Neocarzinostatin: report of a phase II clinical trial.

Fifty-three patients received intensive treatment with neocarzinostatin in doses of 3500 units/m2 by iv bolus infusion daily for 5-14 days. The response rate for 22 patients with leukemia was 9%. One complete and one partial remission were observed among nine patients with chronic myelogenous leukemia in blast cell crisis. None of the 31 patients with solid tumors responded to treatment. With this dose schedule, prolonged thrombocytopenia and cumulative bone marrow toxicity limit the intensity and duration of neocarzinostatin therapy. Acute allergic reactions occurred in 28% of the treatment courses, and three patients developed anaphylaxis during the second or third course of therapy.

The chemotherapy of lymphoblastic lymphoma.

Thirty-two patients treated on consecutive Southwest Oncology Group (SWOG) protocols for malignant lymphoma were subsequently diagnosed as having lymphoblastic lymphoma. Combination chemistry, usually adriamycin-based, produced complete responses (CR) in 17 patients (53%). Median survival was 15 mo. Patients achieving a CR survival significantly longer than patients with partial or no response (p < 0.01). Ten of 24 patients not receiving central nervous system (CNS) prophylaxis developed leptomeningeal lymphoma while none of the seven patients who received prophylactic intrathecal cytosine arabinoside or methotrexate developed CNS lymphoma (p = 0.04). Implications of these results for planning future treatment programs of lymphoblastic lymphoma are discussed.

Neocarzinostatin: a phase I clinical trial with five-day intermittent and continuous infusions.

Neocarzinostatin, a polypeptide antibiotic, was administered by both continuous and intermittent intravenous infusion to 76 patients with a variety of malignant diseases. Doses ranged from 500 to 6500 units/m2 X 5 days. With levels greater than or equal to 1800 units/m2, bone marrow suppression (particularly thrombocytopenia) was the dose-limiting toxicity. Delayed bone marrow recovery was less dose-dependent and occurred in 58% of initial treatment courses in solid tumor patients. Allergic reactions were more frequent with intermittent than with continuous infusions (20% vs. 2% of courses). No complete or partial remissions were observed among solid tumor patients although clinical improvement was noted in one patient with mycosis fungoides and one patient with multiple myeloma. One complete and two partial remissions were noted among 21 patients with acute leukemia. There was one complete remission in a patient with chronic leukemia. Leukemic patients on intermittent therapy evidenced greater change in bone marrow cellularity than those treated by continuous infusion. Although neocarzinostatin has some activity in the treatment of acute leukemia, continuous infusion offers no advantage over intermittent therapy.

Dichloroallyl lawsone.

Dichloroallyl lawsone (DCL, NSC-126771), a synthetic analogue of the antimalarial lapachol, is potentially useful in cancer chemotherapy. Unlike most anticancer agents, DCL is not significantly myelosuppressive in animals but it induces acute cardiac toxicity in the rhesus monkey. This cardiac toxicity seems to be correlated with the maximal plasma DCL concentration, about 130 mg/L in the monkey. We have studied DCL pharmacokinetics in patients in an attempt to define safe dose limits for the Phase I clinical trial. After the rapid intravenous infusion of 10 mg/m2 of radioactive [1- or 4-14C]DCL, 250 muCi per patient, the mean peak plasma concentration of unchanged DCL in four patients was 2.9 +/- 0.3 mg/L. The drug had a mean initial plasma half-life of 48.9 +/- 19 min and a terminal half-life of 20.3 +/- 1.8 hr, with a C X t of 50.1 +/- 12 mg/L/hr, and a clearance rate of 0.08 ml/kg/min. These data suggest that in clinical trials the DCL dose given by rapid intravenous infusion should not exceed 450 mg/m2 so that the maximal plasma drug concentration remains below 130 mg/L.

Combination chemotherapy for mycosis fungoides: a Southwest Oncology Group study.

Between 1972 and 1977, the Southwest Oncology Group studied the following three chemotherapy programs for the treatment of patients with advanced forms of mycosis fungoides: (a) cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) (seven patients); (b) adriamycin, vincristine, and prednisone (HOP) (five patients); and (c) cyclophosphamide, vincristine, prednisone, and bleomycin (COP plus bleomycin) (12 patients). Among the 24 evaluable patients there was an overall objective response rate of 95% with seven (29%) achieving a complete remission. With the adriamycin-containing chemotherapy, five (42%) of 12 patients achieved a complete remission compared to two (17%) of 12 patients treated with COP plus bleomycin. The median duration of remission (partial plus complete) was longer with the COP plus bleomycin combination (median, 47 weeks) than with the adriamycin-containing combinations (median, 22 weeks; P = 0.03). The median survival for all 24 evaluable patients was 95 weeks and was similar regardless of remission-induction therapy. In summary, combination chemotherapy proved to be effective palliative therapy for advanced mycosis fungoides.

Cyclocytidine chemotherapy for malignant melanoma.

Twenty-nine patients with metastatic malignant melanoma were treated with cyclocytidine, 240 mg/m2/day sc for 10 days. All partients had received extensive prior chemotherapy. Only one patient achieved a partial remission; the overall response rate (complete plus partial) was 4%. Unusual toxic effects associated with cyclocytidine chemotherapy included the delayed onset of thrombocytopenia, orthostatic hypotension, and jaw pain.

Curability of non-Hodgkin's lymphomas.

The relapse rates of patients with malignant lymphoma have been analyzed in relation to the number of patients in complete remission (CR) at yearly intervals after the onset of therapy. Several different patterns of relapse have been identified. Patients in CR from nodular poorly differentiated lymphocytic lymphoma have a low rate of recurrent disease (14%) during the first year of treatment but rates of relapse in succeeding years have not decreased. Patients with diffuse poorly differentiated lymphocytic lymphoma have a significantly higher relapse rate during the first year of treatment (33%). However, remission duration curves suggest that the risk of relapse is decreasing with time. Patients with diffuse histiocytic lymphoma, who initially have the greatest risk of disease recurrence (42%), subsequently showed a significant fall in their rate of relapse. As many as 50% of these patients who attain a CR may have been cured of their disease. An analysis of CR duration curves may be used to determine the effective doubling time of various malignant diseases and to estimate cure rates within a few years after the onset of therapy.

Chemotherapy of non-Hodgkin's lymphoma: 10 years' experience in the Southwest Oncology Group.

The Southwest Oncology Group (SWOG) has completed five studies of high-dose intermittent combination chemotherapy for the management of advanced (stage III and IV) non-Hodgkin's lymphoma involving 1143 patients from May 1966 to September 1974. Lack of uniform histopathologic interpretation precludes precise analysis of these data. Although there has been little change in complete response duration over the years of this study, there has been an overall improvement in response rate and survival though there is no statistically significant improvement in the best overall survival when compared to the Stanford experience in stage III and IV disease (1960-71). The response rate and survival in diffuse histiocytic lymphoma have improved since the first study. There is definite evidence of a plateau in the survival curve beyond 2 years. The percentage of survival at which the plateau appears has increased over the years to 40% in the most recent studies, and the survival is suggestively better than the Stanford experience (P = 0.09). Over the years there has been a distinct improvement in response rate and survival of patients with nodular lymphocytic lymphoma, although the best SWOG survival is no different than the Stanford experience (P = 0.36).

Combination chemotherapy ("CHOP-Bleo") in advanced (non-Hodgkin) malignant lymphoma.

Forty-seven adults with advanced malignant lymphoma (the majority in stage IV) were treated with a combination of cyclophosphamide, hydroxyldaunorubicin (Adriamycin), vincristine (Oncovin), prednisone, and bleomycin (CHOP-Bleo). The complete remission (CR) rate was 66%. The overall response (complete + partial remission) was 92%. The CR rate in patients with diffuse histiocytic lymphoma (DHL) was 69%. Only 3 of the 18 patients with DHL in CR have relapsed; the projected median duration of response was calculated to be greater than 2 yr. In patients with nodular poorly differentiated lymphocytic lymphoma (NPDL), the CR rate was 62%. One of the eight patients with NPDL in CR has relapsed; the projected median duration of complete response will be greater than 4 yr. The median survival for all patients entered in this study has not been reached; however, it was estimated that it will be greater than 3 yr. The survival curves became flat at 70 wk for the patients with DHL and at 1 yr for the patients with NPDL. Major complications during chemotherapy with CHOP-Bleo were myelosuppression and alopecia. Only six severe infections occurred during myelosuppression. No hemorrhagic problems were observed. This study indicates that combination chemotherapy with these agents is effective in increasing the CR rate and survival in patients with diffuse histiocytic lymphoma. In patients with NPDL, further observation will be needed to assess the effect of this combination on survival.

Combination chemotherapy with bis chloroethyl nitrosourea (BCNU), vincristine and dimethyl triazeno imidazole carboxamide (DTIC) in disseminated malignant melanoma.

One hundred thirty two patients with disseminated malignant melanoma were treated using a combination of BCNU, vincristine and imidazole carboxamide. A response rate of 23% was observed, while 16% had stable disease. The patients' median survival was 42 months from diagnosis and 5.3 months from the onset of treatment. These results are not significantly different from therapy with imidazole carboxamide alone. Patients on this study were observed to have a significant reduction in the number of lymphocytes in their peripheral blood (mean 1800/mm3, median 1550/mm3). Patients with lymphopenia prior to the onset of therapy (86%) had a similar response rate but a shorter median survival (4.4 months vs. 7.8 months, P = .03) than patients with normal lymphocyte levels. These findings are compatible with recent observations on the importance of host immunocompetence in patients with malignant melanoma. Eosinophil levels were not closely correlated with response, although among patients with eosinophil counts of greater than 300/mm3 (22%), a slightly higher response rate (29%) was observed (P = .13). Eosinophilia did not influence patient survival.

Bis chloroethyl nitrosourea, vincristine, dimethyl triazeno imidazole carboxamide and chlorpromazine combination chemotherapy in disseminated malignant melanoma.

One hundred twenty-one patients with disseminated malignant melanoma were treated with BCNU, vincristine, DTIC, and chlorpromazine (BVD). A response rate of 22% was observed; 28% of the patients had stable disease and 50% had increasing disease. Similar response rates were obtained with both the high dose and low dose treatment schedules. Patients who exhibited some degree of improvement during their initial course of treatment had the highest overall response rate (72%) to BVD chemotherapy. The median survival from onset of therapy was six months for all patients and 18 months for patients who responded to chemotherapy. The median duration of response was 9.9 months. Thus, the addition of chlorpromazine to BVD chemotherapy did not increase tumor response, and the overall results obtained were comparable to DTIC alone. Patients were found to be lymphopenic prior to the onset of therapy. Their median absolute lymphocyte count was 1800/mm3. Those patients with absolute lymphocyte counts above the 2710/mm3 normal mean had significantly higher response rates (35% vs. 19%, P less than .05) and longer survivals (9.8 months vs. 4.3 months, P less than .05) than patients with lower initial lymphocyte levels. Pretreatment eosinophil and monocyte counts were not closely correlated with patient response or survival.

Hydroxyldaunomycin (Adriamycin) combination chemotherapy in malignant lymphoma.

Combination chemotherapy with CHOP (cyclophosphamide, Adriamycin, vincristine, and prednisone) and HOP (Adrimycin, vincristine, and prednisone, was used as treatment for patients with pathologically staged, advanced non-Hodgkin's lymphoma. Among 204 evaluable patients treated on CHOP there were 71% complete remissions with 92% overall responses. Among the 216 evaluable patients on HOP there were 61% complete remissions and 88% responses. Complete remission rates among patients with histiocytic lymphoma were comparable to those of patients with lymphocytic disease. Patients with nodular lymphoma had higher rates of complete remission than their counterparts with diffuse lymphoma. This was noted with both CHOP (78% vs. 67%) and HOP (67% vs. 60%) induction therapy. Rapid responses were common, as more than 14% of complete remissions and 66% of overall responses were achieved with the first course of treatment. Patients in complete remission have been maintained with either cyclophosphamide, vincristine, and prednisone (COP) or arabinosyl cytosine, vincristine, and prednisone (OAP). After 1 year, 86% of patients on COP and 80% on OAP are projected to be free of disease.

Reduction of ifosfamide toxicity using dose fractionation.

Ifosfamide was given in i.v. doses of 600 to 1200 mg/sq m/day for 5 days to 32 cancer patients, refractory to prior therapy, in an attempt to investigate the possibility of reducing toxicity by dose fractionation. Microscopic hematuria occurred in 14% and gross hematuria in only 10% of the patient trials. Azotemia did not occur in any patient on this study. Reversible myelosuppression was comparable to that found by other investigators. Other side effects such as nausea and mental confusion occurred infrequently. Ifosfamide produced antitumor effect in 7 of 27 evaluable patients. This study indicates that the renal and bladder toxicity of ifosfamide can be substantially reduced if the drug is administered in i.v. infusions of 1 to 2 hr daily for 5 days.