Eleanor D. Montague

Management of stage III primary breast cancer with primary chemotherapy, surgery, and radiation therapy

One hundred seventy‐four evaluable patients with noninflammatory Stage III (both operable and inoperable) breast cancer were treated with a combined modality strategy between 1974 and 1985. All patients received combination chemotherapy with 5‐fluorouracil, Adriamycin (doxorubicin), and cyclophosphamide (FAC) as their initial form of therapy. After three cycles of chemotherapy, local treatment in the form of a total mastectomy with axillary dissection, or radiotherapy, or both, was completed. Subsequently, adjuvant chemotherapy was continued. There were 48 patients with Stage IIIA, and 126 patients with Stage IIIB disease. A complete remission was achieved in 16.7% of the patients, and 70.7% achieved a partial remission after the initial three cycles of FAC. The complete response rate was higher for patients with Stage IIIA, than for patients with Stage IIIB disease. All but six of the 174 patients treated were rendered disease‐free after induction chemotherapy and local treatment. The median follow‐up of this group of patients is 59 months. The 5‐year disease‐free survival rates were 84% for patients with Stage IIIA, and 33% for patients with Stage IIIB disease. The 5‐year survival rate for, patients with Stage IIIA was 84%, and for patients with Stage IIIB 44%. At 10 years, 56% of patients with Stage IIIA and 26% of patients with Stage IIIB disease are projected to be alive. Younger patients, and those with estrogen receptor‐positive tumors, had a trend for better survival than older patients and those with estrogen receptor‐negative tumors. The quality of response to induction chemotherapy correlated prominently with prognosis, as did compliance with treatment. Twenty‐six patients (15.3%) had locoregional recurrence. This multidisciplinary approach to locally advanced breast cancer rendered most patients disease‐free and produced an excellent local control rate. Modifications of this treatment strategy may result in further improvement of survival rates.

Multimodal treatment of locoregionally advanced breast cancer

Fifty‐two patients with locally advanced primary breast cancer (T3, T4/N2, N3) without distant metastases were treated with three cycles of combination chemotherapy consisting of 5‐FU, Adriamycin and cyclophosphamide (FAC) and immunotherapy with Bacillus Calmette‐Guerin (BCG) followed by local therapy (simple mastectomy and/or radiotherapy to breast/chest wall and regional lymphatics) and adjuvant chemotherapy to complete two years of treatment. Forty‐nine of 52 (94%) patients were rendered free of clinically detectable disease. The median disease‐free interval was 24 months. At a median follow‐up time of 60 months, 40% of patients remained free of disease, off all therapy. Those patients who completed two years of therapy and started adjuvant chemotherapy promptly after local treatment had a 48% disease‐free survival at five years. Local recurrences were observed in 21% of patients. Distant metastases developed in 40% of patients. Despite good tolerance, treatment compliance was poor. The complete remission rate with this multimodal approach is high and long‐term disease‐free survival is achieved in a considerable number of patients.

Decreased cardiac toxicity of doxorubicin administered by continuous intravenous infusion in combination chemotherapy for metastatic breast carcinoma

Two hundred and seventy‐four consecutive patients with measurable metastatic breast cancer, without prior exposure to cytotoxic agents were treated with tamoxifen, 5‐fluorouracil, doxorubicin, and cyclophosphamide (FAC). The initial 133 patients received doxorubicin by bolus IV administration and for the next group of 141 patients doxorubicin was administered via a central venous catheter over a 48‐hour (79 patients) or 96‐hour (62 patients) continuous infusion schedule. Patients treated with bolus doxorubicin had this agent discontinued usually when 450 mg/m2 were reached; for patients in the infusion group treatment was continued until evidence of progressive disease or clinical or subclinial cardiac dysfunction developed. The complete remission rate was 21% the partial remission rate, 59%. There were no differences in response rate, response duration, or survival duration between groups of patients treated with doxorubicin by bolus, 48‐hour or 96‐hour infusion FAC. The incidence of moderate and severe nausea and vomiting was lower in the group of patients treated with infusion FAC as compared to bolus FAC (P < 0.001); however, the incidence of mucositis was higher in the infusion group than in the bolus group (P < 0.001). Doxorubicin administered by continuous infusion schedules was less cardiotoxic than when administered by bolus, as shown by a >75% decrease in the frequency of clinical congestive heart failure at cumulative dosages ≥ 450 mg/m2 (P = 0.004). Doxorubicin administered as a 48‐hour or 96‐hour continuous IV infusion is safer, and better tolerated than doxorubicin administered by bolus.

Conservation surgery and irradiation for the treatment of favorable breast cancer.

The results in 162 patients with clinically favorable breast cancer treated with conservation surgery and radiation therapy are presented. The surgical procedures were simple excision with and without positive microscopic margins, segmental mastectomy, and segmental mastectomy with axillary dissection. Details of the radiation techniques are described with an explanation of the modifications in technique depending on the prior surgical procedure. Excellent control of local and regional tumor (96%) gives support to the combined treatment without removing the breast. Cancer 43:1058–1061, 1979.

Management of inflammatory carcinoma of the breast. A combined modality approach

FROM MAY 1973 TO DECEMBER 1981, 63 PATIENTS with inflammatory carcinoma of the breast were treated with a doxorubicin-containing chemotherapy regimen (FAC). After a median of three cycles of FAC, 41 patients received primary therapy with irradiation; more recently, 21 had mastectomy as primary therapy. One patient relapsed following a treatment delay and did not receive local therapy. Fourteen of 21 patients who underwent mastectomy had subsequent consolidation therapy with irradiation.At median follow-up of 60 months, median relapse-free survival (RFS) and survival were 24 and 43 months, respectively. The initial site of recurrence was locoregional in eight patients (20%). In addition, two of seven uncensored patients (18%) who suffered initial recurrence in the contralateral breast remained disease-free at 28 and 55 months with further surgery. While no locoregional recurrences were seen in the 14 mastectomy patients who completed comprehensive irradiation, no RFS nor survival advantage was noted for either initial local therapy.Sixteen patients with dermal lymphatic carcinomatosis and 10 patients with negative skin biopsies had median RFS of 31 and 46 months, respectively (p = 0.45). Median RFS was 36 months in patients ≥50 years of age and 19 months in patients <50 (p = 0.05). Response to FAC was the most significant predictor of RFS and survival. Patients who achieved complete or partial remission (PR) with induction FAC as compared to patients who achieved <PR had median RFS of 31 vs. 19 months (p = 0.01) and median survivals of 60 vs. 27 months (p = 0.05), respectively. Categorization of patients according to clinical, mammographie, and pathologic criteria facilitated identification of potential long-term re-sponders. With combined modality approach to inflammatory carcinoma of the breast, we can expect an estimated 31% of patients to be relapse-free at 5 years after treatment.

Management of locoregional recurrent breast cancer

The influence of radiation and/or chemotherapy on locoregional tumor control and survival in patients treated for recurrent breast cancer after radical or modified radical mastectomy is retrospectively evaluated in 164 patients treated between 1972 and 1983 at the University of Texas M. D. Anderson Hospital. Treatment consisted of radiation alone in 57 patients, chemotherapy alone in 50 patients, and a combination of radiation and chemotherapy in 57 patients. Important differences in the composition of these three groups include a preponderance of postmenopausal women (44% vs. 32%) and more patients with four or more positive axillary nodes at the time of initial mastectomy (32% vs. 18%) in the radiotherapy group. Locoregional control of recurrent cancer was achieved in 65% of patients with radiotherapy compared to 46% of patients with chemotherapy (P = 0.049) and 67% with chemotherapy and radiotherapy. The addition of chemotherapy produced a trend toward improved disease‐free survival rates. The two prognostic factors affecting tumor control and survival in this study are the tumor burden of the recurrence and the histologic axillary node status at the time of the initial mastectomy.

Management of inflammatory carcinoma of breast with combined modality approach—an update

Thirty‐two patients with inflammatory breast cancer were treated with a combined modality approach consisting of combination chemotherapy with fluorouracil, doxorubicin hydrochloride, and cyclophosphamide, followed by radiation therapy. The disease‐free interval and survival of this group were compared with 32 patients with inflammatory breast cancer treated with irradiation without systemic therapy at our institution in the past. In the actuarial median follow‐up of 62 months (range: 42+ to 76+ months) of study, 11 patients in combined modality group and three patients in the irradiation group were free of disease. Overall median disease‐free interval was 22.8 months for the combined modality group and nine months for the irradiation group, and survival was 30.1 months and 18 months, respectively. The median disease‐free interval of patients <50 years of age was 19 months for the combined modality group and nine months for the irradiation group; median survival was 24 months for both subgroups. Forty percent of the patients under 50 years of age in the combined modality group and 7% in the irradiation group had recurrence of central nervous system disease. Of the patients ≥50 years of age, the median disease‐free interval was 32.1 months for the combined modality group and nine months for irradiation group; median survival was 42 months and 18 months, respectively. The combined modality approach has resulted in improved disease‐free interval of patients <50 years of age, but survival of this subgroup was not significantly improved possibly because of the high incidence of central nervous system disease recurrence. This treatment was effective in prolonging the disease‐free interval and survival of patients ≥50 years of age, with an estimated 45% of the patients surviving free of disease beyond 42 months.

Results of mastectomy and postoperative irradiation in the management of locoregionally advanced carcinoma of the breast.

Between 1955 and 1984, 376 patients with locoregionally advanced breast carcinoma were treated at The University of Texas M. D. Anderson Cancer Center with mastectomy and irradiation and without adjuvant chemotherapy. Patients with inflammatory carcinoma or synchronous bilateral primary tumors were excluded. There were 202 patients with Stage IIIA disease and 174 patients with Stage IIIB disease (AJC Staging--1983). In 124 patients the surgical management was confined to the breast only--total mastectomy (BR) and in 252 dissection of the axilla was performed--extended total, modified radical, or classic radical mastectomy (BR + AX). All patients had postoperative irradiation. The follow-up period ranged between 8 and 34 years. At 10 years, the actuarial disease-specific, relapse-free survival (DSRFS) rate for the entire group was 40%, and the actuarial locoregional control rate was 82%. For patients with Stage IIIA disease the DSRFS was 48% and locoregional control rate was 88%. For those with Stage IIIB disease, the figures were 30% and 74%, respectively. Most of the failures occurred within 5 years of the mastectomy and essentially all occurred within 10 years. When analyzed by type of surgery, both the locoregional control and DSRFS rates were improved by the axillary dissection, the difference being largely caused by fewer axillary node recurrences after dissection of both the breast and axilla than after removal of the breast alone. In the 252 patients in whom the axilla was assessed, the number of positive nodes was a powerful predictor of both locoregional control and survival. The DSRFS rates at 10 years for patients with 0, 1-3, and greater than or equal to 4 positive nodes were 63%, 48%, and 30%, respectively. The actuarial locoregional control rates at 10 years exceeded 95% for patients with 0-3 positive nodes and 75% for those with greater than or equal to 4 nodes. These results show that locoregionally advanced breast cancer is not a uniformly fatal disease when treated without chemotherapy and provide a baseline upon which to assess the value of adjuvant systemic therapy for this stage of disease.

TREATMENT OF LOCOREGIONALLY ADVANCED BREAST CANCER WITH SURGERY, RADIOTHERAPY, AND COMBINATION CHEMOIMMUNOTHERAPY

Fifty-two patients with locally advanced primary breast cancer (T3, T4, N2, N3) but no evidence of distant metastases were treated with three cycles of combination chemotherapy. The regimen consisted of 5-fluorouracil, Adriamycin, cyclophosphamide, and Bacillus Calmette-Guerin (FAC-BCG), followed by local therapy (simple mastectomy and/or radiotherapy to the breast/chest wall and the regional lymphatic system) and adjuvant chemotherapy for two full years. The results were compared with those in an historical control group of 52 patients matched for initial stage of disease who were treated by a simple mastectomy and postoperative radiotherapy only. Forty-nine (94%) of 52 FAC-treated patients and 48 (92%) of the control patients became free of clinically detectable disease. At the median follow-up time of 56 months, 37.5% of the FAC-treated patients and 19.5% of the control patients had remained free of disease. FAC-treated patients who completed 2 years of therapy and in whom adjuvant chemotherapy was started promptly after local treatment had a 48% disease-free survival rate of 4 years. In those in whom the initial manifestation was supraclavicular involvement, the estimated 5-year disease-free survival rate was 42% for patients treated with FAC and 9% for control patients. There were local recurrences in 25% of FAC-treated patients and 23% of control patients (not significant). Distant metastases developed in 50% of FAC-treated patients and 77% of control patients (p less than 0.01). The median disease-free interval was 25 months in the FAC-treated group and 11 months in the control group (p = 0.025). The greatest improvement in prognosis was in patients with supraclavicular involvement; the median disease-free survival was 26 months in FAC-treated patients and 6 months in the control group (p = 0.007). This multimodal approach effectively renders the majority of patients with locoregionally advanced breast cancer free of disease and prolongs the disease-free survival period.

Combined modality approach in breast cancer with isolated or multiple metastases

One hundred thirty-six patients with isolated recurrence of breast cancer received regional therapy (surgery and/or irradiation) followed by combination chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide (FAC). The disease-free survival of the group receiving FAC was compared to that of a historical control group treated with only regional therapy. The median disease-free interval between the first and second recurrence for the control group was 9 months and for the patients receiving FAC, 38 months (p less than 0.01). The median survivals from first recurrence for the control and the FAC groups were 40 months and 60 months, respectively (p less than 0.02). In addition, 20 selected patients with multiple sites of metastasis or bulky isolated recurrence were initially treated with FAC chemotherapy; following complete or partial response with chemotherapy, these patients had regional therapy at the known sites of metastases. At a median follow-up time of 54 months, 9/20 patients (45%) have remained in complete remission. Combined modality approach significantly prolongs the disease-free survival of patients with isolated recurrences of breast cancer, and in selected patients with multiple metastases, this approach results in extended complete remissions.