Radiol Oncol 2003; 37(2): 79-88. Prognostic outcome of local recurrence in breast cancer after conserving surgery and mastectomy Renata Soumarová1, Hana Horová1, Zuzana Šeneklová1, Ivana Horová2, Marie Budíková2 1 Radiation Oncology Department, Memorial Cancer Institute Brno, 2 Department of Applied Mathematics, Masaryk University Brno, Czech Republic Background. In our retrospective study we analysed local recurrences in breast cancer patients treated with conserving surgery (CS) followed by adjuvant radiotherapy (RT) or mastectomy (ME) with or without ra-diotherapy. We analysed the impact of local recurrence on overall survival. Patients and methods. Between 1980-1995, 306 patients underwent conserving surgery and 1,193 pa-tients were done mastectomy in Masaryk Memorial Cancer Institute. The patients lost to follow-up were ex-cluded. After all, we analysed 236 patients who underwent conserving surgery (Group A), and 1,121 who underwent mastectomy (Group B). All patients with CS received adjuvant RT of the breast with or without regional lymph nodes. In 982 patients (87.6 %) with ME, we performed RT of the chest wall with or with-out regional lymph nodes. Median age at the time of diagnosis was 48.3 years in Group A and 52.1 years in Group B. In Group A, 149 patients (63.1 %) had T1 tumour, 86 (36.4 %) T2 and 1 (0.5 %) T3. In 24.2 % of patients, axillary node involvement was observed. In Group B, 316 patients (30.4 %) had T1 tumour, 607 (58.3 %) T2, 76 (7.3 %) T3, 33 (3.2 %) T4 and 9 (0.9 %) TX. In 46.2 % of these patients, we found ax-illary node involvement. Invasive ductal carcinoma was histologically proved in 67.4% in Group A and 84% in Group B. Systemic treatment was given to 133 patients (56.4 %) from Group A and to 857 patients (76.4 %) from Group B. Results. Median follow-up was 100.5 months in Group A and 121 months in Group B. In Group A, we registered 22 (9.3 %) local recurrences, 5-year local control was 96.2% and median time to local recurrence was 50 months. In Group B, we registered 65 (5.8%) local recurrences; 5-year local control was 96.6%. Five-year local control in patients with T1, T2 tumours was 97.2%. In patients with adjuvant RT median time to local recurrence was 48.5 months, and in patients without adjuvant RT 51 months. Thirteen patients (8.7 %) who underwent mastectomy without RT had local recurrence . The impact of local recurrence on overall survival was statistically significant in Group B (p = 0.002) and not exactly statistically significant in Group A (p = 0.062). Patients who developed local recurrence had lover overall survival. Unambiguous linear dependence was confirmed between the time to local recurrence and overall survival. Conclusions. The impact of local recurrence on overall survival was found statistically significant. Probability of local recurrence and time to local recurrence was the same in the patients treated with CS or ME. The overall survival increased with local disease free interval. Key words: breast neoplasms - surgery; mastectomy; neoplasms recurrence, local; prognosis; radiothera-py, adjuvant; survival analysis 80 Soumarová R et al. / Local recurrence in breast cancer Received 12 November 2002 Accepted 18 December 2002 Correspondence to: Renata Soumarová, M.D., Department of Radiation Oncology, Masaryk Memorial Cancer Institute, Žlutý kopec 7, Brno 656 53, Czech Republic; Phone: +420 5 4313 1116-7; Fax: 420 +420 5 4321 1169; E-mail: soumarova@mou.cz Introduction Significance of local recurrence after breast conserving surgery (CS) or radical mastecto-my (ME) has been discussed. Local recur-rence after ME is supposed to have worse prognosis than after CS. The role of postoperative locoregional radiotherapy (RT) (to the chest wall or whole breast and regional lymph nodes) has been evaluated in ran-domised studies during the last 50 years. The results confirmed the impact of locoregional treatment on reduction of local recurrence, but the impact on overall survival (OS) is still not clear.1 The impact on OS was proved on-ly in the patients with positive lymph nodes and systemic therapy.2 Breast cancer is a sys-temic disease. This new approach favoured breast conserving surgery and application of chemotherapy. The number of mutilating op-erations thus decreased. Nevertheless, locore-gional RT remains an important treatment modality. However, some questions have remained unsolved. Further studies need to be per-formed to explain the role of RT and its integration in multimodal therapy of breast can-cer. CS followed by postoperative RT has be-come standard treatment modality. Prospective randomised trials have shown that the number of local recurrences after CS followed with RT is the same as after the mu-tilating ME.3-8 OS rate and the risk of distant metastases development are equal in both, ME and CS followed by RT.9-13 Contra-indications for RT are the same as for CS: pregnancy, prior breast or chest irradiation (i.e. mantle technique), collagenosis. Other Radiol Oncol 2003; 37(2): 79-88. known contraindications for CS are: multifo-cal tumour, diffuse microcalcification, breast and tumour size disproportion.14 Patients’ opinion has to be respected. The meta-analysis of 36 randomised stud-ies compared the results of postoperative RT in early breast cancer patients (17 273 pa-tients.) and ME alone. A treble decrease of risk of local recurrence was shown after adju-vant RT. The difference in 10-year survival was not significant.15 Fisher’s study shows similar results.4 The prognosis of local recurrence is still uncertain. The impact of local recurrence on overall survival is not clear. Patients and methods Patients with breast conserving surgery (CS) Between January 1983 and December 1994, a total number of 306 patients underwent adju-vant RT after CS at the Masaryk Memorial Cancer Institute (Figure 1). Our report evalu-ates the available data of 236 patients. For sta-tistical evaluation, SPSS, Matlab, Gehan-Wilcoxon (for survival analysis) and log-rank tests were used. Local therapy (surgery + RT) was followed by adjuvant chemotherapy or hormonal therapy in 54%. Table 1 shows the characteristic of patients. Figure 2 shows the age range. Tumour size up to 2 cm (63.1%) (Figure 3) and invasive ductal carcinoma 70 60 50 40 30 20 10 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 Figure 1. Number of patients treated by conservative surgery and radiotherapy. 0 Soumarová R et al. / Local recurrence in breast cancer 81 Table 1. Characteristics of patients treated by conser- vative surgery (n = 236) Age (years) Mean 49.68±0.64 Median 48.29 (25.3-80.3) Stage of tumour T1 149 (63.1%) T2 86 (36.4%) T3 1 (0.5%) Histology Ductal 159 (67.4%) Lobular 23 (9.7%) Others 54 (22.9%) Margins Free 214 (90.7%) Positive 22 (9.3%) Axillary nodes Positive 36 (24.2%) Negative 118 (44.7%) Unknown 82 (31.1%) Side Left 124 (52.5%) Right 112 (47.5%) Quadrant Outer upper 168 (71.2%) Outer lower 22 (9.3%) Inner upper 37 (15.7%) Inner lower 2 (0.8%) Central 7 (3.0%) (67.4%) were found in most cases. The mean follow-up was 110.4 months (median 100.5 months). Treatment After the elimination of distant metastases, wide local excision (23.7%) or quadrantecto-my (76.3%) was performed. Axillary dissec-tion was not performed and a limited number of axillary lymph nodes were examined in 31.1% of patients. All patients received postoperative RT to the whole breast, with or without irradiation of regional lymph nodes (axillary and supraclavicular). The mean interval between surgery and RT was 23 days (range 10-120, median 28.8 days). The entire (24;31] (31;37] (37;43] (43;49] (49;55] (55;61] (61;67] (67;73] (73;79] years Figure 2. Age distribution of patients after conserva-tive surgery and radiotherapy. Stage of tumour Number of pts. pT 1 149 63, 1% pT 2 86 36, 4% pT 3 1 0,5% Figure 3. Stage of tumour in patients after conserva-tive surgery and radiotherapy. breast was included in the target volume. The superior border lay at about the level of the suprasternal notch medially and just bellows the level of the abducted arm laterally. The inferior border lay 1-2 cm below the breast. The medial border was usually in the mid-line, and the lateral border was in the mid-axillary line. Two tangential fields were used for irradiation of breast. Four fields - two tangential and two convergent - were used for irradiation of the breast and regional lymph nodes. Radiol Oncol 2003; 37(2): 79-88. 82 Soumarová R et al. / Local recurrence in breast cancer The lymph nodes were irradiated in 169 patients (71.6%). Sixty-two patients (22.7%) were treated with linear accelerator (photons 6MV) and 174 patients (73.7%) with cobalt unit. Electron beam of linear accelerator or caesium unit were used as boosting to tumour bed or axilla. The applied dose was prescribed according to ICRU (International Commission on Radiation Units and Measurements). Systemic adjuvant therapy was given to 133 patients (56.4%). Hundred and nine patients (46.1%) completed 2-6 cycles of chemotherapy. Eighty-three patients (35.2%) received CMF regimen (cyclophosphamide, methotrexate, and 5-fluorouracil), 11 patients (7.6%) FAC regimen (5-fluorouracil, doxorubicin, and cyclophosphamide), and 8 patients had both regimens, CMF and FAC. Hormonal therapy (tamoxifen 20 mg per day) was given to 68 patients (28.8%). Twenty-nine patients (11%) received chemotherapy and hormonal therapy simultaneously. All patients were routinely examined every 3-6 months. Once a year, they underwent ultrasonography of the breast or mammography, lung X-ray, ultrasonography of the liver and bone scintigraphy. Patients with radical mastectomy (ME) Between 1980 and 1995, a total number of 1,193 patients underwent ME at the Masaryk Memorial Cancer Institute (Figure 4). We 2 100 80 60 40 Table 2. Characteristics of patients treated by radical mastectomy, number of patients 1121 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 Mean Median Age (years) 53.1 52.1 Hormonal status Premenopausal 488 Postmenopausal 633 43.5 % 56.5 % Grade of tumours T1 342 30.4 % T2 647 57.7 % T3 84 7.5 % T4 39 3.5 % TX 9 0.8 % Mamma Left 548 48.9 % Right 573 51.1 % Histology Ductal 942 84 % Lobular 111 9.9 % Others 68 6.1 % Axillary nodes Positive 518 46.2 % Negative 521 46.5 % Unknown 82 7.3 % Radiotherapy Yes 982 87.6 % Only on chest wall 392 39.9 % No 139 12.4 Chemotherapy Yes 466 41.6 % No 655 58.4 % Hormonotherapy Yes 381 34 % No 740 66 % Figure 4. Number of patients treated by radical mas-tectomy in Masaryk Memorial Cancer Institute. evaluated 1,121 patients. The patients lost to follow-up were excluded. Table 2 shows the characteristics of patients. Mean age at the time of diagnosis was 53.1 years (median 52.1) (Figure 5). Tabel 3 and Figure 6 show the size of tumours. Rare occurrence of T3, T4 tu-mours is due to the exclusion of patients who underwent neoadjuvant RT or chemotherapy. Mean follow-up was 124.6 months (median 121). Radiol Oncol 2003; 37(2): 79-88. 20 Soumarová R et al. / Local recurrence in breast cancer 83 60 56 52 ............... 48 44 40 36 __ 32 28 ............... 24 ...............------- 20 ................ 16 ------- 12 <= 2 0 (20;30] (30;40] (40;50] (50;60] (60;70] (70;80] (80;90] > 9 0 Figure 5. Age of patients after radical mastectomy. Figure 6. Stages of tumours after radical mastectomy. Table 3. Patients after conservative surgery and radio-therapy with local recurrence, number of patients 22 (9.3%) Age (years) 49.1 (36-69.7) Surgery Partial mastectomy 12 (54.5 %) Tumourectomy 10 (45.5 %) Histology Ductal 15 (68.2 %) Lobular 1 (4.5 %) Others 6 (27.3 %) Source of RT Cobalt Co-60 17 (77.3 %) Linear accelerator 5 (22.7 %) Nodes Positive 8 (36.4 %) Negative 6 (27.3 %) Unknown 8 (36.4 %) Treatment of local recurrence Radical mastectomy 11 (35.3 %) Exstirpation 4 (23.5 %) Only systemic 7 (41.2 %) therapy (CT or HT) Treatment Radiotherapy to the chest wall with or with-out regional lymph nodes was performed in 982 patients (86.6%) who underwent ME. The patients were treated with linear accelerator (photons 6MV). Two tangential fields were used for the irradiation of the chest wall, two convergent fields for the regional lymph nodes. The lymph nodes were irradiated in 59.5% patients. Median dose of 44 Gy was given to the chest wall, 40 Gy to the regional lymph nodes. Systemic adjuvant therapy (chemotherapy, hormonal therapy or both) was applied to 817 patients (76.9%). Results Patients with conservative surgery (CS) and radiotherapy (RT) Till the date of evaluation (December 2001), 47 patients (19.9%) died, all of them due to the progression of breast cancer. Local recurrence occurred in 22 patients (9.3%). Table 3 shows the characteristics of patients. The mean time to local recurrence was 63.4 months (range 5 - 168, median 50 months). The mean survival of patients with local recurrence was 41.4 months (range 5 -122). From 22 patients with local recurrence, 9 developed distant metastases (40.9%). Distant metastases occurred simultaneously or after local recurrence. The mean of follow-up of patients with local recurrence was 101.8 months (range 41 - 187). Till the date of evaluation, 8 patients (36.4%) died. Local recur-rence in the primary involved quadrant oc-curred in 18 cases. Diffuse breast involve-ment was described in 4 cases. Three patients had lymphangioinvasion described in prime histology; two of them developed diffuse lo-cal recurrence. Five-year local control in the whole group of patients was 96.2%. Nine pa-tients (3.8%) had local recurrence within 5 years. Ten-year local control was 91.9%; in 217 patients, local treatment failure was not Radiol Oncol 2003; 37(2): 79-88. 84 Soumarová R et al. / Local recurrence in breast cancer observed within 10 years. The histology of lo-cal recurrence corresponded to the histology of primary tumour. Among 22 patients with local recurrence, 6 patients were younger than 40 years at the time of diagnosis. Local recurrence had negative impact on survival, p = 0.06 (Figure 7). 1,05 1,00 0,95 0,90 0,85 0,80 0,75 0,70 0,65 0,60 0,55 0,50 Cumulative Proportion Surviving (Kaplan-Meier) O Complete + Censored 100 150 200 250 Time Figure 7. Influence of local recurrence on overall sur-vival in patients after conservative surgery. Patients with radical mastectomy (ME) Till the date of evaluation, 65 patients (5.8%) developed local recurrence (Table 4). Five-year local control was 96.6%; in the patients with T1, T2 tumours it was 97.2%. There was no difference in the time to local progression in the irradiated patients (48.5 months) and in the patients without RT (51 months). Local recurrence developed in 13 patients (8.7%) with ME without RT, 44.6% of them had lymph nodes involvement. Lymph node in-volvement and local recurrence developed in-Table 4. Characteristic of patients with local recur-rence after radical mastectomy, number of patients 65 (5.8%) Histology Ductal 56 Lobular 4 Others 5 86.15 % 6.15 % 7.7 % Nodes Positive 29 Negative 36 44.6 % 55.4% Radiol Oncol 2003; 37(2): 79-88. dependently. Higher number of local recur-rences associated with lobular carcinoma was not statistically significant. Patients with lo-cal recurrence developed distant metastases more frequently. The impact of local recur-rence on OS was statistically significant (p=0.002) (Figure 8). Of patients without local recurrence, 12.9% died, and in the group that locally relapsed 39.1% died. Significant linear correlation between the time to local progression and OS was observed. Cumulative Proportion Surviving (Kaplan-Meier) O Complete + Censored 150 Time Figure 8. The Influence of local recurrence on overall survival in patients after radical mastectomy. Discussion In a French retrospective study of 528 pa-tients with breast cancer, stages I and II, an attempt was made to determine predictive factors for local recurrence.16 A multivariante analysis of this study showed 4 independent factors most important for local control: young age (up to 40 years), premenopause, bi-focality and extensive intraductal component (=25%). The impact of local recurrence on OS is not clear. Our study showed negative impact of local recurrence on OS. The difference was on the border of statistic significance in the patients with CS (p=0.06) and significant in the patients with ME (p=0.002). The analysis of 4 prospective studies comprising more than 2000 breast cancer patients tried to eval-uate the role of isolated local recurrence.17 The impact on OS and dissemination was 1.0 0 50 0 50 100 200 250 300 Soumarová R et al. / Local recurrence in breast cancer 85 proved. Elkhuizen reported similar conclu-sion.18 A very important prognostic factor is the interval between the time of diagnosis and lo-cal recurrence.19 In our group of patients (with CS and ME), the time to local progression was equal - 50 months. The patients with longer time to local progression had longer survival. The impact of histologic type of tu-mour on local recurrence was not proved. Lobular carcinoma, often multifocal and mul-ticentric, was considered not to be conven-ient for breast conserving surgery. The stud-ies comparing the results of both carcinomas, ductal and lobular, did not show any differ-ence in local control or other parameters.20,21 The patients with local recurrent ductal carci-noma in situ had significantly better progno-sis. Patients with lobular carcinoma in situ have significantly higher risk of unilateral re-currence.22 Tamoxifen seems to decrease this risk. Histologic type of tumour did not have any impact on local recurrence in our groups of patients. Lobular carcinoma should not be a contraindication for CS. Till the end of 1970’s, postoperative RT was given to all patients with ME. As the knowledge about dissemination of tumour cells advanced, the treatment strategy changed accordingly. Positive outcome of RT after ME must be compared to potential acute and late effects of RT. Modern techniques of RT reduce the doses to the heart and the large vessels. RT after ME is a standard in patients with high risk of local recurrence: locally advanced tumours - pT3, pT4, 4 or more axillary lymph node involvement, extracapsular invasion.23,24 The role of postoperative RT is not clear in pT1, pT2, pN0 tumours and 1 - 3 axillary lymph node involvement. A Danish study evaluated the role of postoperative RT.2 Combined sys-temic treatment with RT and chemotherapy alone (CMF regimen) were compared. OS and disease-free interval significantly increased in combined therapy. Janni’s retrospective analysis evaluated the impact of RT given to the chest wall on local recurrence rate and OS.25 The decrease of local recurrence and positive impact on OS was statistically signif-icant in the group of patients with RT. Meta-analysis of 36 randomised studies (Early breast cancer trialist’s collaboration group EBCTCG) compared postoperative RT and surgery alone in early breast cancer pa-tients (17,273 patients with mastectomy). The risk of local recurrence after adjuvant RT was treble lower, but the difference in 10-year sur-vival was not significant.15 No difference was found between the patients with ME and the patients with CS and RT. Fisher’s study re-ported similar results.4 The above negative results do not correlate with the results of other randomised studies: Danish 82b and 82c trials, British Columbia study.2,24.26 Van de Steene tried to solve this contradiction. He confirmed the impact of postoperative RT on survival if modern tech-niques and standard fractionation of RT were used.27 Levitt’s study showed the impact of RT on OS in the patients with negative resec-tion margin and negative lymph nodes.28 Another meta-analysis of 6,367 patients veri-fied that locoregional therapy of breast cancer increases disease-free interval and OS.1 In our study, the impact of local recurrence on OS was found statistically significant. We did not see any benefit of postoperative RT. Among 65 patients with local recurrence, 51 (78.4%) underwent irradiation of the chest wall. In primary operated part of the breast, 65 -80% of local recurrences occurred.29 In select-ed group of patients, only tumour bed could be postoperativelly irradiated. Brachytherapy as a separate method of adjuvant treatment of breast carcinoma was described in few re-ports.30-34 The studies showed that this treat-ment was well tolerated and had good cos-metic effect. Good cosmetic effect and reduc-tion of treatment time are the main aim of this method. Radiol Oncol 2003; 37(2): 79-88. 86 Soumarová R et al. / Local recurrence in breast cancer Conclusions There was no difference in the time to local progression found between our two groups of patients. Median time to local progression was equal - 50 months. Five-year probability of local recurrence was equal for the patients with CS (and RT) and patients with ME (with-out RT) - 9.3%, 8.7% respectively. Patients with CS who developed local re-currence had equal over-all survival com-pared to the patients with ME due to T1, T2 tumours with local recurrence (Figure 9). Prognostic outcome of local recurrence after CS or ME does not differ. Cumulative Proportion Surviving (Kaplan-Meier) C Complete * Censored 1,0 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0,0 -0,1 100 150 Time 200 250 300 Figure 9. The overall survival of patients with local re-currence treated by conservative surgery or radical mastectomy. References 1. Whelan TJ, Julian J, Wright J, Jadad AR, Levine ML. Does locoregional radiation therapy improve survival in breast cancer? A meta-analysis. Clin Oncol 2000; 18(6): 1220-9. 2. Overgaard M, Hansen PS, Overgaard J, Rose C, Andersson M, Bach F, et al. Postoperative radio-therapy in high-risk premenopausal woman with breast cancer who receive adjuvant chemothera-py. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med 1997; 337: 949-55. 3. 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