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Positive margins after conservative treatments impacts local control and possibly survival in node-negative breast cancer
I. J. R a d i a t i o n O n c o l o g y * B i o l o g y • P h y s i c s
126
Volume
42, Number
1 Supplement,
1998
3 POSITIVE MARGINS AFTER CONSERVATIVE TREATMENTS IMPACTS LOCAL CONTROL AND POSSIBLY SURVIVAL IN NODE-NEGATIVE BREAST CANCER Didier Cowen 1, Remy Largillier 1, Val6rie-Jeanne Bardou 2, Jocelyne Jacquemier 3, Gilles Houvenaeghel4, Patriee Viens 5, Dominique Maraninchi 5, Brigitte Puig2 Michel Resbeut 1. Departments of Radiation Ontology 1, Statistics 2, Pathology 3, Surgery 4, and Chemotherapy 5, Paoli-Calmettes Cancer Center, Marseille, France. PURPOSE: The impact of positive margins of excision after conservative surgery in breast cancer has probably been underestimated in series in which patients received adjuvant chemotherapy. To assess the impact of positive margins of excision on Ioco-regional failure and metastases after breast-conserving treatments in node-negative breast cancer, we have selected a very homogenous group of patients receiving no chemotherapy. MATERIALS AND METHODS: Between 1980 and 1995, 3697 women with breast cancer were referred to Paoli-Calmettes Cancer Center, Marseille. Patients included in this study had undergone axillary dissection and were node-negative (n=1840), were treated with conservative surgery and radiotherapy (n=1241), received no chemotherapy (n=1024). Among the 1024 remaining patients, 756 had negative margins of resection and were presented previously (D Cowen eta/, Proc. 39th ASTRO Meeting, /nt J Radial Onco/ Bio/Phys 39:137; 1997), while 152 had positive margins and represent the core of the present abstract. For the remaining 116 patients, information concerning the margins was unknown. After surgery, the whole breast received 46-50 Gy and 97% of the patients were given a 10 to 30 Gy boost to the tumor bed where median total dose delivered was 70 Gy. Boost was usually given with electrons (n=127) rather than brachytherapy (n=20). One third of the patients received hormonal treatment. RESULTS: Median follow-up was 72 months (range 13-212 ). Median age was 57 yrs (range 33-85). There were 7.2% women aged less than 40 yrs. Median tumor size was 18 ram. There were 8 1 % estrogen receptor positive (ER+) and 7 1 % progesteron receptor positive (PR+) tumors. Peritumoral vessel invasion was found in 83 tumors and extensive intraductal component (EIC) in 42 tumors whereas histologic multifocality (HM) was found in 103 cases. There were 33 local recurrences and 14 metastases as first events. Fourteen other metastases occurred after a Ioco-regional failure. Five and ten-year DFS was 72.7% + 8% and 62.2% + 10%. Five and ten-year local recurrence-free (LR) rates were 20 % + 7% and 28% + 9% respectively. Including metastases as first events or occurring after a LR, five and ten-year metastases rates were 16.5% + 6% and 26.7% + 10% In the univariate analysis, the following factors were linked with local failure: ER- (p=0.0001), HM (p=0.O03), age _<40 yrs (p=O.O04), and hormonal therapy (p=0.004), of which RE-, HM and hormonal treatment were kept by the Cox model. The following factors were linked with metastases: ER(p=O.0001), SBR Grade III (p=O.O01), local failure (p=0.O05) and tumor size > 20 mm (p=O.009), of which only ER- and SBR Grade were kept in the Cox model. Total dose to tumor bed, presence of extensive intraductal component, and histology of excision margins (infiltrating vs. in situ) had no influence on the occurrence of local failure. The multivariate analysis will be presented but should be interpreted very cautiously because of the sample size and the limited number of events. A historical comparison with the same selection criteria except for the margin status (n=756) showed that positive margin patients had worse LR and metastases-free survival rates. CONCLUSION: Positive margins of excision after breast conserving surgery in node negative patient~ with no further treatment requires re-excision Hormonal therapy reduces local recurrences in this group of patients.
4 PATIENTS WITH CLOSE OR POSITIVE MARGINS TREATED WITH CONSERVATIVE SURGERY AND RADIATION HAVE AN INCREASED RISK OF BREAST RECURRENCE THAT IS DELAYED BY ADJUVANT SYSTEMIC THERAPY
Freedman, G., Fowble, B., Hanlon, A., Fein, D., Nieolaou, N., Hoffman, J., Sigurdson, E., Boraas, M., Goldstein, L. Fox Chase Cancer C e n t e r , Philadelphia, PA. Purpose: The association between a positive resection margin and an increased risk of ipsilateral breast tumor recurrence (IBTR) after conservative surgery and radiation is controversial, especially in tumors without an extensive intraductal component (EIC). While adjuvant systemic therapy may decrease the risk of an IBTR in all pts, its impact on pts with positive or close margins has not been reported. In addition, the width of the margin that minimizes the risk of IBTR is also unknown. This study examines the interaction between margin width and adjuvant systemic therapy on the 5 and 10 yr risks of IBTR after conservative surgery and radiation. Methods and Materials: 1,262 pts with clinical stage I or II breast cancer were treated by conservative surgery, axillary node dissection, and radiation between 3/79 and 12/92. The median age was 55 yrs (range 24-89). Figure 1. A: Positive/CloseMargins Clinical size was Tl in 66% and T2 in 34%, and 73% of pts were node negative. Only 7% of all tumors (5% of B: NegativeMargins those with close or positive margins) were EIC positive. 41% had a single excision, and 59% had a reexcision. The final margins were negative in 77%, positive in 12%, and close (<2 mm) in 11%. The median total dose to the 13% tumor bed was 60 Gy (negative margins), 64 Gy (close margins), or 66 Gy (positive margins). 22% had radiation to the supraclavicular _+axillary nodes. Chemotherapy (82% CMF, 16% CAF, 2% other) _+tamoxifen was used in 28%, tamoxifen alone in 20%, and no adjuvant systemic therapy in 52%. Pts with positive margins were more frequently node positive (42%), T2 (45%), treated with regional nodal irradiation (39%) and adjuvant systemic 6% B therapy (57%) than those with negative tnargins. The median follow-up is 6.3 yrs (range 0.1-15.6). Results: The 5 yr cumulative incidence (CI) of IBTR was not significantly different between pts with negative (4%), positive (5%) or close (7%) margins. However, by 10 yrs, a significant difference in 1BTR became apparent 12 24 36 4g 60 72 g4 ¢6 10g 120 (negative 7%, positive 12%, close 14% p--0.04). Pts with a close margin had an increased risk of IBTR that was MONTIIS FROM ONSET OF TREA1 MEN g the same as or slightly higher than that of pts with a positive margin. Reexcision of an initially close or positive margin diminished the IBTR rate to 7% at 10 yrs if the final margin was negative. However, the IBTR was Figure 2. significantly increased if the margin remained positive (13%) or close (21%) (p=0.02). The highest CI of IBTR A: Positive/closemargins,no adj rx B: Negativemargins,no adj rx was seen in pts with a persistant close or positive margin despite reexcision not treated with adjuvant systemic C: Negativemargins,any adj r× therapy (19-32%). Figure l shows the risk of IBTR was doubled for pts with a close or positive margin compared D: Positive/closemargins,any adj rx to a negative margin. There was a delay in time to failure by the use of adjuvant systemic therapy: the median interval to failure was 3.7 yrs after no adjuvant systemic therapy, 5.0 yrs after chemotherapy ::!:tamoxifen, and 6.7 yrs after tamoxifen alone. Figure 2 shows this delay by adjuvant systemic therapy was seen in pts with a close or c positive margin, with little impact on the time to failure with negative margins. The 5 yr C[ of IBTR in pts with t 1 16% A close or positive margins was t% with adjuvant systemic therapy and 11% with no adjuvant therapy, but by 10 yrs r 11~ , ~J 12~_ D the CI of IBTR was similar (16% versus 12%) due to late failures in the pts receiving adjuvant systemic therapy. Conclusions: 1) A negative margin as defined in this series (>2mm) correctly identifies pts with a very low risk of 7% g IBTR after conservative surgery and radiation. 2) Pts with a close margin (<2mm) are at an equally increased risk C of recurrence as with a positive margin. 3) Reexcising initial close or positive margins is supported by the finding that a final negative margin after reexcision is associated with the same low risk of 1BTR as an initially negative 12 24 36 4~ ~ 72 R4 96 lug 120 margin. 4) The nredian time to IBTR is delayed but not significantly decreased by adjuvant systemic therapy in pts M O N T H S F R O M O N S ~ OF T R E A T M E N T with close or positive margins - the 5 year results in these pts underestimates their ultimate risk of recurrence which at 10 yrs is twice that of pts with negative margins.
126
Volume
42, Number
1 Supplement,
1998
3 POSITIVE MARGINS AFTER CONSERVATIVE TREATMENTS IMPACTS LOCAL CONTROL AND POSSIBLY SURVIVAL IN NODE-NEGATIVE BREAST CANCER Didier Cowen 1, Remy Largillier 1, Val6rie-Jeanne Bardou 2, Jocelyne Jacquemier 3, Gilles Houvenaeghel4, Patriee Viens 5, Dominique Maraninchi 5, Brigitte Puig2 Michel Resbeut 1. Departments of Radiation Ontology 1, Statistics 2, Pathology 3, Surgery 4, and Chemotherapy 5, Paoli-Calmettes Cancer Center, Marseille, France. PURPOSE: The impact of positive margins of excision after conservative surgery in breast cancer has probably been underestimated in series in which patients received adjuvant chemotherapy. To assess the impact of positive margins of excision on Ioco-regional failure and metastases after breast-conserving treatments in node-negative breast cancer, we have selected a very homogenous group of patients receiving no chemotherapy. MATERIALS AND METHODS: Between 1980 and 1995, 3697 women with breast cancer were referred to Paoli-Calmettes Cancer Center, Marseille. Patients included in this study had undergone axillary dissection and were node-negative (n=1840), were treated with conservative surgery and radiotherapy (n=1241), received no chemotherapy (n=1024). Among the 1024 remaining patients, 756 had negative margins of resection and were presented previously (D Cowen eta/, Proc. 39th ASTRO Meeting, /nt J Radial Onco/ Bio/Phys 39:137; 1997), while 152 had positive margins and represent the core of the present abstract. For the remaining 116 patients, information concerning the margins was unknown. After surgery, the whole breast received 46-50 Gy and 97% of the patients were given a 10 to 30 Gy boost to the tumor bed where median total dose delivered was 70 Gy. Boost was usually given with electrons (n=127) rather than brachytherapy (n=20). One third of the patients received hormonal treatment. RESULTS: Median follow-up was 72 months (range 13-212 ). Median age was 57 yrs (range 33-85). There were 7.2% women aged less than 40 yrs. Median tumor size was 18 ram. There were 8 1 % estrogen receptor positive (ER+) and 7 1 % progesteron receptor positive (PR+) tumors. Peritumoral vessel invasion was found in 83 tumors and extensive intraductal component (EIC) in 42 tumors whereas histologic multifocality (HM) was found in 103 cases. There were 33 local recurrences and 14 metastases as first events. Fourteen other metastases occurred after a Ioco-regional failure. Five and ten-year DFS was 72.7% + 8% and 62.2% + 10%. Five and ten-year local recurrence-free (LR) rates were 20 % + 7% and 28% + 9% respectively. Including metastases as first events or occurring after a LR, five and ten-year metastases rates were 16.5% + 6% and 26.7% + 10% In the univariate analysis, the following factors were linked with local failure: ER- (p=0.0001), HM (p=0.O03), age _<40 yrs (p=O.O04), and hormonal therapy (p=0.004), of which RE-, HM and hormonal treatment were kept by the Cox model. The following factors were linked with metastases: ER(p=O.0001), SBR Grade III (p=O.O01), local failure (p=0.O05) and tumor size > 20 mm (p=O.009), of which only ER- and SBR Grade were kept in the Cox model. Total dose to tumor bed, presence of extensive intraductal component, and histology of excision margins (infiltrating vs. in situ) had no influence on the occurrence of local failure. The multivariate analysis will be presented but should be interpreted very cautiously because of the sample size and the limited number of events. A historical comparison with the same selection criteria except for the margin status (n=756) showed that positive margin patients had worse LR and metastases-free survival rates. CONCLUSION: Positive margins of excision after breast conserving surgery in node negative patient~ with no further treatment requires re-excision Hormonal therapy reduces local recurrences in this group of patients.
4 PATIENTS WITH CLOSE OR POSITIVE MARGINS TREATED WITH CONSERVATIVE SURGERY AND RADIATION HAVE AN INCREASED RISK OF BREAST RECURRENCE THAT IS DELAYED BY ADJUVANT SYSTEMIC THERAPY
Freedman, G., Fowble, B., Hanlon, A., Fein, D., Nieolaou, N., Hoffman, J., Sigurdson, E., Boraas, M., Goldstein, L. Fox Chase Cancer C e n t e r , Philadelphia, PA. Purpose: The association between a positive resection margin and an increased risk of ipsilateral breast tumor recurrence (IBTR) after conservative surgery and radiation is controversial, especially in tumors without an extensive intraductal component (EIC). While adjuvant systemic therapy may decrease the risk of an IBTR in all pts, its impact on pts with positive or close margins has not been reported. In addition, the width of the margin that minimizes the risk of IBTR is also unknown. This study examines the interaction between margin width and adjuvant systemic therapy on the 5 and 10 yr risks of IBTR after conservative surgery and radiation. Methods and Materials: 1,262 pts with clinical stage I or II breast cancer were treated by conservative surgery, axillary node dissection, and radiation between 3/79 and 12/92. The median age was 55 yrs (range 24-89). Figure 1. A: Positive/CloseMargins Clinical size was Tl in 66% and T2 in 34%, and 73% of pts were node negative. Only 7% of all tumors (5% of B: NegativeMargins those with close or positive margins) were EIC positive. 41% had a single excision, and 59% had a reexcision. The final margins were negative in 77%, positive in 12%, and close (<2 mm) in 11%. The median total dose to the 13% tumor bed was 60 Gy (negative margins), 64 Gy (close margins), or 66 Gy (positive margins). 22% had radiation to the supraclavicular _+axillary nodes. Chemotherapy (82% CMF, 16% CAF, 2% other) _+tamoxifen was used in 28%, tamoxifen alone in 20%, and no adjuvant systemic therapy in 52%. Pts with positive margins were more frequently node positive (42%), T2 (45%), treated with regional nodal irradiation (39%) and adjuvant systemic 6% B therapy (57%) than those with negative tnargins. The median follow-up is 6.3 yrs (range 0.1-15.6). Results: The 5 yr cumulative incidence (CI) of IBTR was not significantly different between pts with negative (4%), positive (5%) or close (7%) margins. However, by 10 yrs, a significant difference in 1BTR became apparent 12 24 36 4g 60 72 g4 ¢6 10g 120 (negative 7%, positive 12%, close 14% p--0.04). Pts with a close margin had an increased risk of IBTR that was MONTIIS FROM ONSET OF TREA1 MEN g the same as or slightly higher than that of pts with a positive margin. Reexcision of an initially close or positive margin diminished the IBTR rate to 7% at 10 yrs if the final margin was negative. However, the IBTR was Figure 2. significantly increased if the margin remained positive (13%) or close (21%) (p=0.02). The highest CI of IBTR A: Positive/closemargins,no adj rx B: Negativemargins,no adj rx was seen in pts with a persistant close or positive margin despite reexcision not treated with adjuvant systemic C: Negativemargins,any adj r× therapy (19-32%). Figure l shows the risk of IBTR was doubled for pts with a close or positive margin compared D: Positive/closemargins,any adj rx to a negative margin. There was a delay in time to failure by the use of adjuvant systemic therapy: the median interval to failure was 3.7 yrs after no adjuvant systemic therapy, 5.0 yrs after chemotherapy ::!:tamoxifen, and 6.7 yrs after tamoxifen alone. Figure 2 shows this delay by adjuvant systemic therapy was seen in pts with a close or c positive margin, with little impact on the time to failure with negative margins. The 5 yr C[ of IBTR in pts with t 1 16% A close or positive margins was t% with adjuvant systemic therapy and 11% with no adjuvant therapy, but by 10 yrs r 11~ , ~J 12~_ D the CI of IBTR was similar (16% versus 12%) due to late failures in the pts receiving adjuvant systemic therapy. Conclusions: 1) A negative margin as defined in this series (>2mm) correctly identifies pts with a very low risk of 7% g IBTR after conservative surgery and radiation. 2) Pts with a close margin (<2mm) are at an equally increased risk C of recurrence as with a positive margin. 3) Reexcising initial close or positive margins is supported by the finding that a final negative margin after reexcision is associated with the same low risk of 1BTR as an initially negative 12 24 36 4~ ~ 72 R4 96 lug 120 margin. 4) The nredian time to IBTR is delayed but not significantly decreased by adjuvant systemic therapy in pts M O N T H S F R O M O N S ~ OF T R E A T M E N T with close or positive margins - the 5 year results in these pts underestimates their ultimate risk of recurrence which at 10 yrs is twice that of pts with negative margins.