Inoperable recurrence after breast-conserving surgical treatment and radiotherapy.

Factors associated with inoperable local recurrence were investigated by a clinical and pathologic review of 596 patients with Stages I and II carcinoma of the breast treated by breast-conserving operations and megavoltage radiotherapy. After a median follow-up period of 71 months, 13 of 70 local recurrences observed were anatomically unsuitable for salvage surgical treatment, affecting 2.2 per cent of patients initially treated. In most, inoperable recurrences clinically resembled primary inflammatory carcinoma of the breast. All inoperable failures occurred in patients with invasive ductal carcinoma and were associated with the presence of unfavorable prognostic features (positive nodes, histologic grade 3, negative estrogen receptor, vascular invasion and lymphocytic stromal reaction). Despite doxorubicin-based chemotherapy, prognosis after inoperable recurrence was quite poor, although survival time in excess of two years was seen in receptor positive, lower grade recurrent tumors in which treatment included hormone therapy.

How important is adequate radiotherapy for the long-term results of breast-conserving treatment?

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.

[Reevaluation of indications for adjuvant hormone therapy in primary breast cancer with high metastatic risk]. / Réévaluation des indications d'une endocrino-hormonothérapie adjuvante dans les cancers primitifs du sein à haut risque métastatique.

This study concerns the correlation between ER and PR status, menopausal status and the effect of adjuvant hormonotherapy in high risk primary breast cancer patients. We have compared the results obtained in a randomized trial (Institut Paoli-Calmettes, Marseille) with those of a historic series (Centre René Huguenin, Saint-Cloud). The patients presented the same clinical and histological criteria and received identical therapeutic protocols (chemotherapy and/or hormonotherapy). Compared with patients receiving no adjuvant treatment, it appeared that: 1) in post-menopausal patients, a significant detrimental effect of tamoxifen was found in ER-negative patients, while in ER-positive patients hormonal treatment was well correlated with both the presence and level of steroid receptors; 2) in pre-menopausal patients, hormonal therapy (oophorectomy + tamoxifen) appeared to be mediated by a complex mechanism involving more than an ER-positive cell population. In the light of the published results, the present findings underline the importance of reevaluating the indications of hormonotherapy in terms of hormone receptors and menopausal status. They also indicate the importance of biological factors in the evaluation of response to therapy. They can identify, subsets of patients in whom a given therapeutic protocol is detrimental, even though it may be beneficial for the overall population. heterogeneity in response to therapy among patient subsets is one of the most important problems which confronts medical statisticians and clinical investigators.

Is breast conservation after local recurrence feasible?

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.

Breast-conserving therapy for macroscopically multiple cancers.

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.

An assessment of extensive intraductal component as a risk factor for local recurrence after breast-conserving therapy.

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.

Why are local recurrences after breast-conserving therapy more frequent in younger patients?

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.

Risk factors for breast recurrence in premenopausal and postmenopausal patients with ductal cancers treated by conservation therapy.

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 prognostic significance of late local recurrence after breast-conserving therapy.

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.

Local recurrence after breast-conserving surgery and radiotherapy. Frequency, time course, and prognosis.

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.

Conservation therapy for breast cancers other than infiltrating ductal carcinoma.

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.

Local recurrence after breast-conserving surgery and radiotherapy.

The time course and prognosis of local recurrence was studied for 1593 stage I-II patients treated by macroscopically complete excision of the primary tumor with or without axillary dissection, followed by megavoltage radiotherapy (mean tumor bed dose 78 Gy). The actuarial cumulative breast failure rate was 7% at 5, 14% at 10, 18% at 15 and 20% at 20 years. The proportion of recurrences occurring at a distance from the original tumor bed increased with time, most recurrences after 10 years being "new tumors". Of 178 breast recurrences observed, 159 (89%) were operable. Overall survival following operable relapse was 69% at 5 and 57% at 10 years. Prognosis after local failure depended both upon the disease-free interval and the extent of the recurrence. Late recurrences diagnosed after 5 years had an excellent outlook (5-year survival 84%). Small recurrences confined to the breast had a favorable prognosis, even if occurring before 5 years. Local control after salvage mastectomy (88% at 5 years) was better than after conservative salvage surgery. This extensive experience illustrates that recurrence in the breast after conservation therapy is characterized by a protracted course, and is not associated with the poor prognosis attributed to local relapse after mastectomy. The diagnosis and surgical treatment of mammary recurrence is an important component of the breast-conserving strategy.

[Clinically impalpable mammary carcinoma: morphologic and histogenetic analysis. Apropos of 114 cases]. / Carcinomes mammaires impalpables: analyse morphologique et histogenèse. A propos de 114 cas.

In a population of 2,372 consecutive cases of breast carcinomas, 114 cases of clinically occult non palpable breast lesions have been diagnosed (4.8%). 51% of them can be considered as minimal breast carcinomas (MBC) by Gallager's definition and 72% by that of the American College of Surgeons; whatever the definition this category has an excellent prognosis with 11% of axillary invasion for the infiltrating tumors under 5 mm and 7% for these under 10 mm and 100% 5-year survival rate in both cases. The category of infiltrating tumors of over 5 mm and 10 mm also has a good prognosis with 21% and 26% of axillary lymph node invasion respectively, with a survival rate of 83.82% and 77.92%. The comparative histological analysis shows at this stage an increase in the intraductal carcinomas (IC) (35% instead of 6% for the palpable carcinomas), the infiltrating ductal carcinomas with predominant intraductal component (IDCPIC) (19% instead of 12%) and the tubular carcinomas (11% instead of 3%). The study of the peritumoral and environmental mastopathy and the histological repartition, confirms the classical histogenetic arguments regarding breast carcinomas.

Mammary recurrences in women younger than forty.

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%.

Contralateral breast cancer and other second malignancies in patients treated by breast-conserving therapy with radiation.

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 T1-26%; 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 prognostically more favorable than ipsilateral breast recurrence. Among 72 other second malignancies (320 per 10(5) 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.

Results of wide excision for mammary recurrence after breast-conserving therapy.

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.