Muhimodal Therapy in Locally Advanced Breast Carcinoma Marvin J. Lopez, MD, FACS, FRCS(C), Dorothy P. Andriole, MD, William G. Kraybill, MD, FACS, All Khojasteh, MD, st Louis,Missouri,Columbia, Missouri
onsiderable progress in the management of locally advanced carcinoma of the breast has occurred during the last decade, resulting in substantial improvements in local disease control and survival for a disease once considered to be uniformly and rapidly fatal. Patients
with tumors in this category generally have high local recurrence rates and dismal survival due to progression of micrometastases not controlled by local therapy alone. During the first half of this century, radical mastectomy predominated as the primary treatment m0dality. The poor results obtained with surgery alone when the carcinoma had ulcerated, was fixed to the chest wall, developed satellite nodules, or produced edema of the breast or massive axillary metastases prompted Haagensen and Stout [1] in 1943 to develop criteria of inoperability. Previous treatment reports from our institution in patients with inflammatory carcinoma revealed a local recurrence rate of 46% and only one 5-year survivor among 50 patients treated only with radiotherapy and/or surgery [2]. In the subsequent 25 years, radiotherapy dominated as the primary and often the only form of management. The results of treatment improved further as radiotherapeutic technology and dosimetry advanced, but only in terms of local disease control rates. Several investigators reported increasing rates of local disease control during the 1960s and 1970s, when larger doses of supervoltage irradiation were administered safely and also with the use of interstitial implants [3,4]. Median surviva! approximating 2 years and 5-year survival rates below 25% were common [5,6]. Although the combination of surgery and radiotherapy may increase local disease control rates, it does not appear to influence preexisting occult distant metastases nor influence overall survival rates [7]. During the decade of the 1980s, multimodal management of locally advanced carcinoma of the' breast with induction chemotherapy became firmly established as the first line of treatment. Induction chemotherapy produced dramatic initial response rates permitting effective local control by surgery, irradiation, or both, while also controlling distant micrometastases [813]. In a preliminary report, we compared the results of treatment of locally advanced and inflammatory breast carcinoma before and after the advent of induction chemotherapy [14]. Because of the paucity of data regarding long-term survival results, we sought to determine if the initial response to treatment in our group of patients translated into long-term survival. Thus, the purpose of this report is to provide an update of our experience with foUow-up ranging from 4 to 15 years.
From the Departmentsof Surgery, Washington UniversitySchoolof Medicine, Barnes Hospital,St. Louis, Missouri (MJL, DPA, WGK), and Ellis FischelState Cancer Center, Columbia,Missouri (AK). Requestsfor reprintsshouldbe addressedto MarvinJ. Lopez,MD, FACS, FRCS(C), 5102 Queeny Tower, Barnes Hospital Plaza, St. Louis, Missouri63110. Presentedat the 42nd Annual Meetingof the SouthwesternSurgical Congress,La Quinta, California,April 22-25, 1990.
PATIENTS AND M E T H O D S During the years 1975 to 1984, 879 patients with primary carcinoma of the breast were treated at the Ellis Fischel State Cancer Center in Columbia, Missouri. Advanced disease was found at the time of diagnosis in 125 patients (14%). Chosen for further study was a subgroup of 34 patients (4%) who presented with untreated, locally
Among 8 7 9 patients treated for breast cancer between 1975 and 1984, advanced disease was found in 125 ( 1 4 % ) . A subgroup of 34 ( 4 % ) presented with untreated locally advanced disease without demonstrable distant metastases at the time of diagnosis (stage l l I B = T 4 a b c d , NX-2,MO). During the first 5 years ( 1 9 7 5 through 1 9 7 9 ) , 17 patients were treated primarily with sequential radiotherapy and chemotherapy (Group A). From 1980 to 1984 (Group B), the management consisted of four courses of induction multi-drug chemotherapy followed primarily by mastectomy and additional chemotherapy. The mean follow-up for the most recent group (Group B) is 48 months. Follow-up was complete. While the local disease control rate was the same for both groups ( 7 6 % ) , the survival was remarkably different. Group A patients experienced a median survival of 15 months, and only one survived 5 years. In Group B, the median survival was 5 6 months with nine patients ( 5 3 % ) alive between 4 0 and 76 months, seven ( 4 1 % ) of whom are 5year survivors. While the overall mortality of patients with inflammatory breast cancer was greater in both groups when compared with the group with noninflammatory disease, the survival of patients in Group B was better than in Group A for both inflammatory and noninflammatory cancers (p < 0 . 0 1 ) . Estrogen receptor, nodal, and menopausal status did not influence survival. These data suggest that neoadjuvant chemotherapy improves survival for patients with stage IIIB breast carcinoma and delays the establishment or progression of distant metastases. Mastectomy is an important component in the treatment of this disease.
C
THE AMERICAN JOURNAL OF SURGERY VOLUME160 DECEMBER 1990 669
LOPEZ ET AL
advanced breast carcinoma without demonstrable distant metastases. Only patients with the most locally advanced tumors falling into the stage IIIB category (T4abod, NX2,MO) are included in this review to provide some uniformity in a notoriously heterogeneous group of carcinomas. This stage was defined in accordance with the 1988 Manual for Cancer Staging of the American Joint Committee on Cancer [15]. Follow-up was complete in all cases. The patient population, all rural white women, was treated during a 10-year period from 1975 to 1984. During the first 5 years of the study, half of the patients (n = 17) were treated without induction chemotherapy (GroUp A), In 1980, a protocol of induction chemotherapy was instituted and applied in the treatment of the remaining 17 patients (Group B). Characteristics of Groups A and B were comparable in terms of age, proportion of cases of inflammatory versus noninflammatory disease, and estrogen receptor, menopausal, and nodal status. RESULTS From 1975 to 1979, 17 women were treated (Table I, Group A). Their ages ranged from 32 to 89 years (mean: 61 years). Fifteen of these patients were initially treated with radiotherapy consisting of 6,000 Cgy of cobalt-60 delivered in 30 fractions. Simple mastectomy was performed as primary treatment in two patients. Multi-drug adjuvant chemotherapy consisting of cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU) was subsequently offered to all patients, but accepted only by 6 or 35% of the 17 patients initially treated with radiotherapy. The two patients who underwent simple mastectomy were treated with postoperative radiation. In this group, eight patients had clinical and histologic characteristics of inflammatory carcinoma, two of whom were estrogen receptor positive and six of whom had metastases to the axillary lymph nodes. Nine patients presented with other characteristics of locally advanced carcinoma of the breast but without signs of inflammatory carcinoma. In this subgroup, four patients were estrogen receptor positive and seven had lymph node metastases to the ipsilateral axilla. The overall local disease control rate in this group of 17 patients was 76% (13 of 17). In the remaining four patients, radiotherapy did not produce a complete response, and these four patients died with evidence of progressive chest wall disease. Clinical manifestations of disseminated disease developed in all but one patient, and the mean survival was 15 months. The only survivor, a patient with inflammatory breast carcinoma treated with rnastectomy and postoperative irradiation, is alive and clinically disease-free 9 years after diagnosis. Group B consisted of 17 women treated between 1980 and 1984 (Table I). Their mean age was also 61 years, and their ages ranged from 40 to 76. All patients in this group were initially given an average of 4.6 monthly cycles (ranging from 3 to 9) of chemotherapy consisting of the following: cyclophosphamide 100 mg/m 2 orally on days 1 to 14, doxorubicin 25 mg/m 2 intravenously on days 1 and 8 of the cycle, and 5-FU 500 mg/m 2 intravenously on days 1 and 8 (CAF). Two patients also received vincristine, two received methotrexate, and two received 670
THE AMERICAN JOURNAL OF SURGERY
prednisone. Twelve of the 17 patients treated with induction chemotherapy subsequently underwent mastectomy. Simple mastectomy was performed in eight patients, modified radical mastectomy in two patients, and radical mastectomy in two patients. Five patients refused mastectomy following chemotherapy; three of these patients consented to receive radiotherapy. The remaining two patients refused both radiotherapy and surgery and were continued on chemotherapy alone. The objective of surgery was to resect all gross disease; random samples of margins were histologically negative for carcinoma in all 12 patients. In Group B, seven patients had inflammatory carcinoma, six of whom had metastatic axillary nodes, and two were estrogen receptor positive. Ten patients presented with noninflammatory stage IIIB disease, 9 of whom had metastases to the axillary lymph nodes, and 5 were estrogen receptor positive. The overall local control rate, defined as the total clinical absence of chest wall disease, was 76% (13 of 17), the same rate as in Group A. However, the four patients from Group B in whom the primary tumor was not controlled had a relatively stable course in contrast to the rapid progression of local disease in the four Group A women whose tumor persisted locally. Of the 17 patients in Group B treated with induction chemotherapy, tumor size was reduced by more than 50% in 10 patients (58%). The tumor regressed, but by less than 50% from the original size, in an additional six patients. In one patient, local disease progressed during induction chemotherapy. The four failures of local control occurred in two of three patients who received radiotherapy after induction chemotherapy and in both patients who refused either surgery or radiotherapy. There were no local recurrences in 12 patients who underwent mastectomy. The median survival was 56 months, with nine patients (53%) alive and disease-free between 40 and 76 months, seven of whom are 5-year survivors. Two of the eight deaths were unrelated to breast carcinoma. In one patient, overwhelming sepsis occurred during longterm chemotherapy, and the second patient died of a cerebrovascular accident 5 years after diagnosis. Both patients were clinically free of disease at the time of their death. Thus, the breast cancer-related mortality was 35% (6 of 17), and the disease-free and overall 5-year survival rate was 41% (7 of 17). The difference in survival for patients in Group B compared with patients in Group A was significant (p _
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onsiderable progress in the management of locally advanced carcinoma of the breast has occurred during the last decade, resulting in substantial improvements in local disease control and survival for a disease once considered to be uniformly and rapidly fatal. Patients
with tumors in this category generally have high local recurrence rates and dismal survival due to progression of micrometastases not controlled by local therapy alone. During the first half of this century, radical mastectomy predominated as the primary treatment m0dality. The poor results obtained with surgery alone when the carcinoma had ulcerated, was fixed to the chest wall, developed satellite nodules, or produced edema of the breast or massive axillary metastases prompted Haagensen and Stout [1] in 1943 to develop criteria of inoperability. Previous treatment reports from our institution in patients with inflammatory carcinoma revealed a local recurrence rate of 46% and only one 5-year survivor among 50 patients treated only with radiotherapy and/or surgery [2]. In the subsequent 25 years, radiotherapy dominated as the primary and often the only form of management. The results of treatment improved further as radiotherapeutic technology and dosimetry advanced, but only in terms of local disease control rates. Several investigators reported increasing rates of local disease control during the 1960s and 1970s, when larger doses of supervoltage irradiation were administered safely and also with the use of interstitial implants [3,4]. Median surviva! approximating 2 years and 5-year survival rates below 25% were common [5,6]. Although the combination of surgery and radiotherapy may increase local disease control rates, it does not appear to influence preexisting occult distant metastases nor influence overall survival rates [7]. During the decade of the 1980s, multimodal management of locally advanced carcinoma of the' breast with induction chemotherapy became firmly established as the first line of treatment. Induction chemotherapy produced dramatic initial response rates permitting effective local control by surgery, irradiation, or both, while also controlling distant micrometastases [813]. In a preliminary report, we compared the results of treatment of locally advanced and inflammatory breast carcinoma before and after the advent of induction chemotherapy [14]. Because of the paucity of data regarding long-term survival results, we sought to determine if the initial response to treatment in our group of patients translated into long-term survival. Thus, the purpose of this report is to provide an update of our experience with foUow-up ranging from 4 to 15 years.
From the Departmentsof Surgery, Washington UniversitySchoolof Medicine, Barnes Hospital,St. Louis, Missouri (MJL, DPA, WGK), and Ellis FischelState Cancer Center, Columbia,Missouri (AK). Requestsfor reprintsshouldbe addressedto MarvinJ. Lopez,MD, FACS, FRCS(C), 5102 Queeny Tower, Barnes Hospital Plaza, St. Louis, Missouri63110. Presentedat the 42nd Annual Meetingof the SouthwesternSurgical Congress,La Quinta, California,April 22-25, 1990.
PATIENTS AND M E T H O D S During the years 1975 to 1984, 879 patients with primary carcinoma of the breast were treated at the Ellis Fischel State Cancer Center in Columbia, Missouri. Advanced disease was found at the time of diagnosis in 125 patients (14%). Chosen for further study was a subgroup of 34 patients (4%) who presented with untreated, locally
Among 8 7 9 patients treated for breast cancer between 1975 and 1984, advanced disease was found in 125 ( 1 4 % ) . A subgroup of 34 ( 4 % ) presented with untreated locally advanced disease without demonstrable distant metastases at the time of diagnosis (stage l l I B = T 4 a b c d , NX-2,MO). During the first 5 years ( 1 9 7 5 through 1 9 7 9 ) , 17 patients were treated primarily with sequential radiotherapy and chemotherapy (Group A). From 1980 to 1984 (Group B), the management consisted of four courses of induction multi-drug chemotherapy followed primarily by mastectomy and additional chemotherapy. The mean follow-up for the most recent group (Group B) is 48 months. Follow-up was complete. While the local disease control rate was the same for both groups ( 7 6 % ) , the survival was remarkably different. Group A patients experienced a median survival of 15 months, and only one survived 5 years. In Group B, the median survival was 5 6 months with nine patients ( 5 3 % ) alive between 4 0 and 76 months, seven ( 4 1 % ) of whom are 5year survivors. While the overall mortality of patients with inflammatory breast cancer was greater in both groups when compared with the group with noninflammatory disease, the survival of patients in Group B was better than in Group A for both inflammatory and noninflammatory cancers (p < 0 . 0 1 ) . Estrogen receptor, nodal, and menopausal status did not influence survival. These data suggest that neoadjuvant chemotherapy improves survival for patients with stage IIIB breast carcinoma and delays the establishment or progression of distant metastases. Mastectomy is an important component in the treatment of this disease.
C
THE AMERICAN JOURNAL OF SURGERY VOLUME160 DECEMBER 1990 669
LOPEZ ET AL
advanced breast carcinoma without demonstrable distant metastases. Only patients with the most locally advanced tumors falling into the stage IIIB category (T4abod, NX2,MO) are included in this review to provide some uniformity in a notoriously heterogeneous group of carcinomas. This stage was defined in accordance with the 1988 Manual for Cancer Staging of the American Joint Committee on Cancer [15]. Follow-up was complete in all cases. The patient population, all rural white women, was treated during a 10-year period from 1975 to 1984. During the first 5 years of the study, half of the patients (n = 17) were treated without induction chemotherapy (GroUp A), In 1980, a protocol of induction chemotherapy was instituted and applied in the treatment of the remaining 17 patients (Group B). Characteristics of Groups A and B were comparable in terms of age, proportion of cases of inflammatory versus noninflammatory disease, and estrogen receptor, menopausal, and nodal status. RESULTS From 1975 to 1979, 17 women were treated (Table I, Group A). Their ages ranged from 32 to 89 years (mean: 61 years). Fifteen of these patients were initially treated with radiotherapy consisting of 6,000 Cgy of cobalt-60 delivered in 30 fractions. Simple mastectomy was performed as primary treatment in two patients. Multi-drug adjuvant chemotherapy consisting of cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU) was subsequently offered to all patients, but accepted only by 6 or 35% of the 17 patients initially treated with radiotherapy. The two patients who underwent simple mastectomy were treated with postoperative radiation. In this group, eight patients had clinical and histologic characteristics of inflammatory carcinoma, two of whom were estrogen receptor positive and six of whom had metastases to the axillary lymph nodes. Nine patients presented with other characteristics of locally advanced carcinoma of the breast but without signs of inflammatory carcinoma. In this subgroup, four patients were estrogen receptor positive and seven had lymph node metastases to the ipsilateral axilla. The overall local disease control rate in this group of 17 patients was 76% (13 of 17). In the remaining four patients, radiotherapy did not produce a complete response, and these four patients died with evidence of progressive chest wall disease. Clinical manifestations of disseminated disease developed in all but one patient, and the mean survival was 15 months. The only survivor, a patient with inflammatory breast carcinoma treated with rnastectomy and postoperative irradiation, is alive and clinically disease-free 9 years after diagnosis. Group B consisted of 17 women treated between 1980 and 1984 (Table I). Their mean age was also 61 years, and their ages ranged from 40 to 76. All patients in this group were initially given an average of 4.6 monthly cycles (ranging from 3 to 9) of chemotherapy consisting of the following: cyclophosphamide 100 mg/m 2 orally on days 1 to 14, doxorubicin 25 mg/m 2 intravenously on days 1 and 8 of the cycle, and 5-FU 500 mg/m 2 intravenously on days 1 and 8 (CAF). Two patients also received vincristine, two received methotrexate, and two received 670
THE AMERICAN JOURNAL OF SURGERY
prednisone. Twelve of the 17 patients treated with induction chemotherapy subsequently underwent mastectomy. Simple mastectomy was performed in eight patients, modified radical mastectomy in two patients, and radical mastectomy in two patients. Five patients refused mastectomy following chemotherapy; three of these patients consented to receive radiotherapy. The remaining two patients refused both radiotherapy and surgery and were continued on chemotherapy alone. The objective of surgery was to resect all gross disease; random samples of margins were histologically negative for carcinoma in all 12 patients. In Group B, seven patients had inflammatory carcinoma, six of whom had metastatic axillary nodes, and two were estrogen receptor positive. Ten patients presented with noninflammatory stage IIIB disease, 9 of whom had metastases to the axillary lymph nodes, and 5 were estrogen receptor positive. The overall local control rate, defined as the total clinical absence of chest wall disease, was 76% (13 of 17), the same rate as in Group A. However, the four patients from Group B in whom the primary tumor was not controlled had a relatively stable course in contrast to the rapid progression of local disease in the four Group A women whose tumor persisted locally. Of the 17 patients in Group B treated with induction chemotherapy, tumor size was reduced by more than 50% in 10 patients (58%). The tumor regressed, but by less than 50% from the original size, in an additional six patients. In one patient, local disease progressed during induction chemotherapy. The four failures of local control occurred in two of three patients who received radiotherapy after induction chemotherapy and in both patients who refused either surgery or radiotherapy. There were no local recurrences in 12 patients who underwent mastectomy. The median survival was 56 months, with nine patients (53%) alive and disease-free between 40 and 76 months, seven of whom are 5-year survivors. Two of the eight deaths were unrelated to breast carcinoma. In one patient, overwhelming sepsis occurred during longterm chemotherapy, and the second patient died of a cerebrovascular accident 5 years after diagnosis. Both patients were clinically free of disease at the time of their death. Thus, the breast cancer-related mortality was 35% (6 of 17), and the disease-free and overall 5-year survival rate was 41% (7 of 17). The difference in survival for patients in Group B compared with patients in Group A was significant (p _
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