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 x 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.

Late intensification with POMP chemotherapy prolongs survival in acute myelogenous leukemia--results of a Southwest Oncology Group study of rubidazone versus adriamycin for remission induction, prophylactic intrathecal therapy, late intensification, and levamisole maintenance.

Between August 1978 and September 1982, 642 patients with newly diagnosed acute myelogenous leukemia (AML) were entered onto a Southwest Oncology Group Study which addressed four questions. (i) What is the comparative utility of rubidazone versus adriamycin in remission induction? (ii) What is the role of prophylactic intrathecal therapy in AML? (iii) Does late intensification affect treatment outcome? (iv) Does maintenance with levamisole affect disease-free survival or overall survival? Among 611 evaluable patients, 329 (54%) achieved complete remission. There was no difference in the remission rate between those patients receiving rubidazone (54%) and those receiving adriamycin (54%) as part of the induction regimen. Prophylactic intrathecal therapy with cytosine arabinoside had no effect on the incidence of central nervous system disease or survival. After nine months of complete remission, patients were randomized between late intensification with POMP (mercaptopurine + vincristine + methotrexate + prednisone) or continued maintenance with OAP (vincristine + cytosine arabinoside + prednisone). T patients randomized to late intensification had better survival and disease-free survival, compared to those randomized to receive no late intensification (p = 0.027 and 0.030, respectively). At twelve months of remission, surviving patients were randomized to receive levamisole or no further treatment. There was no evidence that levamisole affected survival or disease-free survival.

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/M2 on 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.

Randomized comparisons of radiotherapy and carmustine versus procarbazine versus dacarbazine for the treatment of malignant gliomas following surgery: a Southwest Oncology Group Study.

Between 1977 and 1981, the Southwest Oncology Group entered 278 patients on a randomized study (SWOG 7703) to compare the effect of three different chemotherapeutic agents given in combination with radiotherapy (6000 rads over 7 weeks) following surgery for malignant gliomas. The chemotherapy regimens were: carmustine (BCNU)--80 mg/m2 iv daily X 3 every 6 weeks; procarbazine (PCB)--100 mg/m2 orally; or dacarbazine (DTIC)--175 mg/m2 iv daily X 5 every 4 weeks. Patients were stratified according to age, and degree of resection, with no differences identified between groups. The response rates (complete plus partial) for BCNU and DTIC were significantly better than for PCB [BCNU, 39%; PCB, 13%; and DTIC, 38% (P less than 0.01)]. The response duration and survival were somewhat better in patients treated with BCNU and DTIC, but compared to patients treated with PCB, the difference was not statistically significant. Median survival times were: BCNU, 45 weeks; PCB, 31 weeks; and DTIC, 49 weeks (P greater than 0.3). There were six toxic deaths with BCNU and four with PCB, most of which were due to infection associated with leukopenia. The high toxicity and minimal benefit of chemotherapy added to radiotherapy compared to historical results with radiotherapy alone suggest that combined treatment may not be indicated for some patients.

Phase II evaluation of aclarubicin in refractory adult acute leukemia: a Southwest Oncology Group Study.

Aclarubicin, a new anthracycline antibiotic, was used to treat 24 adult patients with refractory adult leukemia, using a total dose of 300 mg/m2 (75 mg/m2/day X 4). There were 20 patients with acute myelogenous and four with acute lymphoblastic leukemia. Approximately two-thirds of the patients had a Karnofsky score of less than or equal to 2, and two-thirds had received two or more previous induction programs. Interim bone marrow evaluation was obtained in 18 of 30 remission induction courses and revealed marked hypocellularity in 14, inadequate specimens in three, and persistent disease in one. Seven patients received more than one course. Two patients refused further therapy. In patients with myelogenous leukemia, there were two complete remissions lasting 10 and 16 months and one partial remission lasting 4 1/2 months. There were no responders in patients with lymphoblastic leukemia. Toxicity included profound leukopenia and thrombocytopenia, moderate nausea and vomiting, diarrhea, and mucositis. There were no cardiac symptoms associated with the drug infusion, but there were three late events possibly associated with anthracycline cardiotoxicity. Used in this dosage schedule, aclarubicin is an active, but toxic, agent in the acute myelogenous leukemias.

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.

Identification of a toxoplasma cyst by fine-needle aspiration.

In the course of evaluating the fine-needle aspiration technic a toxoplasma cyst was identified in a lymph node excised from a patient in whom toxoplasmosis subsequently was confirmed serologically. This is the first reported case in which a cyst was identified by this method. The recognition of a cyst and characteristic cytologic features in the aspirate demonstrates the utility of fine-needle cytologic examination in diagnosing toxoplasmic lymphadenitis.

Management of patients with metastatic adenocarcinoma of unknown origin: a Southwest Oncology Group study.

The Southwest Oncology Group evaluated 51 patients with a histologic diagnosis of metastatic adenocarcinoma and an occult primary tumor. Even though all patients received an extensive diagnostic evaluation, only six (12%) primary sites were found. Thirty-six patients whose primary tumor sites remained occult were randomized to receive either 5-FU or combination chemotherapy (5-FU, doxorubicin, and cyclophosphamide [FAC]). There were no responses in either group. The median survival with 5-FU was 105 days and with FAC was 95 days. Toxicity with FAC was more common and more severe.

Phase II evaluation of rubidazone (NSC-164011) in advanced carcinoma of the breast. A Southwest Oncology Group study.

The 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.

Adjuvant therapy of breast cancer: the Southwest Oncology Group experience.

The Southwest Oncology Group in a prospective randomized study compared one year of adjuvant combination chemotherapy with continuous CMFVP (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 estrogen-receptor (ER) content of the primary tumor and axillary nodal status to select therapy.

Enhancement of colony-stimulating activity production by lithium.

Since lithium causes granulocytosis in some patients, its effect upon granulocyte production was investigated using mouse marrow in the agar culture system. When lithium was added to semisolid cultures of mouse marrow, there was no stimulation of colony formation in the absence of colony-stimulating activity (CSA). In addition, lithium did not potentiate the action of already formed CSA. However, lithium did stimulate the production of CSA by lung tissue. Lithium enhancement of CSA production was blocked by puromycin, indicating that lithium action required active new protein synthesis. It was concluded that lithium promoted enhanced granulocyte production in vitro by stimulating the synthesis of CSA.

STimulation of granulocytopoiesis by a diffusible factor in vivo.

A millipore diffusion chamber system was used to cultivate mouse marrow in the abdomens of irradiated and unirradiated host mice for 24 hr. When the irradiated hosts were 72, 96, or 120 hr postirradiation, the number of blasts and promyelocytes in the implanted chambers after cultivation was greater than those in the same marrow cultivated in unirradiated hosts. These data indicate that in vivo, there is stimulation of granulocytopoiesis by a diffusible factor or factors.

Leukokinetic studies. XIV. Blood neutrophil kinetics in chronic, steady-state neutropenia.

The kinetics of blood neutrophils was investigated by means of the in vitro radioactive diisopropyl fluorophosphate method in 35 patients with a chronic, steady-state neutropenia. There were 17 patients in whom the half disappearance time of neutrophils was normal. In 10 of these patients, the production of neutrophils was low and in 7, production was normal. In 18 patients the half disappearance time of neutrophilic granulocytes was shorter than normal. The production of neutrophilic granulocytes was low in five of these patients, normal in eight patients, and increased in five. An attempt was made to correlate other laboratory measurements with the kinetic picture, but no relationship was found; the marrow neutrophil reserve as measured by endotoxin or cortisol injection; marrow cellularity on aspiration or biopsy; in vitro-labeling index with (3)HTdR; or serum lysozyme concentration proved of no value in identifying the various kinetic groups. The only finding that seemed to correlate with the kinetic picture was the presence or absence of splenomegaly. In 12 of the 18 patients with a short half disappearance time, splenomegaly was present whereas in 15 of 17 patients with a normal half disappearance time, there was no splenomegaly. Of 20 patients with greater than 1000 neutrophils per mm(3), 17 were found to have a normal total-blood neutrophil pool. Thus these patients, with many of their cells marginated, agree to have a "shift neutropenia."Myelocyte to blood transit time and myelocyte generation time, as measured in seven patients by in vivo labeling with diisopropy fluorophosphate, proved to be essentially normal. Thus, it appears that in chronic neutropenia, increased or decreased production of neutrophils is accomplished by increasing or decreasing early precursor input into the system.