James S. Hewlett

Combination chemotherapy for multiple myeloma

Response rate, remission duration, and survival time were compared in 236 patients with multiple myeloma receiving a melphalan‐prednisone‐procarbazine combination and in 156 patients receiving only melphalan‐prednisone. Response was confirmed when myeloma protein production had been reduced to less than 25% of the pretreatment value. Of the evaluable trials, 59% of patients responded to the procarbazine combination, and 48% to melphalan and prednisone. In both treatment groups, the survival time of all patients (22 months) and the remission duration of responding patients (21 months) were similar. Maximum degrees of myeloma protein reduction were associated with longer remissions and survival. Previously reported resistance to treatment of patients with only lambda Bence Jones protein was not apparent with these superior treatment regimens. Results support the value of combination chemotherapy with melphalan‐prednisone‐procarbazine for remission induction in patients with multiple myeloma.

Combined cyclophosphamide, vincristine, and prednisone therapy of malignant lymphoma

A combination of intravenous cyclophosphamide and vincristine (Oncovin) and oral prednisone (COP) was given every 2 weeks to 262 patients with disseminated Hodgkins disease, lymphosarcoma, reticulum cell sarcoma, and follicular lymphoma. A complete remission was produced in 36% of patients with Hodgkins disease, 50% of patients with lymphosarcoma, and 39% of patients with reticulum cell sarcoma. These remission rates are significantly superior to those produced by single agents. Patients who achieved a complete remission were randomly allocated to monthly COP (maintained remission) or to no treatment (unmaintained remission). The median duration of maintained remission was longer than unmaintained remission for Hodgkins disease (42 weeks vs. 19 weeks) and lymphosarcoma (49 weeks vs. 21 weeks) but not for reticulum cell sarcoma (24 weeks vs. 25 weeks). The duration of remission for patients with little or no prior therapy was compared to that for patients in a similar study in which single agents were used.4 For lymphosarcoma and reticulum cell sarcoma, remissions maintained with COP were longer than remissions maintained with cyclophosphamide. For Hodgkins disease and lymphosarcoma, unmaintained remissions after COP induction were longer than after single agent induction. All parameters of response, that is, complete remission rate, duration of remission, and survival were adversely affected by major prior treatment with radiotherapy and chemotherapy. The initial response to treatment correlated positively with survival. The survival of patients with lymphosarcoma or reticulum cell sarcoma receiving COP treatment was significantly superior to a comparable group of patients treated sequentially with single agents.

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.

Hepatic artery infusion of 5‐fluorouracil and mitomycin C in cholangiocarcinoma and gallbladder carcinoma

Eleven patients with histologically proven cholangiocarcinoma and gallbladder carcinoma were treated with hepatic artery infusion (HAI) of 5‐fluorouracil (5‐FU) and mitomycin C (Mito‐C). Catheters were placed percutaneously through the femoral artery. The schedule used was 5‐FU 1200/mg/m2/day given as a continuous infusion for 4 days, plus Mito‐C 6 mg/m2 on days 1 and 4. Courses were repeated every 4 weeks. Complete responses (CR) occurred in one patient (9%), and partial response (PR) occurred in six patients (55%). Median survival for all patients from the start of the first treatment was 12.5+ months. Median duration of the response was 3.0 months. Median survival of the patients with gallbladder carcinoma was 12.5 months, and for patients with cholangiocarcinoma has not yet been reached. Drug toxicity was mild, and morbidity of the HAI was minimal. Further trials of chemotherapy in these two neoplasms are warranted.

Effect of schedule on activity and toxicity of 5‐azacytidine in acute leukemia: A southwest oncology group study

One‐hundred‐fifty‐four patients with acute leukemia and extensive prior chemotherapy were treated with 5‐Azacytidine and evaluated according to five different schedules. One‐hundred‐twenty patients received adquate trials; 34 patients died within 14 days of onset of treatment. Nine patients achieved a complete remission (CR) and two achieved a partial remission. Although two of the treatments have a higher remission rate, the data were not statistically significant. The median time to CR was 48 days (range 21–173). The median duration of CR was 65 days (range 39–369). There was no difference in responders. Proportionately there were more women among responders (5M/6F) and more men (70M/39F) among nonresponders. At onset of therapy the median leukocyte counts were similar between responding (5.4 × 103) and nonresponding (5.7 × 103) patients, but the proportion of leukemic cells was significantly higher among nonresponding patients (46% vs. 7%). Toxicities included nausea, vomiting, diarrhea, skin rash, myalgias, prolonged myelosuppression, hypotension, and central nervous system stupor and/or coma. Lower dose continous infusion schedules of five‐, seven‐, and ten‐days duration appear effective and were associated with less toxicity.

Hyperinsulinism due to islet-cell tumors simulating sarcoma: a report of two cases of large tumors composed of round and spindle cells associated with hypoglycemia.

Functioning islet-cell tumors are usually composed of nests, cords, or sheets of cells, resembling beta cells and associated with varying amounts of intercellular stroma. Such tumors are usually small. In contrast, we have observed two very large neoplasms which caused hypoglycemia and were composed predominantly of spindleshaped cells with cytoplasmic processes. Associated with these spindle cells in both of the tumors were round cells without cytoplasmic processes. The purpose of this paper h to describe the clinical features and pathologic findings of these two cases in order to substantiate the thesis that these tumors are actually functioning isletcell neoplasms.

Immunotherapy of disseminated renal cell carcinoma with transfer factor.

Ten patients with disseminated renal cell carcinoma have been treated with transfer factor as an immunostimulant. In 5 patients with metastatic disease evident at the time of initial diagnosis treatment involved removal of the primary tumor followed by transfer factor therapy. Of these patients 3 had a temporary stabilization of metastatic disease. Three patients with recurrent metastatic disease after previous nephrectomy were treated, 2 of whom showed a temporary stabilization of metastatic disease. There were 2 additional patients without clinically evident metastases but at a high risk for recurrent disease who were treated and remain free of disease. We used 5 immunologic parameters to evaluate the clinical effects of transfer factor. No objective clinical regression was noted in any patient treated with measurable disease.

Phase II trial of 5‐fluorouracil, adriamycin, mitomycin C, and streptozotocin (FAM‐S) in pancreatic carcinoma

Twenty‐five patients with unresectable and metastatic pancreatic carcinoma were treated with the combination of 5‐fluorouracil, Adriamycin, mitomycin C and streptozotocin (FAM‐S). Twelve of 25 patients responded (48%) and four patients demonstrated stable disease. Median survival of all patients was 6.75 months, and seven of 25 patients survived more than 12 months. Hematologic toxicity was moderate, and the predominant side effect recorded was nausea and vomiting (80% patients). Combination chemotherapy in pancreatic carcinoma may provide palliation and randomized trials are warranted to confirm these results.

Prognostic factors affecting remission, remission duration, and survival in adult acute nonlymphocytic leukemia

The medical records of 94 consecutive patients with acute nonlymphocytic leukemia (ANLL) were reviewed to identify significant prognostic factors. The data were analyzed using 1) Coxs linear hazard and linear logistic models, 2) chi‐square comparison of the groups living longer than 2 years and those living less than 2 years, and 3) the Gehan‐Breslow test of equal survival curves. The only statistically significant finding was that the presence of promyelocytic cell type and complete remission correlated with increased survival (p < 0.05), but this was negated by the small number of patients with this cell type. There was a suggestive association between higher initial hemoglobin and survival (p = 0.09). The Gehan‐Breslow test revealed a possible difference in survival between those patients more than 51 years of age and those less than 51 (p = 0.10). Thus none of the commonly accepted prognostic factors in acute nonlymphocytic leukemia was definitely shown to be useful. The findings of this study support an aggressive approach toward all patients with this disease.

High dose BCNU with autologous bone marrow rescue in the treatment of recurrent malignant gliomas

Eleven patients with malignant gliomas recurring after surgery and radiation therapy, were treated with high dose BCNU 1050-1200 mg/ M2 with autologous bone marrow rescue. Four patients also received concomitant 5-fluorouracil 1000 mg/ M2/24 hr daily for three days. Eight of ten evaluable patients demonstrated improvement on CAT scan as well as a decrease in steroid requirement. All patients surviving longer than two weeks after BCNU administration experienced full hematologic recovery. No delayed myelosuppression was seen after a single course of high dose therapy. Two patients died as a result of therapy, one following a second induction of BCNU for a total cumulative BCNU dose of 2 400 mg/ M2 and one of infection while cytopenic. Additional toxicity includes one steroid-responsive interstitial pneumonitis, one centrilobular necrosis of the liver which spontaneously resolved and one episode of deep vein thrombosis. With limitation on the maximum BCNU dose and distribution of the total dose over three days, high dose BCNU can be administered with acceptable toxicity. This approach may offer a higher response rate than that expected for standard dose BCNU.