential threat to life. Although no studies to date have shown a significant difference in breast cancer-specific survival for DCIS patients, regardless of treatment, most are flawed by lack of prospective treatment randomization and/or inadequate length of follow-up. For invasive cancer, numerous prospective randomized studies have concluded that there is no difference in survival whether a patient is treated with mastectomy or breast conservation. Furthermore, the National Surgical Adjuvant Breast Project has concluded that local invasive recurrence, increase with longer follow-up. The 8-year breast cancer-specific mortality and distant-disease probability for the subgroup of 74 patients with locally recurrent disease was 8.8% and 20.8%, respectively. If only the invasive recurrences are considered as events, the 8-year breast cancer-specific mortality and distantdisease probability was 14.4% and 27.1%, respectively. Conclusion: Invasive local recurrence after breastpreservation treatment for patients with DCIS is a serious event that converts patients with previous stage 0 disease to patients with disease that ranges from stage I to stage IV. These results, however, indicate that most DCIS patients with local recurrence can be salvaged. J Clin Oncol 16: o 1998 by American Society of Clinical Oncology. when it occurs in a patient previously treated for invasive breast cancer, is a marker of poor prognosis but not an instigator of distant disease.16 This concept, however, cannot be extended to patients with DCIS. An invasive recurrence in a patient previously treated for DCIS upstages that patient from stage 0 disease to at least stage I breast cancer. An invasive recurrence in a patient who previously had noninvasive disease has profound implications. This study will focus on the stage of presentation and outcome, measured by the probability of distant disease and breast cancer mortality, for patients with local invasive recurrence after initial treatment for DCIS. PATIENTS AND METHODS Seven hundred seven patients with DCIS were accrued from 1972 through June 1997 at two centers; The Breast Center, Van Nuys, CA (628 patients) and Childrens Hospital, San Francisco, CA (79 patients). From the Divisions of Surgical Oncology, Medical Oncology, Breast Imaging, and Radiation Oncology, The Breast Center, a Salick healthcare subsidiary, and the Western Tumor Medical Group, Van Nuys; and the Department of Pathology and Breast Consultation Service, St Marys Hospital, San Francisco, CA. Submitted October 2, 1997; accepted December 19, Presented at the 33rd Annual Meeting of The American Society of Clinical Oncology, Denver, CO, May 19, Address reprint requests to Melvin J. Silverstein, MD, The Breast Center, Sherman Way #600, Van Nuys, CA 91405; melsilver9@aol.com by American Society of Clinical Oncology X/98/ $3.00/0 Journal of Clinical Oncology, Vol 16, No 4 (April), 1998: pp

2 1368 The treatment selection process was not randomized, evolved over time, and has been described in numerous prior publications ,4,,', The median follow-up time for all patients was 69 months. The Childrens Hospital series was a pilot series designed to evaluate the feasibility of excision alone for a small group of DCIS patients that met a strict set of criteria, which included the following: the DCIS lesion was nonpalpable, detected mammographically, and 25 mm in maximum diameter or smaller; all margins were clear by 1 mm or more; and microcalcifications were not present on postoperative mammography. The Van Nuys series did not have a rigid set of treatment criteria and patient preference played an important role in the treatment selection process. In general, patients with lesions 40 mm or smaller and with all margins clear by at least 1 mm were advised to undergo breast preservation. Patients with lesions larger that 40 mm or with persistently positive surgical margins after re-excision were generally advised to accept mastectomy, usually with immediate reconstruction. These guidelines were not absolute, and some patients, who could have been treated with breast preservation, elected mastectomy and vice versa. Radiation therapy was routinely added to most breast-preservation patients' treatment regimen until 1989; thereafter, most breastpreservation patients were treated with excision alone. Whole-breast external-beam irradiation (40 to 50 Gy) was performed on a 4 or 6 MV linear accelerator with a boost of 10 to 20 Gy to the tumor bed by iridium-192 implant or external beam. Eighty-nine of 208 patients treated with radiation therapy received a boost by interstitial iridium- 192, 95 patients were boosted with photons or electrons, the nature of the boost is unknown in 15 patients, and nine patients received no boost. Disease-free survival and breast cancer-specific survival probabilities were determined by the Kaplan-Meier method and all results are estimates at 8 years. RESULTS There were 74 local recurrences; 39 were noninvasive (DCIS) and were invasive. Table 1 lists the number of patients, the type and rate of local and distant recurrence, the SILVERSTEIN ET AL size of the original lesion, the size of the recurrence, follow-up time, and mortality, by initial treatment method and by treatment groups. In addition, Table 1 lists these parameters by analysis of all patients with local recurrences and invasive local recurrences as separate subgroups. For the entire group of 707 patients, at 8 years the local-recurrence probability (both invasive and noninvasive) was 12.5%, the local-invasive-recurrence probability was 6.5%, the breast cancer-specific mortality was 1.4%, and the overall mortality rate (death from any cause) was 7.6%. For 259 patients treated with mastectomy, the 8-year probability of a local invasive recurrence was 0.5% and the probability of a breast cancer-specific mortality was zero. For 448 patients treated with breast conservation (240 excision-only patients and 208 excision-plus-radiationtherapy patients), the 8-year probability of a local invasive recurrence was 9.3% and the probability of a breast cancerspecific mortality was 2.1%. The local-invasive-recurrence probability was higher for patients treated with excision only than for patients treated with excision plus radiation therapy (11.5% v 8.8%; P = NS). However, the distant-disease probability was higher for patients treated with excision plus radiation therapy than for patients treated with excision only (3.4% v 1.0%; P = NS). In addition, the breast cancer-specific mortality was higher for patients treated with excision plus radiation therapy than for patients treated with excision only (3.0% v 0.9%; P = NS) (Table 1). For the 74 patients who recurred locally, the probability of developing distant disease was 20.8% and breast cancer- Table 1. Patient Data by Specific Treatment, Treatment Groups, and Recurrences No. of patients Total recurrences Noninvasive (DCIS) recurrences Invasive recurrences Local only Local + distant Breast cancer specific deaths Average size original DCIS, mm Median size original DCIS, mm Average size of recurrence, mm Median size of recurrence, mm Average follow-up, months Median follow-up, months Local recurrence probability, invasive + All Patients Mastectomy All BCT Excision + Radiation Excision Only All Recurrences Toofew Too few DCIS,% Local invasive recurrence probability, % Distant recurrence probability, % Breast cancer-specific mortality probabiility, % Overall-mortality probability, % NOTE. All probabilities are Kaplan-Meier estimates at 8 years. NOTE. All probabilities are Kaplan-Meier Abbreviation: BCT, breast conservation therapy. estimates at 8 years. Abbreviation: BCT, breast conservation therapy Invasive Recurrences

3 RECURRENCE IN PATIENTS WITH DCIS 1369 No. of Patients Table 2. Median Time to Recurrence, Median Size, and Percent Palpable for All Recurrences By Treatment and Type of Recurrence Excision Only Radiation Median time to recur, months Invasive DCIS Median size of recurrence, mm Invasive DCIS Percent palpable Invasive 25 DCIS 6 12 Fig 1. The number of recurrences (both invasive and noninvasive) by treatment (excision only v excision plus radiation therapy) are plotted over time. The median time to local recurrence after excision only was 23 months; after excision and radiation therapy, it was 56 months. specific mortality was 8.8%. Because no patient with a noninvasive recurrence (DCIS) developed distant disease or died from breast cancer, it may be more appropriate to consider only the invasive recurrences as events. When this is done, the 8-year probability of developing distant disease for a patient with a local invasive recurrence was 27.1% and breast cancer-specific mortality was 14.4%. Figure 1 shows the time from original diagnosis to all local recurrences (both invasive and noninvasive) by treatment (excision only v excision plus radiation therapy). The median time to local recurrence after excision only was 23 months; after excision plus radiation therapy, it was 56 months. Figure 2 shows the time from original diagnosis to local recurrence by the type of recurrence (invasive v noninvasive [DCIS]). The median time to a noninvasive local recurrence was 22 months; for an invasive local recurrence, it was 58 months. Table 2 lists the median time to recurrence, the median size and the percent of lesions that were palpable for all recurrences by both treatments (radiation therapy v excision only) and type of recurrence (invasive v noninvasive [DCIS]). No. of Patients 34 30:: i,,, Noninvasive Recurrences Invasive Recurrences 0 S Fig 2. The number of recurrences by type (invasive v noninvasive) are plotted over time. The median time to a noninvasive recurrence was 22 months; median time to an invasive recurrence was 58 months. Invasive recurrences in irradiated patients tended to be larger and were more likely to be palpable than recurrences in any other subgroup. In addition, they had the longest median time from initial treatment until diagnosis of recurrence. Twelve of 18 irradiated patients with invasive recurrences treated during the 1980s received a 2,000-cGy boost to the tumor bed using a minimum two-plane interstitial iridium- 192 implant. Of the five irradiated patients who developed distant disease, four were boosted in this manner. None of 39 patients with noninvasive recurrences developed metastatic disease nor died from breast cancer. Of the patients who had invasive recurrences, seven patients developed metastatic disease: one patient originally treated by mastectomy, one patient originally treated by excision only, and five patients originally treated with excision plus radiation therapy. Five of seven patients with metastatic disease died from breast cancer: one patient originally treated by excision only and four patients originally treated with excision plus radiation therapy. Figure 3 shows the stage of disease at the time of diagnosis of recurrence for all patients who developed invasive recurrences. Slightly more than half (18 of patients; 51%) were diagnosed with stage I disease; the remainder had more advanced disease at the time of diagnosis. Four patients presented with stage IIA disease, No. of Patients 51% o- 11% 23% 11% IIA IIB IIIB IV Stage at Time of Local Invasive Recurrence Fig 3. The number of patients with each stage of disease at the time of diagnosis of invasive recurrence.

4 1370 eight with stage IIB, four with stage IIIB, and one with stage IV disease. No patient presented with stage IIIA disease. When stage was evaluated by whether radiation therapy was given, 60% (nine of 15) of excision-only patients presented with stage I disease at the time of recurrence, whereas 44% (eight of 18) of previously irradiated patients presented with stage I disease (P = NS). The median follow-up for the patients with invasive recurrences from the time of the initial DCIS diagnosis was 127 months (58 months from initial diagnosis to invasive recurrence and 69 additional follow-up months after recurrence). The breast cancer-specific mortality rate for the subgroup of DCIS patients with invasive recurrences was 14.4% at 8 years (Fig 4); the distant recurrence rate for this subgroup was 27.1% (Fig 5). DISCUSSION Invasive local recurrence after breast-preservation treatment for patients with DCIS is a serious event that converts patients with previous stage 0 disease to patients with disease that ranges from stage I to stage IV. The results of staging, however, may be somewhat misleading. Many patients in this series were treated in the 1980s when it was common to perform a standard axillary lymph node dissection for patients with DCIS. The axillary nodes, therefore, had already been removed in most patients and were not available for staging purposes at the time of local invasive recurrence. There were only five of patients with invasive recurrences in this series in whom axillary nodes were available at the time of local invasive recurrence; in four (80%) of those, one or more nodes contained metastatic cancer. The staging for the remaining 30 patients was based on recurrence size, skin involvement, and metastatic work-up without benefit of current axillary node status. It is probable that some of those 30 patients would have had positive nodes if axillary nodes had been available for evaluation. This would be particularly important for the 18 patients evaluated % Fig 4. Breast cancer-specific survival is shown from the time of initial DCIS diagnosis for patients with invasive recurrences A SILVERSTEIN ET AL Fig 5. Distant disease-free survival is shown from the time of initial DCIS diagnosis for patients with invasive recurrences. as stage I at the time of invasive recurrence. In all likelihood, this group of 30 patients is probably understaged because of the lack of axillary nodal data at the time of local invasive recurrence. In our experience, the diagnosis of recurrent breast cancer after conservative treatment for DCIS has been more difficult after radiation therapy than in patients treated with excision alone, particularly in those patients who received an interstitial boost to the tumor bed. Radiation therapy causes some degree (from very mild to severe) of radiation fibrosis and scarring that may obscure the earliest signs of local recurrence in some patients. In this series, recurrences in the irradiated breast were larger (Tables 1 and 2), more commonly palpable, slightly higher stage, and their diagnosis possibly delayed (longer median time from initial treatment until diagnosis of recurrence) (Fig 1). The inability to detect the earliest possible signs of recurrence in irradiated patients may be due to the radiation techniques of the 1980s, which often included higher daily doses than currently used today and, more importantly, interstitial boosts. In the results section, we noted that 12 of 18 irradiated patients with invasive recurrences were boosted with a 2,000-cGy iridium-192 interstitial implant to the tumor bed. Most of these patients (84%) received 200 cgy per day, 4 days per week (rather than 5 days), to a total-dose of 5,000 cgy. We raised this issue to emphasize that this treatment technique, which was sometimes used in the 1980s, often yielded more internal fibrosis and external skin changes than current radiation therapy techniques (for example, 180 cgy per day, 5 days per week, to a total of 4,500 to 5,000 cgy followed by a 1,000- to 1, cGy electron or photon boost). When local recurrence-free survival is analyzed by whether patients are treated 4 or 5 days per week, there is no difference in outcome. 19 In other words, both treatment methods are equally effective at reducing cancer recurrences. Our concern is not the number of days per week of treatment, but rather that patients who received a boost by

5 RECURRENCE IN PATIENTS WITH DCIS interstitial implant are more likely to develop radiation fibrosis and should they develop a local recurrence, its diagnosis could be delayed. Of 89 patients in this series who were treated with interstitial implants (median follow-up, 122 months), four patients developed metastatic disease, three of whom presented with inflammatory (dermal lymphatic carcinomatosis)-type recurrences. Only one of 104 patients who received photon or electron boosts or no boost at all developed metastatic disease (median follow-up, 61 months). This difference may be explained by the longer median follow-up of radiation-therapy patients treated with interstitial implants. Current radiation methods yield a better cosmetic result (externally), less internal scarring (fibrosis), and, therefore, a patient who is easier to follow up clinically and mammographically, which makes an earlier diagnosis of recurrence more likely. In support of this, it should be noted that, in this series, the median time from initial treatment until diagnosis of local recurrence was 62 months for 18 irradiated patients treated with an interstitial implant and 32 months for the remaining 18 irradiated patients who did not receive interstitial implants. At The Breast Center, it is our policy to perform ipsilateral mammography and physical examination every 6 months on conservatively treated DCIS patients (both irradiated and nonirradiated) with yearly mammography of the contralateral breast. At Childrens Hospital, bilateral mammography was performed yearly along with physical examination every 3 to 6 months. The mobile population of California and changes in the health care delivery system have occasionally made follow-up difficult. Two of our patients who presented at the time of local recurrence with stage IIIB disease were followed up for more than 5 years at other facilities with a diagnosis of progressive radiation fibrosis; however, they both received yearly mammography. The progressive changes suggestive of recurrent breast cancer were simply not appreciated. Invasive recurrences were not a consequence of poor follow-up. Overall, follow-up was good. Of the patients with invasive recurrences, 12 had mammography, interpreted as within normal limits, 6 months or less before their recurrences; 11 had normal mammography 7 to 12 months before recurrence; and in only three patients was mammography performed from 24 to 48 months before recurrence. In nine patients, none of whom developed metastatic disease, the date of the most recent mammogram before recurrence was unknown. For the seven patients who developed distant disease, a delay in mammography did not contribute to metastases; mammography, interpreted as within normal limits, was performed within 12 months before recurrence in six (86%) 1371 patients. The recurrences in this subgroup, however, were more advanced with six of seven patients presenting with stage IIB or more disease. We would caution all physicians who follow up conservatively treated DCIS patients to carefully evaluate any patient who presents with increasing radiation fibrosis more than 2 to 3 years after initial treatment. This may represent the development of an invasive recurrence and biopsy may be indicated. Recurrent breast cancer after conservative treatment for DCIS may present mammographically as microcalcifications, a mass, or both. 20 In some patients, there may be a palpable mass with false-negative mammography. An occasional patient with recurrent breast cancer may present with progressive breast shrinkage. 20 Any suspicious or progressive change must be biopsied. We would suggest that surgeons who perform conservative procedures for patients with DCIS mark the biopsy cavity with metallic clips. This will focus the radiologist's attention on the exact area of the original DCIS and make long-term mammographic follow-up easier. The absence of radiation fibrosis permits better mammographic follow-up of the excision-only patients and is one explanation why the median time to local recurrence for excision-only patients is 23 months compared with 56 months for a patient treated with excision plus radiation therapy. Another explanation is that radiation therapy delays local recurrence. Both explanations are likely to play a role here. The probability of local recurrence and local invasive recurrence is higher for excision-only patients when compared with excision-plus-radiation-therapy patients (Table 1). Paradoxically, the probability of distant disease and breast cancer-specific mortality is higher for excision-plusradiation-therapy patients than for patients treated with excision alone. The differences in distant-disease probability and breast cancer-specific mortality in favor of excisiononly patients when compared with excision-plus-radiationtherapy patients, although statistically insignificant, require discussion. The radiation therapy patients in this series had larger initial lesions (15 mm v 9 mm) and have been followed up for a longer median period of time (91 v 55 months) and hence, a higher recurrence rate might be expected. On the other hand, this is balanced, to some extent, by the fact that the median time to recurrence after excision only is 23 months compared with 56 months for patients treated with excision plus radiation therapy (Fig 2). As follow-up of the excision-only patients lengthens, there may be a small increase in the distant disease rate and breast cancer-specific mortality. Although radiation therapy decreases the local recurrence rate for both invasive and noninvasive disease, if patients do recur with invasive breast cancer, the recurrence may carry a worse prognosis because

6 1372 of a delay in the diagnosis and/or because a DCIS that survives radiation therapy and becomes an invasive cancer may be biologically more aggressive. If the breast conservation patients were evenly matched by tumor size, margin width, and nuclear grade, and prospectively randomized, then excision-only patients would be expected to experience a significantly higher rate of local failure than excision-plus-radiation-therapy patients." 3,21 The more advanced stage noted in the radiation-therapy patients at the time of local recurrence, however, is troubling. Ten of 18 (56%) radiation-therapy patients presented with stage IIA or more disease at the time of recurrence, whereas only six of 15 (40%) excision-only patients presented with stage IIA or more recurrences (P = NS). Overall, after 67 months of median follow-up, the probability of breast cancer mortality for 259 patients with DCIS in this series treated with mastectomy was zero. With longer follow-up, the mortality rate is not likely to rise beyond 1%. This confirms other long-term studies that report an extremely low mortality rate after mastectomy for DCIS. " However, this figure is low because it excludes those patients with a biopsy diagnosis of DCIS, subsequently treated with mastectomy, in whom an invasive focus was found at the time of mastectomy. Patients such as this were then reclassified as having invasive carcinoma and were no longer included in this DCIS series. Patients treated with breast preservation do not benefit from this exclusion (unless invasion is found at re-excision and then, of course, they too are excluded). Therefore, some breast-preservation patients, albeit a very small percentage, likely harbor occult undocumented foci of invasion. The 8-year breast cancer-mortality probability for all 448 patients treated conservatively was 2.1%. With increased follow-up, we expect this rate to rise slightly. The 8-year breast cancer-mortality probability for the subgroup of 208 patients treated with excision plus radiation therapy was 3%, a result similar to the one reported by Solin et al.' 5 This multi-institutional group reported a 15-year actuarial mortality rate of 4% for 268 women with DCIS treated with excision and radiation therapy, with a median follow-up of SILVERSTEIN ET AL 10.3 years. There is no doubt that radiation therapy decreases the local recurrence rate; 13,21 but when patients recur in spite of radiation therapy, it is possible that their recurrences will be more difficult to diagnose and therefore larger in size. Because of this, they may be more difficult to manage and prognosis may suffer. Breast preservation for patients with DCIS is not without a theoretical mortality risk. Mastectomy eliminates almost all of the breast tissue and almost all chance of recurrence, but for many patients, it is overtreatment. Breast preservation preserves significant residual tissue, all of it at risk for local recurrence. Patients committed to breast preservation must also be committed to careful, close clinical follow-up and, in our opinion, should be examined physically and mammographically twice a year for at least 10 years. The results of this study indicate that most patients with local recurrence can be salvaged. Overall, the 8-year probability for breast cancer-specific mortality for all 74 patients who recurred locally (both invasive and noninvasive) was 8.8%, an outcome similar to patients with Tla or Tlb breast carcinoma. 22, 23 For the small subgroup of patients who recurred with invasive breast cancer, there was a 14.4% risk of death from metastatic disease within 8 years of initial treatment, a mortality rate similar to a patient with stage IIA breast cancer. 22, 23 In summary, DCIS is an extremely favorable disease. Although our data suggest a slight (but statistically insignificant) survival advantage for mastectomy when compared with breast conservation (100% v 97.9%) (Table 1), we continue to be strong proponents of breast-conservation therapy for DCIS. Regardless of treatment choice, the overall mortality rates are low. Mortality rates are likely to be a few percentage points higher for breast preservation than for mastectomy, but cosmetic results will be superior. Patients who develop significant or progressive radiation fibrosis after radiation therapy should be followed up extremely closely because local recurrence may be obscured. Patients should be informed of these data and allowed to participate in the treatment selection process. 1. Sunshine JA, Moseley HS, Fletcher WS, et al: Breast carcinoma in situ. A retrospective review of 112 cases with a minimum 10 year follow-up. 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7 RECURRENCE IN PATIENTS WITH DCIS 7. Fisher B, Anderson S, Redmond C, et al: Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 333: , Silverstein MJ, Lagios MD, Craig PH, et al: A prognostic index for ductal carcinoma in situ of the breast. Cancer 77: , Lagios NM, Margolin FR, Westdahl PR, et al: Mammographically detected duct carcinoma in situ. Frequency of local recurrence following tylectomy and prognostic effect of nuclear grade on local recurrence. Cancer 63: , Solin LJ, Yet I-T, Kurtz J, et al: Ductal carcinoma in situ (intraductal carcinoma) of the breast treated with breast-conserving surgery and definitive irradiation. Correlation of pathologic parameters with outcome of treatment. Cancer 71: , Bellamy COC, McDonald C, Salter DM, et al: Noninvasive ductal carcinoma of the breast. The relevance of histologic categorization. Hum Pathol 24:16-23, Fisher ER, Constantino J, Fisher B, et al: Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) Protocol B-17. Cancer 75: , Fisher B, Digman J, Wolmark N, et al: Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: Findings from the National Surgical Adjuvant Breast and Bowel Project B-17. J Clin Oncol 16: , Solin LJ, Fourquet A, McCormick B, et al: Salvage treatment for local recurrence following breast-conserving surgery and definitive irradiation for ductal carcinoma in situ (intraductal carcinoma) of the breast. Int J Radiat Oncol Biol Phys 30:3-9, Solin LJ, Kurtz J, Fourquet A, et al: Fifteen-year results of 1373 breast-conserving surgery and definitive breast irradiation for the treatment of ductal carcinoma in situ of the breast. J Clin Oncol 14: , Fisher B, Anderson S, Fisher E, et al: Significance of ipsilateral breast tumour recurrence after lumpectomy. Lancet 338: , Lagios MD, Westdahl PR, Margolin FR, et al: Duct carcinoma in situ: Relationship of extent of noninvasive disease to the frequency of occult invasion, multicentricity, lymph node metastases, and short-term treatment failures. Cancer 50: , Lagios MD: Ductal carcinoma in situ: Controversies in diagnosis, biology, and treatment. Breast Journal 1:68-78, Beron P, Lewinsky BS, Silverstein MJ: Van Nuys experience with excision plus radiation therapy, in Silverstein MJ (ed): Ductal Carcinoma In Situ of the Breast. Williams & Wilkins, Baltimore, MD, 1997, pp Gamagami P: Follow-up mammography after treatment of breast cancer, in Gamagami P (ed): Atlas of Mammography: New Early Signs in Breast Cancer. Blackwell Science, Cambridge, MA, Fisher B, Costantino J, Redmond C, et al: Lumpectomy compared with lumpectomy and radiation therapy for the treatment of intraductal breast cancer. N Engl J Med 328: , Rosen PP, Groshen S, Saigo PE, et al: A long-term follow-up study of survival in stage I (T1NOMO) and stage II (TlN1MO) breast carcinoma. J Clin Oncol 7:5-366, Rosen PP, Groshen S, Kinne DW, et al: Factors influencing prognosis in node-negative breast carcinoma: Analysis of 767 T1NOMO/ T2NOMO patients with long-term follow-up. J Clin Oncol 11: , 1993