Barth Hoogstraten

Dose response evaluation of adriamycin in human neoplasia.

Because patients treated with 60–90 mg/m2 every three to four weeks reach cardiotoxic doses of 550 mg/m2 within 36 weeks, prolonged treatment with Adriamycin is limited. The purpose of this study was to determine whether lower doses could be given over longer periods without loss of efficacy. Good risk patients treated with 75, 60, or 45 mg/m2 had remission rates of 25, 27, and 19%; poor risk patients treated with 50 and 25 mg/m2 had remission rates of 16 and 12% respectively. Although a dose response was identified, there were no statistically significant differences in remission rates, durations of remission, or toxicities in the dose schedules studied. Irreversible congestive heart failure occurred in five patients with cumulative doses of 240–390 mg/m2. Unless rapid remission induction is urgent, we recommend 60 mg/m2 X four doses and measurement of myocardial function if treatment is to continue.

Combination chemotherapy and adriamycin in patients with advanced breast cancer. A Southwest Oncology Group study

In January, 1972, the Southwest Oncology Group initiated two randomized studies for patients with advanced breast cancer. The study for patients with prior chemotherapy showed a 33% response rate with adriamycin. The study for patients without previous chemotherapy consisted of three treatment regimens: a weekly repeated combination of cyclophosphamide, methotrexate, 5‐flu‐orouracil, vincristine, and prednisone; these same five drugs given in courses of 5 days repeated every 4 weeks; and adriamycin as a single agent every 3 weeks. For the 283 evaluable patients, the response rates were: weekly combination 63/106 (59%); intermittent combination 39/98 (40%); and adriamycin 31/79 (39%). The median duration of response was 8 months for weekly combination, 10 months for intermittent therapy and only 4 months for adriamycin. Leukopenia was the dose‐limiting toxicity with all three regimens. The weekly combination is the most effective therapy for patients with advanced disease. Extensive trials of combinations that include adriamycin are underway.

Phase II evaluation of bleomycin. A Southwest Oncology Group study

Bleomycin given intravenously (i.v.) or intramuscularly (i.m.) in twice‐weekly doses of 10 mg/m2 was evaluated for efficacy and toxicity in 382 patients. Responses were observed in 11/27 Hodgkins diseases, 10/30 lymphomas, 9/22 squamous cell cancers of ectodermal origin, 12/26 germinal cancers, and 3/8 renal adenocarcinomas. The i.m. route is less, likely to cause pulmonary toxicity or hypotension than the i.v. route. Advanced age and total doses exceeding 200 mg were Associated with a higher risk of lung toxicity. All responders had shown at least improvement upon receiving 200 mg; higher total doses should be used only in responding patients.

Combination chemotherapy (CMFVP) versus L-phenylalanine mustard (L-PAM) for operable breast cancer with positive axillary nodes. A southwest oncology group study

The Southwest Oncology Group in a prospective randomized study compared one year of adjuvant combination chemotherapy with continuous CMFVP to two years of intermittent L‐PAM in women with operable breast cancer with histologically positive axillary lymph nodes. In fully evaluable patients with a 42‐month median and 30‐month minimum follow‐up, treatment failures have occurred in 26% of 145 receiving CMFVP and 47% of 167 women given L‐PAM (P = 0.002). Disease‐free survival times were significantly longer with CMFVP than with L‐PAM in the following subgroups: premenopausal women (P = 0.002), postmenopausal women (P = 0.002), women with 1–3 involved axillary nodes (P = 0.003), and women with four or more involved axillary nodes (P = 0.002). CMFVP was effective in pre‐ and postmenopausal women. There is a significant difference in survival in favor of CMFVP compared to L‐PAM (P = 0.005). The life table estimates of survival at 42 months are 86% for women on the CMFVP treatment arm and 73% for women on the L‐PAM treatment arm. There was no correlation between the interval from mastectomy to onset of chemotherapy (between one and six weeks) and recurrence rates. Acute toxicity with both treatment arms was moderate and reversible. These results show that continuous CMFVP is superior to intermittent L‐PAM in decreasing recurrences and increasing survival in both pre‐ and postmenopausal women with operable breast cancer with histologically involved axillary nodes.

Combination chemotherapy for disseminated malignant melanoma

BCNU, hydroxyurea, and imidazole carboxamide (DTIC) were administered to 89 patients with disseminated malignant melanoma. A response rate of 27% was observed. The addition of vincristine in another 89 patients did not significantly improve the response rate (30%). This includes patients who died during or after one course of therapy (<28 days). If the early deaths are not considered, the over‐all response rate was 38%. The best responses occurred in patients with skin, lung, and/or lymph node involvement. Liver and brain involvement heralded poor responses. This response rate appeared to be independent of age, sex, or previous therapy. Moderate and severe toxicity, predominantly nausea and vomiting, was noted in most patients. The median survival for all evaluable patients was 17 months, and was independent of the regimen used.

5‐azacytidine in acute leukemia

101 patients with acute leukemia in relapse were treated with 5‐azacytidine according to three schedules: Regimen A—300 mg/m2(day divided intravenously at 8 hour intervals for 5 days; Regimen B—750 mg/m2 as a single iv pulse dose administered at 2 to 3 weeks intervals; and Regimen C—300 mg/m2/day by continuous infusion daily for 5 days. Twelve patients achieved a complete remission (CR) and six achieved a partial remission (PR) for an overall 18% response rate. Of 78 patients receiving an adequate trial the response rate was 23%. An average of 1.5 courses and a median of 5 weeks were necessary to achieve a response. The median duration of CR patients was 21 weeks and for PR patients it was 5 weeks. Response rates were 24% for Regimen A, 0 for Regimen B, and 1 of 8 for Regimen C. The CR rate for AML and AMML was 13%. Two of eight AMOL patients achieved a CR. Only 2 of 23 ALL patients responded, one of whom achieved a CR. Toxicity included moderate to severe nausea and vomiting, diarrhea, stomatitis, skin rash, and prolonged myelosuppression. 5‐azacytidine has significant activity in the acute nonlymphoblastic leukemias. Cancer 42:2111–2114, 1978.

Superiority of adriamycin over oral nitrosoureas in patients with advanced breast carcinoma. A southwest cancer chemotherapy study group study

In a continuing search for agents effective in advanced breast cancer, nonrandomized studies by the Southwest Cancer Chemotherapy Study Group have shown a 29% response rate with BCNU, a 19% response rate with CCNU, and a 36% response rate with adriamycin. Following these leads, a randomized Phase III study has compared adriamycin (60–75 mg/m2 intravenously every 3 weeks) with the oral nitrosoureas, CCNU (100–130 mg/m2 orally every 6 weeks) and methyl CCNU (125–150 mg/m2 orally every 6 weeks) in patients with advanced breast cancer, all of whom had already failed in at least one trial with conventional chemotherapeutic agents. The patients age, menopausal status, sites of metastatic involvement, and extent of prior therapy were nearly identical in the three treatment groups. Ten inevaluable patients died within the first 2 weeks from tumor. For the remaining 100 patients, the response rate was: adriamycin 15/40 (38%); CCNU 4/20 (14%); and methyl CCNU 1/31 (3%). The median durations of response for adriamycin, CCNU, and methyl CCNU were 7, 3, and 1 1/2 months respectively. Patients receiving adriamycin had significantly superior survival from die start of chemotherapy, and the duration of survival of adriamycin responders (12+ months) was significantly superior (P <.001) to adriamycin non‐responders (5 months). Metastatic lesions responding to adriamycin included skin and soft tissue (46% response rate), lungs (36%), liver (20%), and bones (19%) compared with only soft tissue and skin responses (12%) with the nitrosoureas. Myelosuppression was the dose‐limiting toxicity with all three regimens, but was less prominent with methyl CCNU, suggesting that the dose of this agent could have been higher. An exploration of adriamycin in patients without prior chemotherapy is presently ongoing, with a response rate that is currently in excess of 50% and equal to the response rate of a control population receiving a commonly used five‐drug combination regimen. Adriamycin is an effective new agent in the therapy of breast cancer, and combination trials seem indicated.

CCNU (1‐[2‐chloroethyl]‐3‐cyclohexyl‐1‐nitrosourea, NSC‐79037) in the treatment of cancer. Phase II study

CCNU (1‐[2‐chloroethyl]‐3‐cyclohexyl‐1‐nitrosourea, NSC‐79037), was used to treat 141 evaluable patients with a variety of advanced malignancies, 56% of whom had not received prior chemotherapy. Patients with an adequate bone marrow reserve received 130 mg/m2 as the initial dose and those with an impaired reserve received 100 mg/m2. Therapy was repeated every 6 weeks and the dosage modified according to the hematologic toxicity. Responses greater than 50% reduction in tumor size were noted in 26 patients; stable disease or reduction in tumor size of less than 50% was observed in 21 patients. The well‐differentiated adenocarcinomas and squamous cell tumors appeared to be least sensitive to CCNU. Bone marrow depression was the major dose‐limiting factor. Without adequate antiemetic therapy, all patients would have had nausea and vomiting. Hepatocellular toxicity was noted in two patients.

5 FU infusion with mitomycin‐C vs. 5 FU infusion with methyl‐CCNU in the treatment of advanced upper gastrointestinal cancer. A Southwest oncology group study

A randomized trial was conducted by the Southwest Oncology Group (SWOG) in advanced carcinoma of the stomach and pancreas. Patients were assigned to receive monthly 5‐fluorouracil 96‐hour continuous infusions with either bolus mitomycin‐C or oral methyl‐CCNU. Mitomycin‐C and methyl‐CCNU were administered every eight weeks. The 5 FU‐mitomycin combination produced a 14% and 22% response rate in disseminated stomach and pancreatic carcinoma, respectively. The combination of infusion 5 FU and methyl‐CCNU achieved responses in 9% and 5% of stomach and pancreatic tumors, respectively. There was ho significant difference in survival between limbs for either tumor. Median survival in gastric carcinoma on the 5 FU‐mitomycin regimen was 25 weeks vs. 18 weeks on the 5 FU‐methyl‐CCNU arm. In pancreatic carcinoma median survival on the mitomycin limb was 19 weeks as compared to 17 weeks on the methyl‐CCNU program. Leukopenia was greater for the first course on the mitomycin limb. Regression analysis demonstrated that performance status was the most important pretreatment characteristic for predicting survival in both tumors. Neither 5 FU infusion combination appears to significantly alter the dismal prognosis of advanced upper gastrointestinal neoplasms.

Adriamycin in combination for the treatment of breast cancer: a Southwest Oncology Group study.

Patients with advanced breast cancer who had not previously received chemotherapy were treated on a three‐arm prospective study: adriamycin day 1 plus 5‐FU on day 1 and 8 (AF), adriamycin day 1, plus 5‐FU day 1 and 8, and cyclophosphamide day 1 (AFC), and adriamycin day 1 plus 5‐FU day 1 and 8, cyclophosphamide day 1 and methotrexate day 1 (AFCM). These courses were repeated every 21 days. The response rate was 44/105(42%) AF, 44/103(43%) AFC and 52/105 (49%) AFCM. The length of response was 22, 33 and 35 weeks, respectively, for AF, AFC and AFCM (P =0.21). The median survival, 64 weeks, was equal in all three limbs. The major toxicity was leukopenia. Twenty‐eight percent developed a WBC of less than 2,000/μ1, which resulted in seven deaths (2.2%).