Biomedical subjects
R T Silver
Publications and source records attributed to R T Silver.
Administration of a complex chemotherapy regimen: inpatient versus outpatient treatment.
The ability to administer a complex chemotherapy regimen, adriamycin and cis-platinum, was evaluated in two different settings, inpatient and outpatient. On comparison, outpatient administration proved superior. This resulted from the interest and experience of the staff administering the medications. It is recommended that outpatient administration of chemotherapy, even with complex protocols, be employed whenever feasible.
Mitoxantrone in acute lymphoblastic leukemia.
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Four-drug combination chemotherapy (methotrexate, cyclophosphamide, hexamethylmelamine, and CCNU) for non-small cell bronchogenic carcinoma: a Cancer and Leukemia Group B study.
Ninety-eight evaluable patients with nonresectable regional or metastatic non-small cell bronchogenic carcinoma were treated with a four-drug combination chemotherapy program of methotrexate, cyclophosphamide, hexamethylmelamine, and CCNU (MCHC). Fifteen partial or complete responses (15%) were obtained, all but one of which occurred in good performance status (0-1) patients. While "responders lived longer than non-responders", this was due more to initial performance status among responding patients than to achievement of partial (greater than 50%) or complete disease regression. Evaluation of those patients with good performance status (PS 0-1), indicated no statistically significant differences in median survival time for complete response and partial response patients compared to patients with "improved" or "stable" disease status in this group. This combination of modestly active single agents produced disappointing results in our lung cancer population. A search for more active single agents in lung cancer is necessary.
Mitoxantrone in patients with acute leukemia in relapse.
Twenty-six patients with acute leukemia in relapse were treated with mitoxantrone (dihydroxyanthracenedione dihydrochloride). The drug was given as a rapid i.v. infusion for 5 days, and doses were escalated from 8 mg/sq m daily for 5 days to 20 mg/sq m daily for 5 days. Five of 12 patients with acute lymphoblastic leukemia were induced into complete remission; one patient was induced into complete remission twice. The marrow response lasted from 3 to 50+ weeks. Among 12 patients with acute myelogenous leukemia, there was one complete and one partial remission, with response duration lasting 8 and 2 weeks. One patient with chronic myelogenous leukemia in blastic crisis also had a partial remission lasting 17 weeks. Remissions occurred at doses ranging from 8 to 14 mg/sq m daily for 5 days. All responders had been treated previously with anthracyclines. Drug-induced side effects included dose-limiting oral mucositis, sporadic nausea and vomiting, and transient elevations of the hepatic enzymes. Approximately one-third of the patients had septic complications during the myelosuppressive phase following treatment. We believe that mitoxantrone has definite utility in the treatment of acute leukemia in relapse.
Comparison of oral melphalan, CCNU, and BCNU with and without vincristine and prednisone in the treatment of multiple myeloma. Cancer and Leukemia Group B experience.
A total of 361 evaluable patients with previously untreated multiple myeloma were randomized to receive oral melphalan (0.15 mg/kg/day for seven days, followed by 0.05 mg/kg/day after recovery from the nadir of the leukocytes), BCNU (150 mg/m2 intravenously every six weeks) or CCNU (100 mg/m2 orally every six weeks). All patients received a tapering six-weeks) or CCNU (100 mg/m2 orally every six weeks). All patients received a tapering six-week course of prednisone starting at 0.8 mg/kg for the first two weeks. At week 22, one-half of the patients were randomized to receive vincristine (1 mg/m2) and prednisone (0.6 mg/kg for seven days) every two months in addition to previous therapy. The melphalan treated patients showed a significantly higher overall objective response frequency (59%), according to Myeloma Task Force criteria, when compared to those treated with BCNU (40%) or CCNU (42%). The survivals for all patients were not statistically different for the three treatment programs. However, the good-risk patients treated with melphalan had significantly longer survival (P = 0.02) than the equivalent patients who received BCNU or CCNU. The addition of vincristine and prednisone at week 2 did not significantly increase the percentage of subsequent objective responses or prolong the subsequent survival of any treatment group. It is concluded that oral melphalan is superior to BCNU and CCNU in producing objective responses and in prolonging survival in good risk patients.
Continuous infusion vincristine and bleomycin with high dose methotrexate for resistant non-Hodgkin's lymphoma.
Sixteen patients with resistant non-Hodgkin's lymphoma were treated with continuous infusions of vincristine (1-2 mg/m2 daily X 2 days) and bleomycin (0.25 mg/kg bolus dose, then 0.25 mg/kg/daily X 5 days). Responding patients received high dose methotrexate (1500 mg/m2) with citrovorum rescue on days 15, 22, 29, 36. Treatment cycles were repeated every six weeks in responding patients. The response frequency was 50% (three complete and five partial responses). Median response duration was 29 weeks. Major toxicity included stomatitis (63%) and leukopenia (44%). One episode each of possible hypersensitivity pneumonitis and paralytic ileus occurred. Continuous infusions of vincristine and bleomycin should be studied further in less critically ill patients.
Combination chemotherapy of advanced diffuse histiocytic lymphoma with the six-drug COP-BLAM regimen.
A new multiple-drug protocol consisting of cyclophosphamide, vincristine, prednisone, bleomycin, doxorubicin, and procarbazine, known as COP-BLAM, was administered to 48 patients with stage III or IV diffuse histiocytic lymphoma. Twenty-four of the 33 previously untreated patients had a complete remission, and eight patients had a partial response. The median survival for all previously untreated patients has not yet been reached at 23 months. Median survival for complte responders has not yet been attained at 26 months, although survival of partial responders is 12.5 months. There were no patients with a complete response who had a central nervous system relapse. The COP-BLAM therapy is an easily administered outpatient program capable of inducing a high frequency of durable complete remissions in advanced diffuse histiocytic lymphoma, a malignancy formerly considered to have a poor prognosis.
Expression of Ia-antigens on normal and chronic myeloid leukemic human granulocyte-macrophage colony-forming cells (CFU-GM) is associated with the regulation of cell proliferation by prostaglandin E.
The presence of la-antigens and their relationship to the inhibitory effect of prostaglandin E on the proliferation of human CFU-GM was studied in animals and patients with chronic myeloid leukemia. Consistent reduction of normal colony formation to approximately 50% of baseline levels was observed using a monoclonal anti-human la antibody in a complement-dependent cytotoxicity assay titrated over serial dilutions. ELimination of the la-antigen-bearing CFU-GM population was associated with virtually a complete loss of responsiveness to the inhibitory effects of prostaglandin E. Maintenance of bone marrow cells in short-term suspension culture at 37 degrees C prior to agar culture resulted in the loss of detectable la-antigen on the CFU-GM and, similarly, loss of response to prostaglandin. In contrast, most patients with chronic myeloid leukemia showed greatly reduced levels of la-antigens on their CFU-GM in fresh marrow together with lack of prostaglandin sensitivity, suggesting a correlation with the abnormal growth regulation observed in these patients. In two chronic myeloid leukemia patients, levels of la-antigen higher than that observed in the majority of patients could be detected and correlated with a residual response to prostaglandin E. These results suggest a relationship in normals between the expression of la-antigens on CFU-GM and the physiologic response to regulation by prostaglandin E, and a possible mechanism for the aberrant regulatory response in patients with chronic myeloid leukemia.
Cytosine arabinoside with daunorubicin or adriamycin for therapy of acute myelocytic leukemia: a CALGB study.
A randomized comparison of the relative efficacy and toxicity of daunorubicin (DNR) at 30 or 45 mg/sq m or adriamycin (ADM) at 30 mg/sq m, given on the first 3 days of a 7-day continuous infusion of cytosine arabinoside (ara-C) at 100 mg/sq m/day, shows the outcome to be dependent on anthracycline, dose, and patient age. DNR 45 is significantly better than DNR 30 or ADM 30 for inducing complete remissions (CR) in patients younger than 60 yr, (72%, 59%, 58% CRs, respectively). DNR 30 is better than DNR 45 or ADM 30 for inducing CR in patients older than 60 yr (47%, 31%, 35%, respectively). There was a corresponding shift in the induction mortality for the age, dose, and anthracycline groups. Adriamycin was significantly more toxic to the gastrointestinal tract than daunorubicin. The duration of complete remission, with cyclic courses of maintenance therapy, was independent of the patient's age, the dose, or choice of anthracycline used in induction, and of whether the maintenance courses were given every 4 wk or every 8 wk.
Multiple (five) primary malignancies in one patient.
We have described a patient surviving five different malignancies, and have reviewed the need for characterization of genetic risk and for meticulous cancer screening. In multiple primary malignancies, the management of each cancer must be considered individually to ensure optimal patient care.
Treatment of acute myelocytic leukemia: a study by cancer and leukemia group B.
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Resistance to therapy of acute leukemia developing in the course of polycythemia vera.
Thirteen patients in whom acute leukemia developed in the course of polycythemia vera were initially treated with vincristine and prednisone in an attempt at remission induction. None responded, and four died during this initial course of therapy. Induction was then attempted in the nine survivors, using cytosine arabinoside and adriamycin. Only one complete remission of 38 weeks and one partial remission were achieved, while median survival was 32 days. Poor results may reflect both the intrinsic biologic properties of the acute leukemia occurring in this setting and the advanced age of the patients.
A new effective four-drug combination of CCNU (1-[2-chloroethyl]-3-cyclohexyl-1-nitrosourea) (NSC-79038), vinblastine, prednisone, and procarbazine for the treatment of advanced Hodgkin's disease.
Five hundred and sixty-six patients with either Stage III or IV Hodgkin's disease were prospectively randomized to test whether CCNU and/or vinblastine are more effective than mechlorethamine and/or vincristine with procarbazine and prednisone. The combination of CCNU, vinblastine, procarbazine, and prednisone (CVPP) was shown to be a highly effective program with a complete response frequency of 69%. The use of CCNU as part of the induction program was also shown to be the most significant determinant of prolonged remissions (P = .025). Reduced vomiting and neurotoxicity, as well as the oral administration, were the chief advantages of the CVPP as compared with MOPP. These factors resulted in improved patient and physician compliance. The MVPP regimen was also shown to be a highly effective regimen with a complete response frequency of 73% in patients without prior exposure to chemotherapy. However, the induction regimens containing vinblastine were associated with a significantly higher frequency of fatal hematopoietic toxicities than the induction regimens containing vincristine (P = .05). This higher frequency was almost exclusively seen in the elderly or in patients previously treated with both chemotherapy and radiotherapy. At this time, the remission durations maintained by vinblastine with periodic reinforcement are longer when compared with vinblastine maintenance alone (P = .06), but there is no corresponding increase in survival.
Clinical trial of VP 16--213 (NSC 141540) I.V. twice weekly in advanced neoplastic disease: a study by the Cancer and Leukemia Group B.
The epipodophyllotoxin derivative VP 16--213 (NSC 141540) was studied by the Cancer and Leukemia Group B in a broad phase II trial at three dose levels: 60 mg/m2, 90 mg/m2, and 135 mg/m2 I.V. twice weekly. No correlation between dose of VP 16--213 and response frequency in a particular disease category could be demonstrated. Of the 382 patients, 8% obtained a complete (CR) or partial remission (PR), 8% showed improvement, and 14% had stable disease. By tumor type the best responses were obtained in lymphomas (8/31 CR + PR), uterus (2/9), prostate (1/5), rhabdomyosarcoma (2/6), neuroblastoma (2/4), colon/rectum (5/81), other gastrointestinal (4/32). In lung tumors, 4/80 patients obtained CR or PR. VP 16--213 has definite antineoplastic activity but the response frequency with the twice weekly schedule may be lower than that reported with other schedules.
The dying patient: a clinician's view.
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Combination chemotherapy for terminal-phase chronic granulocytic leukemia: cancer and leukemia group B studies.
A 34% response was obtained in 202 evaluable patients in the terminal phase of chronic granulocytic leukemia using combinations of hydroxyurea, 6-mercaptopurine, and corticosteroids. Twelve percent of responses were complete and 22% partial. Overall median survival was 12 wk. A 30 wk median survival for responding patients was statistically superior to the 7-wk survival for nonresponders (p less than 0.001). Response was inversely correlated with toxicity. No responses were obtained in patients sustaining both severe infectious and bleeding complications. No benefit could be demonstrated from the addition of vincristine in induction and daunorubicin for consolidation. Although the response frequency and duration of survival with this combination chemotherapy were generally superior to those previously reported by our group, the terminal phase of chronic granulocytic leukemia still remains a formidable and generally refractory disease.
Combination chemotherapy for non-Hodgkin lymphomas: a ten year follow-up study.
In 1968 the Cancer and Acute Leukemia Group B (CALGB) demonstrated optimal control of disseminated non-Hodgkin lymphomas (NHL) with vincristine-prednisone induction followed by cyclophosphamide maintenance. A study was then begun to determine whether four drugs in combination or sequence could achieve greater control. NHL patients at each participating CALGB institution were randomly assigned to one of three regimens:I) Cyclic vincristine-streptonigrin alternating every 2 weeks with cyclophosphamide-prednisone up to 155 days; II) Sequential treatment with the same 4 drugs taken singly up to 182 days; and III) Vincristine-prednisone induction for 6 weeks followed by cyclophosphamide maintenance. Results are now reported after a 10 year follow-up period. The 203 evaluable patients are those on whom Rappaport histopathologic classification was available. Frequency of complete-response did not differ significantly among the three regimens: I) 38%; II) 30%; and III) 45%. Remission durations were significantly longer among patients receiving maintenance therapy. After ten years, two patients from Regimen I, one from Regimen II, and five from Regimen III remain alive and well. It was concluded that neither of the four-drug regimens conferred a significant advantage in terms of response rate or survival time over the standard treatment.