R. B. Livingston

COMB (cyclophosphamide, oncovin, methyl-CCNU, and bleomycin): a four-drug combination in solid tumors.

One hundred eighty‐nine patients received a four‐drug combination consisting of cyclophosphamide, Oncovin (vincristine), methyl CCNU, and bleomycin (COMB), according to three different drug regimens, performed sequentially. Of the 189, 62 had a partial response (33%) including 11/33 with squamous lung cancer, 11/32 with squamous carcinoma of the head and neck, 13/15 with oat cell carcinoma of the lung, and 7/41 with malignant melanoma. The response rate for patients with squamous lung or head and neck cancer appeared to be higher at weekly bleomycin doses of 30 and 60 mg (15/33 = 45%), compared to a weekly bleomycin dose of 15 mg (7/32 = 25%). A median survival from treatment of 30 weeks was observed in oat cell carcinoma, which represents considerable prolongation over that expected from supportive care alone or single‐agent chemotherapy. Toxicity included: 1) myelosuppression, resulting in hospitalization for antibiotics in 20% of patients; 2) probable bleomycin lung damage in 4% of patients; and 3) dose‐limiting vincristine neuropathy in 11%. The combination of twice‐weekly vincristine and bleomycin for more than 6 weeks produced a disturbing “debilitation syndrome,” characterized by weakness, anorexia, weight loss, and apathy. The encouraging response rate suggests a future role for these drugs in combination, especially for vincristine and bleomycin, with other agents showing activity in squamous and oat cell carcinoma. Toxicity precludes recommendation of this combination, in the regimens tested, for broader Phase III studies.

Mitomycin-C and megestrol acetate in treatment of breast cancer refractory to hormonal and combination chemotherapy.

Fifty patients with breast cancer refractory to endocrine manipulation and/or combination chemotherapy were treated with mitomycin‐C 20 mg/m2 I.V. every 4–6 weeks and megestrol acetate 160 mg daily. Of 48 evaluable patients, 4% achieved complete remission (CR), 23% had partial remission (PR). Median duration of response for CR and PR was 7 months. Non‐responders had a median survival of 2 months. The difference in survival of responders (both CR and PR) and non‐responders was statistically significant at p<0.01 level. Attenuated doses of mitomycin‐C were administered at increasing intervals due to cumulative myelosuppressive toxicity.

Alternating noncross‐resistant combination chemotherapy and active nonspecific immunotherapy with BCG or MER‐BCG for advanced breast carcinoma

One hundred fifty‐six evaluable patients with metastatic breast cancer were treated with vincristine, Adriamycin and cyclophosphamide alternating at fixed intervals with 5‐FU and methotrexate. Immunotherapy with BCG or MER‐BCG was administered to all patients in two consecutive treatment programs. Overall objective response rate and complete response rate were 67% and 20%, respectively. These were not significantly different between the two immunotherapeutic groups. The median time to progression was sixteen‐and‐a‐half months from initiation of therapy. The median survival of all patients was 21 months and that of responders was 26 months. Response rates, time to progression, and survival showed no significant advantage over a recent historical control group treated with FAC‐BCG. Toxicity related to the gastrointestinal tract and bone marrow was considerably higher in this protocol than in the FAC combinations. MER at the dose, route, and schedule administered in this protocol caused excessive local and systemic toxic reactions. The alternate use of these noncross‐resistant combinations in advanced breast cancer is not superior to combination chemotherapy used in the traditional manner. Cancer 45:742‐749, 1980.

Chemotherapy for adenocarcinoma of the lung with 5-fluorouracil, cyclophosphamide, and CCNU (FCC)

Thirty‐one adult patients with adenocarcinoma of the lung were treated with FCC chemotherapy consisting of 5‐fluorouracil (5‐FU), cyclophosphamide, and CCNU every 4 weeks. Thirteen patients received 5‐FU orally (POF) at the dose of 400 mg/m2/day in 4 divided daily doses for 5 days, whereas 18 patients received 5‐FU at the dose of 800 mg/m2/day for 5 days as a continuous intravenous infusion (CIF). All patients received cyclophosphamide and CCNU orally at doses of 200 mg/m2/day for 4 days and 40 mg/m2/day for 2 days, respectively. The overall response was 22%. Response was greater in patients treated with FCC‐CIF (4/14 vs. 1/9; p = 0.6), in patients with limited disease (4/13 vs. 1/10; p = 0.5), and in patients with good performance status, (4/16 vs. 1/7). The overall median survival duration was 9 months. The patients who achieved tumor regression survived significantly longer than patients who had disease stabilization (median, 21 vs. 9 months; p = 0.01), and the latter survived significantly longer than patients who had progressive disease (median, 9 vs. 2.5 months; p = 0.003). There was no significant difference in survival duration in the two FCC‐treated groups. Pretreatment extent of disease and performance status did not influence the survival of patients. However, the FCC‐CIF‐treated group contained a greater number of patients with extensive disease and poor performance status. Further investigations are indicated to evaluate the efficacy of 5‐fluorouracil administered by continuous intravenous infusion in combination with cyclophosphamide and CCNU in bronchogenic carcinoma.

Phase i studies with baker's antifol (baf) (nsc 139105)

Phase I studies were conducted in 58 adult cancer patients with Bakers Antifol (BAF), a new active‐site directed inhibitor of dihydrofolate reductase. Dose escalation ranged from 10 to 250 mg/m2/day × 5 days and courses of treatment were repeated every 2‐3 weeks. Biologic effects were observed mostly at doses > 100 mg/m2/day × 5 days. The patients developed myelosuppression during 19% of the trials. Other types of toxicity were dermatitis in 12 to 30% and stomatitis in 7 to 38% of the trials. Toxicity was directly related to the impairment of the patients liver function. Two partial responses (in a patient with adenocarcinoma of the lung and a patient with transitional cell carcinoma of the bladder) occurred. BAF is an active new chemotherapeutic agent which deserves further clinical trials in patients with various malignancies.