H. Y. Yap

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.

Dihydroxyanthracenedione: A Promising New Drug in the Treatment of Metastatic Breast Cancer

Thirty-one patients who had metastatic breast cancer extensively pretreated with combination chemotherapy, including doxorubicin, were tested with dihydroxyanthracenedione, 3 to 4 mg/m2 body surface area daily for 5 consecutive days every 4 weeks. Of 27 evaluable patients, one achieved a complete response and five had partial responses. Furthermore, responses were seen in patients who were refractory to doxorubicin, indicating a lack of cross-resistance between doxorubicin and dihydroxyanthracenedione. Acute drug toxicity was insignificant except for severe granulocytopenia at the dose level of 4 mg/m2 . d. The median duration of remission had not been reached, but was more than 26 weeks, with four of the six responding patients still in remission at last follow-up. We believe that dihydroxyanthracenedione has significant activity against refractory metastatic breast cancer and further evaluation is warranted.

Adriamycin therapy by continuous intravenous infusion in patients with metastatic breast cancer

Patients with metastatic breast cancer previously treated with non‐Adriamycin containing chemotherapy were treated with Adriamcyin at a dose of 60 mg/m2 administered as a continuous infusion through a central venous catheter. The duration of Adriamycin infusion was escalated by 100% increments from 24–96 hours, but the majority of patients were maintained on 96‐hour infusions. Thirteen of 27 patients achieved objective response (1 CR, 12 PR), six improved, and eight failed to respond to Adriamycin. Administration of Adriamycin by infusion led to a decrease in the severity of nausea and vomiting, but had no effect on myelosuppression and alopecia secondary to Adriamycin. The cardiac toxicity of Adriamycin was reduced in patients who received maintenance therapy with 96‐hour infusions of Adriamycin.

Treatment for meningeal carcinomatosis in breast cancer.

Forty breast cancer patients with meningeal carcinomatosis were treated with a combined program of whole brain irradiation therapy with intrathecal and intraventricular methotrexate and citrovorum factor rescue. Responses were seen in 26 patients (65%); 13 patients (35%) failed to respond. The median survival time for the responding patients was six months, and for the nonresponders, one month. Factors affecting response and survival included pretreatment spinal fluid glucose, protein, and duration of CNS‐related symptomatology prior to onset of therapy. In contrast, pretreatment CSF tumor cell count, CEA and initial CNS functional status did not appear to have prognostic significance. The authors conclude that following intensive therapy there can be much improvement in the quality of life and disease‐free survival in breast cancer patients with meningeal carcinomatosis.

A comparative study of doxorubicin and epirubicin in patients with metastatic breast cancer

Seventy-seven patients with progressive metastatic breast cancer refractory to prior therapy participated in a prospective randomized trial designed to compare the efficacy and toxicity of doxorubicin and epirubicin administered as single agents. In arm 1, 60 mg/m2 of doxorubicin and, in arm 2, 90 mg/m2 of epirubicin were administered by 48-h continuous i.v. infusion every 3 weeks. In arm 3, 90 mg/m2 of epirubicin was administered by bolus every 3 weeks. Patients in the three groups had similar characteristics, except that in arm 3 more patients were premenopausal, had more extensive disease, and fewer patients had been exposed to doxorubicin. Objective remission rates were 29, 26, and 13%, respectively for the three arms. Median response durations ranged from 4–6 months. No significant differences occurred in response rate, remission duration, or survival among patients in the three arms. The incidence of gastrointestinal toxicity and alopecia was evenly distributed. Hematologic toxicity was more severe in arms 2 and 3, and there was a higher incidence of infectious complications in arms 2 and 3 compared to arm 1 (p=0.05). Two episodes of congestive heart failure occurred in arm 1, one in arm 2, and three in arm 3. Although the total cumulative anthracycline dosage was highest in the arm 2 group, they had the lowest incidence of cardiac toxicity. Epirubicin by bolus and doxorubicin administered by continuous infusion have similar potential for cardiac toxicity. Epirubicin administered by continuous infusion appears less cardiotoxic than doxorubicin by either method of administration or epirubicin given by bolus. Epirubicin appears equally active and less cardiotoxic than the parent compound doxorubicin in patients with metastatic breast cancer.

Management of breast cancer patients failing adjuvant chemotherapy with adriamycin‐containing regimens

Sixty‐two patients with breast cancer treated with Adriamycin‐containing adjuvant chemotherapy developed recurrent disease. Four patients refused to take any form of systemic therapy at the time of relapse. Fifty‐eight patients were managed with various treatment modalities, and of these 33 (57%) achieved on objective remission, 11 (19%) had stable disease and 14 patients (24%) did not respond to any form of therapy. Twenty‐four patients received more than one treatment modality. Thirty‐eight patients were treated with chemotherapy and 35 received endocrine therapy. Eight of 20 patients (40%) achieved objective remission upon retreatment with higher dose of 5‐fluorouracil, Adriamycin, and cyclophosphamide at time of relapse, and seven of 18 patients (38%) treated with other chemotherapeutic agents showed objective remission. Fourteen of 35 patients (40%) achieved objective remission with hormonal therapies. The median survival from first relapse was 15 months for all patients, and was 25.7 months for responding patients. Survival was significantly longer in asymptomatic patients compared with those who were symptomatic from recurrent disease.

Five‐day continuous‐infusion vinblastine in the treatment of breast cancer

One hundred six evaluable patients with metastatic breast cancer refractory to prior chemotherapy were treated with 5‐day intravenous infusions of vinblastine at 1.4 to 2.0 mg/m2/day, through silastic elastomer permanent central venous catheters. Thirty‐nine patients achieved objective responses; 5 were considered complete. The overall response rate of 37% was independent of prior exposure to intermittent intravenous vinca alkaloids or prior response to front‐line doxorubicin combination chemotherapy. Objective responses were documented in 48% of the patients who received daily doses above 1.7 mg/m2 and in 32% and 29% of those treated with 1.7 mg/m2 or less, respectively (P = 0.10). Myelosuppression was more severe in responders, who received higher average doses, (median average nadir, 850 granulocytes/mm3) than in nonresponders (median, 1300 granulocytes/mm3), but was always rapidly reversible. Infections related to neutropenia were uncommon. Catheter‐related toxicities occurred in 13 of 106 patients. Other toxicities were limited. These results confirm that vinblastine given as a continuous 5‐day infusion is one of the most effective agents in the treatment of metastatic breast cancer and suggest that its activity is dose‐dependent.

Chemotherapy-induced neutropenia and fever in patients with metastatic breast carcinoma receiving salvage chemotherapy†

Chemotherapy‐induced neutropenia and associated fever and infection are the most common complications of systemic chemotherapy. In this retrospective analysis, the authors evaluated the incidence of neutropenic fever, infection, and mortality in relation to the level of neutropenia, performance status, course number of chemotherapy, bone marrow metastasis, and age among patients with metastatic breast carcinoma receiving salvage chemotherapy.

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 chemoimmunotherapy for advanced breast cancer: a comparison of BCG and levamisole.

One hundred and fourteen evaluable patients with metastatic breast cancer were treated with a program consisting of 5‐FU, Adriamycin, cyclophosphamide (FAC) and nonspecific immunotherapy with Levamisole. The results of this treatment program were compared to those observed with FAC and Bacillus Calmette Guerin (BCG) and FAC chemotherapy alone, both groups treated prior to the study reported in this paper. The overall response rates and complete response rates for all three treatment regimens were identical. The duration of remission, survival of all patients and survival of responders was similar for both chemoimmunotherapy regimens, being superior to the FAC chemotherapy alone group. Immunotherapy with Levamisole was well tolerated and side‐effects were experienced by less than one‐fourth of the patients. Overall, Levamisole was better tolerated than BCG and was easier to administer than the latter drug. These results suggest that nonspecific immunotherapy with Levamisole might prolong remission and survival of patients with metastatic breast cancer. Since the results achieved with BCG and Levamisole appear similar, the therapeutic ratio favors the use of Levamisole. Cancer 43:1112–1122, 1979.