Adjuvant chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide, with or without Bacillus Calmette-Guerin and with or without irradiation in operable breast cancer. A prospective randomized trial.

Between May 1977 and April 1980, 238 patients with operable breast cancer were treated with adjuvant fluorouracil, doxorubicin, and cyclophosphamide (FAC) chemotherapy. All patients were randomized to receive FAC alone or FAC with nonspecific immunotherapy with Bacillus Calmette-Guerin (BCG) vaccine. A randomization for routine postoperative irradiation was included in the study in May 1978. At the median follow-up of 33 months, 53 patients had developed recurrent disease. Up to the present time, there have been no significant differences in the disease-free survival of patients treated with FAC alone from those treated with FAC + BCG (P = 0.21). The disease-free survival for patients treated with and without routine postoperative irradiation was similar (P = 0.99). Disease-free survival of premenopausal and postmenopausal women was similar. The overall estimate of disease-free survival was 72% at 3 years.

Bisantrene, an active new drug in the treatment of metastatic breast cancer.

Forty-four patients with metastatic breast cancer who had previously received extensive conventional systemic therapy, including combination chemotherapy with doxorubicin, were treated with Bisantrene, a new anthracene derivative. The dose schedule was 250 to 300 mg/sq m body surface administered as a 1- to 2-hr i.v. infusion. Of 40 evaluable patients, there were nine partial responses, and 18 patients had stable disease. Responses were seen in all major sites of organ involvement with a median time to progression of 28 weeks. Moreover, responses were seen among patients who had either failed to respond or had demonstrated refractoriness to prior therapy with doxorubicin, suggesting an apparent lack of cross-resistance between doxorubicin and Bisantrene. Except for myelosuppression and one incidence of acute anaphylactoid reaction, Bisantrene was generally well tolerated by most patients. We believe that Bisantrene may ultimately have a major role in the effective treatment of metastatic breast cancer, and further clinical trials are warranted.

Phase II clinical evaluation of AZQ in metastatic breast cancer.

Thirty-three patients with metastatic breast cancer who have failed prior combination chemotherapy including adriamycin, cyclophosphamide, 5-fluorouracil and methotrexate, were treated with AZQ given on a 5-day I.V. schedule repeated every 4 weeks. The starting doses were 6 or 8 mg/m2/day for poor- and good-risk patients, respectively. There were two partial responses among 29 evaluable patients. Both had soft tissue and/or lymph node involvement. Six patients had stable disease. Myelosuppression, predominantly thrombocytopenia, was dose-limiting. Other toxicities were mild, including nausea, vomiting, anorexia, diarrhea, stomatitis, and malaise. Our results indicate that AZQ given on the 5-day schedule is unlikely to be effective in the treatment of refractory breast cancer.

Combination chemotherapy with continuous infusion vinblastine and peptichemio for patients with advanced metastatic breast cancer.

Forty patients with metastatic breast cancer were treated with a combination of continuous 5-day infusion vinblastine and peptichemio. All patients had received prior therapy with 5-fluorouracil, adriamycin, cyclophosphamide and methotrexate. Vinblastine was given at a dose of 1.2 mg/m2/day for 5 days. Following completion of the 5-day infusion vinblastine, peptichemio was given as a rapid I.V. injection at a dose of 60 mg/m2. Ten partial responses (30%) were observed among the 33 evaluable patients with a median time to treatment failure of 6 months. Myelosuppression, predominantly granulocytopenia, was the major toxicity resulting from this combination. The response rate of this combination is not better than that observed with continuous 5-day infusion vinblastine alone.

Potential cardiotoxicity with mitoxantrone.

Mitoxantrone is a promising new agent developed in an attempt to find drugs with a broad spectrum of antitumor activity and devoid of cardiotoxicity. In a phase II clinical trial for refractory metastatic breast cancer, we observed congestive heart failure in four of 31 high-risk patients either during or after treatment with this drug. This report calls attention to that observation, and recommendation is made that further evaluation of this agent include careful cardiac monitoring.

Peptichemio versus melphalan (L-PAM) in advanced breast cancer.

Peptichemio is a polypeptide complex of L-phenylalanine mustard. Because of structural similarities between melphalan (L-PAM) and Peptichemio a prospective randomized study was done to compare the therapeutic efficacy of these two agents. After failing various combinations of doxorubicin, cyclophosphamide, fluorouracil, methotrexate, and vincristine patients with advanced breast cancer were randomized to receive either Peptichemio or L-PAM. Peptichemio was administered at 75-100 mg/m2 and L-PAM at 30-40 mg/m2 IV q 3-4 week interval. Of 56 evaluable patients, 28 received peptichemio and 28 received L-PAM. There were no objective responses in the L-PAM group, and disease stabilized in four patients (14%). The median duration of stable disease was three months (range, 3-4 months). In the peptichemio group seven patients (25%) achieved a partial remission, one patient (3%) achieved less than partial remission and three patients (11%) had stable disease. The median duration of response was six months (range, 5-7+ months) for responding patients and three months (range, 2-5 months) for stable disease. The major toxicity of both drugs was myelosuppression which was cumulative. In conclusion, peptichemio is an active agent in advanced breast cancer, but L-PAM is ineffective in previously treated patients with metastatic breast cancer.

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.

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.

Combination chemoimmunotherapy with FAC-BCG for metastatic breast cancer: the impact of CMF maintenance chemotherapy.

In an attempt to prolong the durations of remission and survival of patients with advanced breast cancer treated with the FAC-BCG protocol, we modified the CMF maintenance combination by increasing the dose of all three drugs and administering them intravenously. Eighty-five evaluable patients treated with this new regimen were compared with a recent historical control group of 105 evaluable patients treated with FAC-BCG and a lower-dose, oral CMF maintenance program. The overall (70% and 76%) and complete (16% and 19%) response rates were identical in these two groups. The median times to progression for all patients entered were similar too (13 months for both groups.). The durations of response were 17 months (PO-CMF) and 14 months (IV-CMF), not significantly different (P = .16). The durations of survival of the two treated groups were also very similar. After the administration of intensive FAC induction therapy, a high-dose, intravenous CMF maintenance program appears no better than a low-dose oral regimen. Other drug combinations consisting entirely of drugs not used in the induction regimen might be better choices for maintenance treatment