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Ninety-one patients with advanced breast cancer failing adriamycin (ADR)-containing combination chemotherapy were treated with a combination of mitomycin C (MMC) and megestrol acetate. Congestive heart failure (CHF) occurred in 14 (15.3%) of 91 MMC-treated patients compared to three (3.4%) of 89 patients treated with similar ADR-containing combination chemotherapy without MMC (P = 0.01). The median time from the last dose of ADR to evidence of CHF was 8.5 months for the MMC group compared to 1.5 months for the other group. A significantly higher incidence of late onset of CHF implicates MMC as a possible cardiotoxic agent.

Moderate doses of methotrexate and L-asparaginase were added to standard doses fo 5-fluorouracil, Adriamycin, and cyclophosphamide in an attempt to improve the overall response rate and survival following chemotherapy. In addition, nonspecific immunotherapy with either Corynebacterium parvum or Pseudomonas vaccine was integrated into this prospective randomized clinical trial. The overall toxicity (degree of granulocytopenia and thrombocytopenia, length of myelosuppression, and incidence of myelosuppression-related infection and infectious deaths) increased considerably and led to the termination of patient accrual. The incidence of stomatitis and diarrhea was also increased with the addition of methotrexate and L-asparaginase, and apparently was potentiated by the addition of Pseudomonas vaccine to this five-drug combination.

A phase II evaluation of anguidine was carried out in 30 patients with advanced refractory breast cancer. A dose of 5.0 mg/m2 daily for 5 days was explored. The main toxic effects were nausea and vomiting, fever and chills, hypotension, skin erythema, somnolence, confusion, and lethargy. Myelosuppression was minimal. Among these extensively pretreated patients, there was one partial responder and one additional patient who showed improvement (less than a partial response); both responses occurred in soft tissue sites.

Thirty-two patients with metastatic breast cancer refractory to chemotherapy with combinations of cyclophosphamide, methotrexate, 5-FU, vincristine, and prednisone were treated with doxorubicin, mitolactol (dibromodulcitol), and mitomycin C. Two complete and 12 partial remissions were observed for a response rate of 435. When only those patients who were considered evaluable were included (the 26 patients who had received more than one course of therapy), the response rate was 53%. Hematologic toxicity was moderate-to-severe. Responses were seen in visceral, osseous, and soft tissue tumor sites. The median time to the development of disease progression was 30 weeks for responding patients. The median survival of responders has not yet been reached at 48 weeks.

The feasibility of high-dose AMSA followed by autologous bone marrow rescue was studied in seven patients with solid tumors. They received a total of 12 courses of treatment. Total doses ranged from 600 to 1000 mg/m2/course. Major toxic effects were myelosuppression, fever of unknown origin, and stomatitis. One patient with malignant melanoma had stable disease lasting 2 months; the other six had progressive disease.

DTIC was one of the first of several new agents evaluated by the Southwest Oncology Group (SWOG) and the M.D. Anderson Hospital and Tumor Institute (MDAH) in the therapy of adult patients with metastatic sarcomas. It yielded an overall response rate of 17%. This is similar to that seen in a review of 138 patients who represent the total number reported in either published or unpublished data. The subsequent addition of DTIC to adriamycin in several studies carried out at the MDAH and in the SWOG has increased the complete and partial remission rate over that seen with adriamycin alone, and more importantly has increased remission duration and survival. DTIC is currently used in combination with adriamycin in the first-line therapy of patients with metastatic sarcomas and should be considered for patients who have relapsed on primary therapy not including DTIC.

Nineteen patients resistant to an adriamycin-containing regimen were treated with 4 days of amphotericin B and the same adriamycin-containing chemotherapy regimen that had been given without amphotericin B. Of the 14 evaluable patients (11 with breast carcinoma and three with sarcoma), one patient with breast carcinoma achieved a partial remission and a second patient with breast carcinoma remained stable. All other patients developed progressive disease. Both hematologic and nonhematologic toxicity were significantly increased when amphotericin B was added to chemotherapy.

Forty-two patients with metastatic breast carcinoma previously treated with a combination of cyclophosphamide, methotrexate, and 5-FU, with or without vincristine or prednisone, were treated at relapse with a sequential combination of doxorubicin and vinblastine given by continuous infusion. Two patients achieved complete remission and 16 achieved partial remission for a total response rate of 43%. The median time to progression for responders and patients with stable disease was 10 and 4 months, respectively. Neutropenia was the major toxic effect but did not lead to any fatality.

In an attempt to improve the therapeutic index of vinblastine by maintaining a prolonged, constant plasma level, it was given as a continuous 5-day infusion at 1.4-2.0 mg/m2/day. Among the 30 evaluable patients with advanced refractory breast cancer who had been extensively treated previously, there were one complete and 11 partial responders, with an overall response rate of 40%. Six of the 12 patients who had previously received a conventional dose schedule of vinca alkaloids responded, including two who had progressed with intermittent bolus iv injections of vinblastine. Responses were seen in all organ sites of involvement, with durations of 2-8+ months (median, 6). Myelosuppression was mild to moderate at doses of between 1.4 and 1.8 mg/m2/day but became severe at 2 mg/m2, with leukopenia (wbcs, < 2000/mm3) and granulocytopenia (absolute granulocytes, < 1000/mm3) occurring in 75% of administered courses. Other toxic effects were infrequent and acceptable. Our results suggest that vinblastine given as a continuous 5-day infusion is highly effective in the treatment of patients with advanced metastatic breast cancer, including a few whose disease was felt to be resistant to a conventional dose schedule of vinca alkaloids.

Twenty-six patients with metastatic breast cancer received cis-dichlorodiammineplatinum(II) either as a single dose of 100 mg/m2 iv every 3--4 weeks or as a continuous 5-day infusion of 20 mg/m2/day at 4-week intervals. Fourteen patients were treated with the single-dose schedule and 12 patients were treated with the continuous 5-day infusion. No significant response was observed with either dose schedule. Aside from a reduction in the frequency and severity of gastrointestinal toxicity with the continuous 5-day infusion, no real difference was seen with regard to renal and hematologic toxicity with either dose schedule.

A phase II study of 4'-(9-acridinylamino)methanesulfon-m-anisidide (AMSA) was carried out in previously treated patients with metastatic breast cancer. Four of 26 evaluable patients achieved partial responses and four showed minor responses. The maximum tolerated dose of AMSA was 30 mg/m2/day x 3 days and the dose-limiting toxic effect was myelosuppression. Two of the AMSA responders had not responded to initial therapy with an Adriamycin-containing regimen, indicating a lack of cross-resistance between these two DNA binders.

A combination of 5-fluorouracil (5-FU), adriamycin, and cyclophosphamide (FAC) was compared to a combination of 5-FU, adriamycin, and ifosfamide (FAI) in the treatment of metastatic breast cancer. All patients in the FAC and FAI groups also received nonspecific immunotherapy with bacillus Calmette-Guérin (BCG) and levamisole. Of 117 evaluable FAC patients, 19 (16%) achieved complete remission and 66 (56%) achieved partial remission. In the FAI group, eight of 49 (16%) evaluable patients achieved complete remission and 24 (50%) achieved partial remission. The response rates, durations of remission, and survival were similar in both groups. The combination of two immunotherapeutic agents (BCG and levamisole) did not have an additive effect since their results were similar to our previous experience with FAC-BCG and FAC-levamisole. In the FAI group, 25% of the patients had hematuria, while none of the patients in the FAC group had urinary complications. Nausea and vomiting were more severe in FAI-treated patients and some patients required iv fluids to correct dehydration. Ifosfamide in combination with 5-FU and adriamycin was more toxic than and not superior to cyclophosphamide.

One hundred and fourteen evaluable patients with measurable metastatic breast cancer were treated with a combination chemoimmunotherapy program (5-fluorouracil, adriamycin, and cyclophosphamide [FAC-levamisole [LSM]). An additional 117 patients with similar characteristics were treated with the same program with the addition of bacillus Calmette-Guérin (BCG) by scarification (FAC-BCG-LMS). The results were compared to those observed in 44 evaluable patients treated with FAC chemotherapy alone. Overall remission rates were identical in the three studies (72%, 73%, and 72%). The median duration of remission was 9 months for FAC, 13 months for FAC-LMS (P = 0.07), and 14 months for FAC-BCG-LMS (P = 0.05). The median duration of survival was 17 months for FAC and 28.6 months for FAC-LMS (P = 0.01). Although the median survival for the FAC-BCG-LMS group has not been reached, it is significantly superior to FAC alone (P = 0.009). These three sequential studies suggest that the addition of nonspecific immunotherapy with LMS or the combination of BCG and LMS prolongs the duration of remission and survival of responding patients treated with chemotherapy. Combination immunotherapy with BCG and LMS did not seem superior to LMS alone in this study.

Fifty-three patients with metastatic breast carcinoma were randomized to treatment with hexamethylmelamine (HMM) as a single agent versus a three-drug reimen of HMM, vincristine, and mitomycin C (HOM). All patients had received prior treatment with 5-fluorouracil, Adriamycin, and cyclophosphamide with or without methotrexate. HMM alone was used in a dose of 300 mg/m2/day x 14 days every 21 days. In the HOM regimen, the HMM dose was 200 mg/m2/day x 21 days, the vincristine dose was 1.5 mg on Days 1, 8, and 15, and the mitomycin C dose was 12 mg/m2 once every 6 weeks. No objective responses were observed with HMM in 15 evaluable patients. The HOM regimen resulted in five partial responses among the 27 evaluable patients. Gastrointestinal toxicity was the limiting toxicity of HMM, and thrombocytopenia was the major toxicity of the HOM regimen.

Twenty-nine patients with metastatic breast cancer were treated with methyl-GAG at an initial starting dose of 500 mg/m2 iv weekly and then escalated by 50 mg/m2/week to tolerance. There were two partial responders among the 26 evaluable patients. Gastrointestinal and cutaneous reactions were the limiting toxic effects of methyl-GAG. Myelosuppression was mild and infrequent.

Thirty-nine patients with 40 refractory malignant effusions (26 pleural and 14 peritoneal) were treated locally with a nonviable mycobacterial vaccine. The vaccine was administered into the effusion and consisted of BCG cell wall skeleton and trehalose dimycolate attached to oil microdroplets. A dose range of 150--3000 microgram was tested. The overall response rate was 44.0% (complete response [CR] plus partial response [PR]) and was not clearly dose-related. The response rates for each site were 13.6% (CR) and 31.8% (PR) for pleural effusions and 33.3% (CR) and 8.3% (PR) for peritoneal effusions. Toxic effects consisted of fever (40%), serosal pain (37.5%), and increased effusion (27.5%) and were not clearly dose-related. Gastrointestinal toxic effects were seen in 50% of patients treated for peritoneal effusions. Response correlated with prior exposure to BCG vaccine or tuberculosis, and with a febrile response to vaccine administration. This vaccine has a therapeutic effect on both pleural and peritoneal effusions.

9,10-Anthracenedicarboxyaldehyde[bis(4,5-dihydro-1H-imidazol-2-y1)-hydrazone ]dihydrochloride (bisantrene) is one of a series of anthracenedicarboxyaldehyde compounds that has significant antitumor activity similar to that of doxorubicin in experimental mouse tumor systems. A phase I clinical study was conducted using a weekly x 3 schedule. Twenty-six patients with a wide variety of advanced malignant solid tumors received a total of 39 courses of the drug at doses ranging from 40 to 180 mg/m2/week x 3. Leukopenia was the dose-limiting toxic effect. Other toxic effects included malaise, which was observed in 49% of the courses, nausea and vomiting in 36%, fever in 21%, and phlebitis in 21%. No responses were observed in this study. For phase II studies, using this schedule, a starting dose of 150 mg/m2/week x 3 repeated every 4-5 weeks is recommended. In patients who have received minimal or no therapy, the starting dose should be 180 mg/m2.

High-dose infusions of methotrexate with citrovorum factor rescue were evaluated in 27 patients with advanced recurrent breast cancer who had previously been treated with various Adriamycin-containing regimens. Eight of 27 patients (29%) achieved objective tumor regression with a median duration of response of 26 weeks. Nineteen patients had previously received standard doses of methotrexate (less than 50 mg/m2/dose), while eight patients had had no prior exposure to methotrexate. The response rates observed in these two groups of patients were similar. Except for two drug-related deaths, toxic effects were acceptable. Myelosuppression was mild, transient, and noncumulative. Gastrointestinal toxic effects did not appear to be dose-related and were mild in most instances. Central nervous system dysfunction with lethargy, fatigability, confusion, and disorientation was the most significant toxic effect of this high-dose methotrexate therapy and was observed in six (22%) of the patients. In two patients treatment with this program was discontinued because of the development of renal dysfunction. High-dose methotrexate with citrovorum factor rescue appears to be an effective regimen in patients with advanced refractory breast cancer. However, in view of the enormous cost necessitated by this treatment approach, we do not feel further studies would be worthwhile.

Sixty patients with metastatic breast cancer refractory to prior doxorubicin combinations were randomized by performance status, dominant disease site, and number of involved organ sites to receive vindesine either as a bolus injection of 3-4 mg/m2 iv every 10-14 days or as a continuous 5-day infusion of 1-1.2 mg/m2/day every 21 days. There were two patients with partial responses (7%) and six with stable disease among the 26 evaluable patients who received bolus injections. Of the 25 evaluable patients who received continuous infusions, seven achieved a partial response (28%) and 11 had stable disease (0.001 less than P less than 0.005). Thirteen patients, after failing to respond to bolus vindesine, were given continuous infusions. Of these, 11 were evaluable and four had partial response (36%). Responses were seen in all organ sites of involvement, with response duration ranging from 2 to 9+ months. Side effects included nausea, vomiting, stomatitis, constipation, neuropathy, fever, and myelosuppression. Except for myelosuppression, which was more evident with the continuous infusion schedule, no significant difference was seen in the frequency of side effects encountered with the two schedules. These results confirmed that there is an improved therapeutic index for vindesine when it is given as a continuous 5-day infusion.

The combination of sequential L-asparaginase and methotrexate (MTX) was evaluated in 33 patients with advanced refractory breast cancer. There were nine partial responses and one complete response, giving an overall response rate of 30% and a median duration of response of 8 months. Five of 17 patients (28%) who had received prior MTX at doses of less than 50 mg/m2 responded. Toxicity was acceptable. Moderate-to-severe stomatitis occurred in most patients and was the dose-limiting factor. Myelosuppression was minimal until the dose of MTX was escalated to greater than or equal to 180 mg/m2. The maximum tolerated dose of MTX was 280 mg/m2 and the median toxic dose was 220 mg/m2. These data indicate a selective "rescue" from MTX damage to normal target tissue by L-asparaginase. The antitumor effect observed even in patients who had been previously exposed to conventional doses of MTX suggests a possible improved therapeutic index of MTX given sequentially with L-asparaginase in this combination.