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An analysis of 259 women with 261 treated breasts from nine institutions in Europe and the United States was performed to determine the 10-year results of the treatment of intraductal carcinoma of the breast with definitive irradiation. All patients had undergone complete gross excision of the primary intraductal carcinoma, and definitive breast irradiation was delivered in all cases. The median follow-up time was 78 months (range, 11 to 197 months). The 10-year actuarial overall survival rate was 94%, and the 10-year actuarial cause-specific survival rate (including deaths only from carcinoma of the breast) was 97%. The 10-year actuarial rate of freedom from distant metastases was 96%. There were 28 failures in the breast, and the 10-year actuarial rate of local failure was 16%. The pathologic type of local recurrences showed invasive ductal carcinoma in 14 of 28 recurrences (50%) and noninvasive ductal carcinoma in 14 of 28 recurrences (50%). The median time to local failure was 50 months (range, 17 to 129 months). Twenty-four of 28 patients with local failure were salvaged with additional treatment, generally mastectomy, and 4 of 28 patients with local failure subsequently had distant metastases. Median follow-up time after salvage treatment of breast recurrence was 29 months (range, 3 to 90 months). Two patients without local failure subsequently had distant metastases, one of which occurred after a node-positive, contralateral breast carcinoma. These results demonstrate high rates of overall survival, cause-specific survival, and freedom from distant metastases for the treatment of patients with intraductal carcinoma of the breast. The local recurrences within the treated breast were generally salvaged with additional treatment, although with limited follow-up. Because of the long natural history of intraductal carcinoma of the breast, prolonged and careful follow-up of patients after breast-conservation and definitive irradiation is required. Cancer 68:2337–2344, 1991.

The influence of radiotherapy dose parameters on longterm local control was studied in 134 clinical stage I-II breast cancer patients treated by tumorectomy and telecesium therapy during the 1960s. Recurrence in the breast was more frequent in patients receiving 75 Gy or less to the tumor bed (31% versus 15% for higher doses, p less than 0.05), and weekly dose rates of less than 8 Gy/week were associated with increased local-regional failure (30% versus 15% for higher weekly doses, p less than 0.01). The majority of local-regional failures were observed in the 53 patients having "inadequate" total or weekly radiotherapy doses (18/53, 34% versus 9/81, 11%, p less than 0.001). The importance of adequate radiotherapy applied to both older patients, as well as those younger than 40, who appear inherently to have a higher risk of local relapse. The mean interval to recurrence was markedly longer for inadequate radiotherapy (111 months, versus 75 months for adequate treatment), so that significant differences in local control became apparent only after 5 years. These results underscore the importance of radiotherapy technique in breast-conserving treatment, and suggest that an excessive reduction in the intensity of radiotherapy may result in an inordinate number of late local failures.

The feasibility of conservative salvage surgery was addressed in a clinicopathologic study of the results of wide excision for 50 selected parenchymal intramammary recurrences after standard breast conserving treatment. After median follow-up of 51 months, 16 (32%) second local failures were observed (5-year local control 62%). Cox multivariate analysis of 18 parameters indicated that only disease-free interval and resection margins significantly influenced local control. 5-year local control was 92% for recurrences occurring after 5 years vs. 49% for shorter intervals, and 73% for negative vs. 36% for positive or indeterminate margins. Local control appeared independent of morphologic features, initial tumour stage, patient age, recurrent tumour size and location. Median survival after second local failure was 33 months; tertiary therapy obtained ultimate local-regional control in 8 of 16 cases. The authors conclude that wide excision is a particularly satisfactory alternative to salvage mastectomy for late recurrences. Negative margins are essential. Further study will be required to establish additional guidelines allowing improved patient selection.

The influence of extensive intraductal component (EIC) on local recurrence risk was studied for 496 patients with stage I-II infiltrating ductal cancers treated by conservative surgery and irradiation. EIC was diagnosed in 65 of 231 (28%) premenopausal and 41 of 265 (15.5%) post-menopausal patients. Local recurrence risk was markedly increased in EIC+ patients (5-year actuarial risk 18% versus 8% without EIC, P less than 0.001), but this effect appeared limited to premenopausal patients. Local recurrence risk increased with increasing degree of EIC. EIC with more than 50% intraductal carcinoma was more prevalent in patients younger than 40, perhaps accounting to some degree for the higher local recurrence rates observed in younger patients. The presence of EIC had no influence on overall survival, on median time to local recurrence, or on short-term survival after local failure. The usefulness of EIC as a risk factor for local recurrence is discussed.

Our present state of knowledge concerning intramammary recurrence, the only site of failure unique to breast-conserving treatment, necessarily depends upon reports from centers having extensive experience with this form of therapy. One such paper appears in the current issue (3). Based on 1,030 patients with Stage I-II breast cancer treated between 1978 and 1986, Fowble et al. analyze the anatomic distribution of 66 subsequent breast recurrences, present pathologic findings at time of salvage mastectomy, and investigate possible factors affecting prognosis after treatment of local failure. In addition to providing new and original data, this paper concludes with an extensive, meticulously documented and informative discussion. The only significant aspect left untreated concerns factors associated with the development of local failure, an important topic that will not be considered further here. Rather than dwell in any detail on the many interesting points raised by Fowble et al., it may be useful to list in a simplified fashion what is currently known about local failure in the retained breast, and then to consider more carefully the question of salvage surgery: a) Most recurrences are detected by clinical examination, but mammography is useful in many and indispensible in a minority of (apparently favorable) cases. b) Most recurrences arise in the vicinity of the tumor bed, but with the passage of time proportionately more recurrences are located elsewhere in the breast. c) Theoretically, tumor formation in the treated breast (“recurrences” or “new tumors”) can continue indefinitely; although the frequency and clinical significance of such late events are not yet well established, existing data suggest that long-term treatment results are affected little thereby. d) Unlike failure on the chest wall after mastectomy, breast recurrences are seldom (about 10%) associated with clinically apparent distant metastases and are seldom (again about 10%) anatomically inoperable. e) The prognosis of operable recurrence in the breast is clearly more favorable than that of recurrence in the skin flaps after mastectomy, with 5-year survival rates in the former cases averaging about 70%. f) Prognosis after local failure is determined both by the anatomical extent of the recurrence as well as by the biological aggressiveness of the disease; which specific parameters are most useful for assessing either the former (e.g., size and/or multifocality of recurrent tumor, involvement of skin, chest wall, or axilla) or the latter (e.g., disease-free interval, histologic grade or other morphologic features, receptor status, initial tumor stage, cytometric analysis) remains to be determined. References substantiating these statements have been amply cited by Fowble et al. It remains unclear to what degree overall survival after local recurrence is influenced by the type of salvage surgery used. Data cited by Fowble et al., including ours as well as their own, indicate that total mastectomy, with or without axillary dissection as needed, provides very satisfactory local-regional control (about 90% at 5 years). The use of wide excision for small, well-circumscribed, favorable recurrences has been reported by us (6), and is apparently used elsewhere ( 1,2), although other published

Of 586 unilateral stage I-II breast cancers treated with conservative surgery and radiotherapy, 61 patients were found to have two or more macroscopic tumor nodules, diagnosed either clinically (n = 20), mammographically (n = 2), or on gross pathologic examination (n = 39). After a median follow-up of 71 months, 15 of 61 (25%) of the patients with multiple tumors developed recurrence in the treated breast, compared to 56 of 525 (11%) of patients with single cancers (p less than 0.005). Local failure occurred in 6 of 37 (16%) of bifocal tumors and in 9 of 24 (35%) of patients with 3 or more tumor foci. Recurrence was more frequent for multiplicity diagnosed clinically or mammographically (8 of 22 patients, 36%) than when it was apparent only to the pathologist (7 of 39 patients, 18%). Only 1 of 21 bifocal tumors diagnosed on gross examination recurred. Local failure occurred in only 1 of 22 cases with clearly negative resection margins; the remaining recurrences were associated with positive (n = 3) or indeterminate margins (n = 11). In contrast with recurrences of unifocal breast cancers, local failures in these patients tended to be located at a distance from the original foci, to be multifocal, or to be diffuse, including skin involvement. Only four recurrences presented as a single focus in the vicinity of the original primary tumors. This study indicates that macroscopically multiple breast cancers are at higher local failure risk, especially if multiplicity is clinically apparent, or if three or more gross nodules are seen on pathologic examination. Negative resection margins appear to be essential for satisfactory results.

Risk factors for local failure were evaluated for 496 clinical Stage I-II patients with infiltrating ductal carcinomas (median follow-up, 71 months) treated by conservative surgery and radiotherapy. Monofactorial analysis identified the following factors to be correlated with increased risk: moderate/marked mononuclear cell reaction (MCR), high histologic grade (G), extensive intraductal component (EIC), tumor necrosis, macroscopic multiplicity, estrogen receptor negativity, anatomic tumor size, age younger than 40 years, and vascular invasion. Only MCR, G, and EIC proved significant in Cox multivariate analysis. These risk factors were highly age dependent, with EIC markedly more prevalent in women younger than 50, MCR and G in women younger than 40. Separate Cox analysis for premenopausal patients showed that MCR/EIC determined risk independent of resection margins: tumors with MCR had a 28%, and with EIC a 22% probability of recurring locally by 5 years. Premenopausal patients with neither risk factor had a very low failure rate (2.6% at 5 years), regardless of age. For postmenopausal patients risk of breast recurrence was determined both by adequacy of resection margins and grade, with a high local failure rate for patients having G3 tumors with positive or indeterminate margins (31% at 5 years). The authors conclude that the microscopic examination is the only useful tool for assessing the risk of local failure, which is quite low for the majority of patients treated with breast conservation. High-risk patients can be recognized morphologically. The age dependence of morphologic risk factors appears to explain the high local failure rate seen in patients younger than 40.

The influence of patient age on risk of recurrence in the breast was retrospectively studied in 496 stage I-II invasive ductal carcinomas treated by macroscopically complete primary tumor excision followed by radiotherapy. With a median follow-up of 71 months, local recurrence occurred in 13 of 62 (21%) patients younger than 40 years, compared with 48 of 434 (11%) older patients (P less than .025). Cox multivariate analysis of 18 parameters identified four that significantly determined risk: major lymphocytic stromal reaction (MCR), unsatisfactory resection margins, increasing histologic grade, and extensive intraductal cancer (DCIS) within the primary tumor. Compared with older patients, those younger than 40 years had tumors that more often exhibited MCR (36% v 20%, P less than .01), histologic grade 3 (42% v 28%, P less than .025), and very extensive DCIS (21% v 6%, P less than .001). The status of resection margins did not differ significantly between younger and older patients. Restriction of Cox analysis to patients younger than 40 indicated that risk was adequately described by MCR and percentage of DCIS, without consideration of grade or margins. For patients younger than 40, local failure occurred in four of five (80%) tumors with both MCR and more than 50% DCIS, in eight of 25 (32%) with either, and one of 32 (3.1%) with neither of these morphologic features. This study suggests that the higher local failure risk observed in patients younger than 40 years reflects the greater prevalence of certain morphologic characteristics in breast cancers in younger patients. Age itself does not appear to be an independent determinate of risk.

Of 178 local recurrences occurring in 1593 patients with clinical Stages I-II breast cancer treated by conservative surgery and megavoltage radiotherapy, 71 were diagnosed after the 5th year. Compared with recurrences occurring prior to 60 months, late recurrences were less frequently inoperable (1/71, 1.4%, versus 18/107, 17%, p less than 0.001), were more often located at a distance from the initial primary tumor (23/71, 32%, versus 15/106, 14%, p less than 0.005), and had a more favorable prognosis (5-year survival 84% versus 61% for late and early operable recurrences, respectively, p = 0.05). Five-year metastasis-free survival after late failure depended mainly on the anatomic extent of the recurrence (87% for recurrences apparently confined to the breast versus 34% for relapses involving the axilla, p less than 0.002). Prognosis of late recurrence appeared to be unaffected both by location of the recurrence within the breast and by the type of salvage operation used (mastectomy versus wide excision). Local-regional control after salvage surgery was satisfactory (89% at 5 years). Whereas recurrence in the breast prior to 5 years profoundly affected survival after initial diagnosis, patients with late failure had identical 15-year survival as other 5-year survivors who never failed locally. Late recurrences were more frequent in patients younger than 40 at initial treatment, and in patients who had inadequate radiotherapy. We conclude that late local recurrences after breast conservation do not represent a serious management problem.

A retrospective analysis was performed of 118 surgically treated mammary recurrences, occurring following primary conservative excision and radiation therapy for clinical Stages I and II breast cancer. Actuarial cancer-specific survival following salvage surgery was 72% at 5 years and 58% at 10 years. With a median followup of 7 years, further local-regional recurrences were observed in 20 of the 118 patients, many of whom could be treated by further surgery. Actuarial survival after recurrence was significantly influenced by initial clinical stage, as well as by the disease-free interval following primary therapy, but was similar for both premenopausal and postmenopausal patients and for patients treated by radical or breast-conserving salvage operations. For recurrences after the fifth year, actuarial survival following salvage surgery was 83% and 68% at 5 and 10 years, respectively. Survival for Stage I patients was favorable regardless of disease-free interval. It is concluded that recurrences in the breast following primary treatment with limited surgery and irradiation have a considerably more favorable prognosis than that of local failures after primary radical surgery. Suggestions for the management of these recurrences are presented.

Since 1960 more than 3000 consecutive patients with operable infiltrating breast carcinoma were treated by radiation therapy with or without primary limited surgery, which usually consisted of local excision. For tumors smaller than or equal to 5 cm the ten-year crude survival rate is 77% for patients without palpable axillary nodes (T/sub 1-2/N/sub 0/) and 63% for patients having axillary adenopathy (T/sub 1-2/N/sub 1/). For operable tumors exceeding 5 cm in diameter (T/sub 3/N/sub 0-1/) the ten-year crude survival is 34%. Thirty-five percent of the patients alive free of disease at ten years required a secondary operation for presumed local or regional tumor persistence or recurrence, although no residual disease was found in 24% of the operative specimens. Local-regional recurrence had no adverse effect on ten-year survival. This conservative approach offers most women with operable breast cancer an excellent chance at breast preservation with the same chance for ten-year survival as with radical mastectomy.

Pathologic review of 861 Stage I and II breast cancers yielded 152 patients (18%) with histologic types other than invasive ductal carcinoma. All patients had been treated by breast-conserving surgery and radiotherapy, including supplemental radiation to the tumor bed. For 67 patients with predominantly lobular carcinomas, the actuarial overall 5-year survival was 100% and 77% for node-negative and node-positive patients, respectively. The actuarial probability of recurrence in the treated breast (13.5% at 5 years) appeared to be somewhat greater than that observed after treatment of invasive ductal cancers (8.8% at 5 years, P = 0.11). Of 12 mammary recurrences in patients with lobular carcinoma, four occurred at a considerable distance from the original primary and seven were multifocal, involving more than one quadrant in five patients. Of 47 patients with strictly in situ carcinomas, one patient whose axillary nodal status had not been determined subsequently developed distant metastases. Three additional patients developed mammary recurrence, two at the primary tumor site and one in another quadrant. The actuarial 5-year mammary recurrence and overall survival rates were 4% and 98%, respectively. For 27 patients with true medullary cancers, overall survival at 5 years was 90%. One localized mammary recurrence was observed at the site of the original primary. Actuarial mammary recurrence rate was 4% at 5 years. No relapse was observed in ten patients with colloid and one patient with adenoid cystic carcinoma. The authors conclude that, in addition to its well-established efficacy in the treatment of infiltrating ductal carcinomas, the combination of tumor excision and radiotherapy appears to provide adequate local control for other histologic types as well. However, patients with lobular cancer appear to be at somewhat greater risk of mammary failure, and recurrences in such patients tend to be multifocal and multicentric.

Of 1,245 patients treated with breast-conserving surgery and radiotherapy for Stage I and II breast cancers, 118 required a secondary operation subsequently for apparently isolated recurrence in the treated breast. Fifty-two of these 118 patients were selected for salvage treatment with wide excision, with or without axillary dissection, instead of resorting to mastectomy. With a median follow-up of 6 years, the actuarial cancer-specific survival (Kaplan-Meier) after treatment of recurrence was 79% at 5 years and 64% at 10 years. The probability of local control in the treated breast was 79% at 5 years after conservative salvage surgery. Of 12 patients in whom second local or regional recurrences developed, ten could be treated by further surgery. We concluded from this experience that wedge excision represents an adequate alternative to mastectomy in the salvage treatment of isolated breast recurrences that are mobile, 2 cm or smaller in diameter, and without signs of rapid growth.

Metachronous contralateral breast cancers and other second malignancies were evaluated in 2,850 patients treated between 1960 and 1981 primarily with radiotherapy (RT) either alone or following breast-conserving surgery. One hundred eighty-four contralateral cancers were observed in 22,491 patient-years of observation (818 per 10 5 patient-years), with a cumulative probability of 4.5% at 5, 7.9% at 10, and 11% at 15 and 20 years. Compared to patients with unilateral tumors, those destined to develop contralateral cancers were younger (mean age 51.9 vs 56.6) and more often gave a family history of breast cancer. Contralateral breast cancers were more frequent for more extensive tumors (T3 10% vs T1-2 6%; with inflammatory signs 10.6% without 6%), and in patients with ipsilateral local recurrence (with 9.1%, without 5.6%). Patients with contralateral cancers had a significantly less favorable survival experience (15-year actuarial survival after primary therapy 42%) than patients without contralateral cancer (15-year survival 65.5%). In early stage patients treated with conservative surgery and RT, contralateral cancer was not propostically more favorable than ipsilateral breast recurrence. Among 72 other second malignancies (320 per 10 patient-years) were 2 soft tissue sarcomas in the irradiated area. This corresponds to an incidence of 21 cases per 10 5 patient-years for survivors beyond the fifth year. The possible influence of RT on contralateral cancers and other second malignancies is discussed.

For 276 patients with early breast cancer followed from 10–21 years after lumpectomy and radiotherapy, the recurrence rate in the treated breast was 15.6%, and 7.2% developed contralateral breast cancer. Only 63% of breast recurrences occurred within 5 years, and the remainder were "late failures," with 5 of the 43 recurrences observed after 10 years. The proportion of failures occurring late was greater for T 1 than for T 2 tumors (53% vs 25% ).Twenty-six percent of early recurrences were inoperable, and an adverse impact of early recurrence on 10-year survival was clearly demonstrable. Late recurrences were all operable and did not appear to be associated with decreased survival. Only 16 of the 36 patients (44%) with operable breast recurrence ever developed metastatic disease, and 5 year survival following salvage therapy was 62%. Although the treated breast remains at continuous cancer risk even beyond 5 years, the prognosis of late recurrence appears quite similar to that of contralateral breast cancer. We do not consider the phenomenon of late recurrence to lend support to a policy of primary mastectomy, just as the existence of contralateral breast cancer does not justify routine ‘prophylactic' contralateral mastectomy.

A retrospective cooperative study was undertaken to analyze the fate of 300 clinical Stage I and II breast cancer patients who were alive and apparently cured with both breasts preserved, 10 years following primary limited surgery with irradiation. All patients had been treated by tumor excision, with or without axillary dissection, followed by megavoltage radiation therapy. Follow-up ranged from 10.5 to 26 years, median 14.5 years. The overall actuarial survival (Kaplan-Meier) of the 300 “cured” patients was 86% at 15 years and 78% at 20 years, with 38.5% of deaths attributable to breast cancer. The actuarial probability of remaining free of metastatic disease was 91% at both 15 and 20 years, independent of age or clinical stage. Sixteen patients (5.3%) developed recurrent cancer in the treated breast beyond the tenth year, the actuarial probability of remaining free of breast recurrence being 94% and 90% at 15 and 20 years, respectively. Contralateral breast cancers developed during the second decade in 5 patients, with a cumulative risk of 6.5% at 20 years. Significant treatment-related problems appeared during the second decade in 5 patients, including one chest wall sarcoma; all of these patients had received at least 60 Gy to breast and regional nodal areas. A comparison of these results with those in the literature allowed the following conclusions to be drawn: (a) the risk of death, as well as breast cancer mortality during the second decade, are similar for both conservatively and radically treated patients with Stage I and II breast cancer, (b) The risk of contralateral breast cancer is not greater than that observed following primary radical surgery without radiation therapy; (c) Ipsilateral breast “recurrences” continue to occur at about 1% per year during the second decade. Such late recurrences are highly operable and have a favorable prognosis; (d) Late progression of treatment-related sequelae is uncommon. This analysis supports the continued use of breast-conserving surgery with radiation therapy in the treatment of Stage I and II breast cancer.

Mammary recurrences were studied in 1593 patients with Stage I and II breast cancer treated by macroscopically complete tumor excision followed by megavoltage radiotherapy, including a boost to the tumor bed (mean dose, 78 Gy). The actuarial freedom from mammary recurrence was 93% at 5, 86% at 10, 82% at 15, and 80% at 20 years. Seventy-nine percent of the recurrences were in the vicinity of the tumor bed, but with increasing time interval, an increasing percentage of recurrences was located elsewhere in the breast. A majority of recurrences after 10 years could be considered new tumors. Only ten of 181 patients with recurrence had prior or concomitant distant metastases, and 159 of 171 isolated mammary recurrences (93%) were operable. Uncorrected overall survival after operable recurrence was 69% at 5 and 57% at 10 years. Prognosis after late recurrence (after 5 years) was favorable (84% 5-year survival). Operable early recurrences retained a favorable prognosis if smaller than 2 cm and confined to the breast (74% 5-year survival). Disease-free interval and histologic grade also appeared to be important prognostic factors after early recurrence. Survival after recurrence did not depend upon the type of salvage operation. Locoregional control was 88% at 5 years after salvage mastectomy and 64% after breast-conserving salvage procedures. The role of adjuvant systemic therapy at time of local recurrence requires additional study. This experience illustrates the important differences between mammary failure and chest wall recurrence after mastectomy, in particular the protracted time course and more favorable prognosis associated with the former.

The crude mammary recurrence rate was studied in 5-year age intervals for 1,382 Stage I and II breast cancer patients treated by conservative surgery and radiation therapy and followed for a median of 11 years. Patients younger than 40 had a significantly higher local recurrence rate (41/210, 19%) than did older patients (106/1172, 9%). The majority of excess recurrences in the younger patients occurred early, with recurrence rates between 5 and 10 years being equal for the 2 age groups. A comparison of the clinical characteristics of the patient groups yielded no obvious explanation for the higher local recurrence rate in the younger patients, and 15-year cancer-specific survival was identical. Within the younger age group, recurrence rate was independent of clinical tumor size, and was unaffected by adjuvant treatment. Young patients with positive axillary nodes or negative hormone receptors appear to be at particularly high risk for mammary failure. Despite this apparent correlation with biologic aggressiveness, the 41 patients with mammary recurrence experienced long-term survival from time of primary treatment which was not significantly worse than that of patients not having had local recurrence. For 37 patients with operable mammary recurrence, the 10-year survival from time of salvage surgery was 64%.

The frequency, time course, and prognosis of local recurrence following primary radiation therapy in 152 patients with early breast cancer treated before 1967 were examined. Local recurrence occurred at a constant rate over the first 14 years after treatment. The crude 15-year local recurrence rate was 22%. Of the 30 patients who developed an isolated local recurrence and underwent definitive secondary surgery, the 10-year freedom from distant relapse rate was 50%. These results indicate that breast cancer patients treated by primary radiation therapy require long-term follow-up to detect curable local recurrences.

Since the combination of conservative surgery and radiation therapy is being implemented with increasing frequency both in Europe and in North America, it is of considerable interest that the problem of recurrent cancer in the treated breast be studied in depth. As breast recurrence following adequate treatment is an uncommon event and many years of follow-up must be accrued in order to evaluate subsequent prognosis, few treatment centers are in a position to carry out such an analysis. As the combination of primary limited surgery and megavoltage radiotherapy has been practiced at the Marseille Cancer Institute since the early 1960s (Spitalier et al. 1986), we have had the opportunity of treating many local recurrences and observing their subsequent course (Kurtz et al. 1988 a). The purpose of this paper is to analyze the development of breast recurrence as a function of time, as well as to study the prognosis following treatment of local failure.

In this chapter, we will deal with external irradiation used alone as primary treatment for breast cancer, without previous tumorectomy and without systematic postirradiation mastectomy; surgery is discussed only in connection with failure of radiotherapy and recurrences.