John W. Athens

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.

Combined modality therapy for first recurrence of breast cancer. A Southwest Oncology Group Study

The Southwest Oncology Group has completed a study of 213 women with the first recurrence of breast cancer. Eligibility included a radical or modified radical mastectomy for cure and recurrence which had received no other form of therapy. Patients were started on tamoxifen (TAM) 20 mg daily (Phase I). Failures, or responders who subsequently failed, had an oophorectomy if the ovaries were intact, and TAM was continued (Phase II). During Phase III, eligible patients underwent an adrenalectomy, and lastly, in Phase IV, patients received chemotherapy. Responses to TAM were seen in 40% of 56 premenopausal patients, 46% of 95 postmenopausal women, and 44% of 62 patients without intact ovaries. Oophorectomy plus TAM gave responses only in premenopausal women who failed to respond on TAM or in postmenopausal patients who had a prior response to TAM. Adrenalectomy was successful in 7 of 21 patients. Chemotherapy resulted in 13% complete and 47% partial responses. Median overall survival was 108, 155, and 115 weeks, respectively, for the three patient groups. The authors believe that until results with chemotherapy improve significantly, hormonal therapy is the preferred first‐line management of recurrent breast cancer.

Adjuvant therapy of breast cancer: The Southwest Oncology Group experience

SummaryThe Southwest Oncology Group in a prospective randomized study compared one year of adjuvant combination chemotherapy with continuous CVFVP (cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone) to two years of intermittent L-phenylalanine mustard (L-PAM) in women with operable breast cancer with histologically positive axillary lymph nodes. In fully and partially evaluable patients with a 68-month median follow-up, treatment failures have occurred in 27% of 172 receiving CMFVP and 47% of 186 women given L-PAM (p = 0.002). The advantage for women receiving CMFVP was seen for all subsets regardless of menopausal status except among women who were premenopausal and had 1–3 positive nodes. Based on this study, a second study was implemented using both the estrogenreceptor (ER) content of the primary tumor and axillary nodal status to select therapy.

A useful high-dose intermittent schedule of Adriamycin and DTIC in the treatment of advanced sarcomas

One‐hundred‐fourteen evaluable patients with metastatic soft tissue or bony sarcoma with measurable disease were treated with Adriamycin (doxorubicin) administered intravenously at a dose of 60 mg/M2on day 1, followed by DTIC (dacarbazine) at a dose of 750 mg/M2; courses were administered at 3‐week intervals. Ten complete remissions and 17 partial remissions were observed. The most responsive cell type was malignant fibrous histiocytoma with a response rate of 54%. This treatment schedule was very well tolerated, with only moderate myelosuppression and moderate nausea and vomiting. Cardiac toxicity was identified in three patients, with two patients demonstrating electrocardiogram (EKG) changes and arrhythmias and only one patient developing heart failure. The 24% overall response rate suggests no compromise in activity on this schedule, with a significant reduction in toxicity.

Evaluation of Non-Steady-State Neutrophil Kinetics During Endotoxin-Induced Granulocytosis

Summary The mechanism by which bacterial endotoxin induces granulocytosis in man has been investigated by labeling granulocytes with radioactive diisopropylfluorophosphate. In man, a moderate dose of bacterial endotoxin produces a granulocytosis. By labeling circulating granulocytes with DF32P and later giving endotoxin intravenously, the rates of granulocyte inflow and egress from the blood were measured. Equations were written which express these flow rates as a function of the variables derived from the experimental data. These equations were solved for several time intervals during the 24-hr experiments in each of 12 normal subjects. In the six subjects in whom there was a significant granulocytic response to endotoxin there was a mean increase of 180% (58-383) in the rate of granulocyte inflow to the blood and 150% (24-420) in the rate of egress of granulocytes from the blood during the 5-hour period immediately after endotoxin injection. The remaining six subjects did not have a granulocyte response beyond the 99% limits of normal and there was random variation of inflow and egress of granulocytes. In vitro studies with DFP-labeled cells incubated with endotoxin failed to demonstrate a direct effect of endotoxin on the cell label.

Mitoxantrone (dihydroxyanthracenedione) in acute leukemia: An evaluation of two treatment schedules by the Southwest Oncology Group

Fifty-eight evaluable patients with acute leukemia were treated with Mitoxantrone (DHAD) according to two schedules: 14 mg/M2 as a single I.V. pulse dose administered three-week intervals, and 4 mg/M2/day for five days every three weeks. Six of 58 patients achieved a complete remission. One complete remission and 1 partial remission were observed among 26 patients treated with the single pulse schedule. Five (16%) complete remissions were attained among 32 patients treated on the daily × 5 schedule. Responses were observed only in patients with non-lymphoblastic leukemia. DHAD was very well tolerated with myelosuppression as the major toxicity. Nausea and vomiting were minimal. Subclinical cardiac toxicity occurred in two patients. This was identified by serial reductions in cardiac ejection fractions. DHAD appears to have significant activity in acute non-lymphoblastic leukemia with minimal toxicity.

Phase II evaluation of rubidazone (NSC-164011) in advanced carcinoma of the breast

SummaryThe SWOG carried out a Phase II evaluation of rubidazone in patients with advanced breast cancer. Good risk patients were given rubidazone 150 mg/m2 IV every three weeks. Poor risk patients were given a 25% dose reduction at the start of treatment. Rubidazone dose was increased or decreased depending on toxicity. One patient went into complete remission, four had partial remission and nine had stable disease. Forty-two patients showed increased disease on treatment. No cardiotoxicity was seen, but other common toxicities noted included mostly mild to moderate myelosuppression, nausea, vomiting and alopecia. This study failed to indicate significant antitumor activity of rubidazone in patients with advanced breast carcinoma.

An Evaluation of the Present Status of Neutrophil Replacement Therapy

The replacement of shed blood by transfusion of stored, whole blood became practical over 25 years ago and has been widely used ever since. However, it has gradually become evident that in many clinical disorders only one specific component of blood is needed; e.g., erythrocytes in some of the anemias, plasma in burned patients, gamma globulin in agammaglobulinemics, etc. It also has become evident that the administration of unneeded blood components may be undesirable. Illustrative examples are the transfusion reactions due to leukocyte incompatibility, or even more serious, the high incidence of post-transfusion hepatitis due to virus particles transmitted in the often unneeded plasma.