In this phase II multicenter trial, the efficacy and safety of mitoxantrone (Novantrone; Lederle Laboratories, Wayne, NJ) were evaluated in the treatment of 206 patients with relapsed non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD) previously treated with other agents. Sixty-nine percent of the patients had received prior therapy with doxorubicin. The patients received 14 mg/m2 of mitoxantrone every 3 weeks. Nineteen (12%) of the NHL patients and two (7%) of the HD patients had complete responses (CRs). The combined CR and partial response (PR) rates were 37% (60 of 163) for NHL patients and 36% (10 of 28) for HD patients; the median duration of response was 323 days for NHL patients and 209 days for HD patients. The median survival times were 337 days for patients with NHL and 469 days for patients with HD. The median survival time for patients with low-grade NHL was 589 days compared with 298 days for patients with intermediate-grade NHL and 167 days for patients with high-grade NHL. The median time to treatment failure was 73 days for NHL patients and 98 days for HD patients. The major toxicity was myelosuppression, which was moderate and reversible. Nausea, vomiting, and alopecia were mild. There were two cases of congestive heart failure (CHF) considered related to treatment; both patients had received prior treatment with doxorubicin. In this group of heavily pretreated patients, mitoxantrone was effective and well tolerated. Responses were seen with mitoxantrone in patients who had relapsed after prior therapy with doxorubicin and in patients who had failed to respond to prior therapy with doxorubicin. Mitoxantrone should be evaluated in less heavily pretreated patients and should be considered for incorporation into combination chemotherapeutic regimens for the treatment of malignant lymphoma.

One-hundred thirty eligible patients with advanced colorectal carcinoma who had received no prior chemotherapy were randomized to either methyl-CCNU, 70 mg/m2 orally every 6 weeks on day 1, mitomycin C, 10 mg/m2 intravenously every 6 weeks on day 1, and 5-fluorouracil (5-FU), 400 mg/m2 intravenously weekly--(MMF)--or 5-FU, 600 mg/m2 intravenously weekly (5-FU). One hundred twenty-six patients are evaluable for response. Of 62 patients treated with MMF, one (2%) achieved complete remission, and three (5%) attained partial remission. Of 64 patients treated with 5-FU, two (3%) achieved complete remission, and eight (13%) attained partial remission. The median survival for patients receiving MMF was 9.5 months compared with 10.3 months for patients receiving 5-FU. The survival distributions for the two regimens were not significantly different, either unadjusted or adjusted for pretreatment characteristics. Performance status and lactic dehydrogenase (LDH) were both significantly associated with survival. Patients with liver metastases only and normal liver function tests had a median survival of 19.8 months and a 40% response rate. This randomized phase III trial did not show any therapeutic advantage for MMF compared to 5-FU therapy alone in advanced colorectal cancer. In addition, hematologic toxicity was significantly greater with the combination (MMF) regimen.

ABSTRACT Clinical resistance to ara‐C is dose and schedule dependent. Patients refractory to or who have relapsed on combinations of drugs which include standard doses of ara‐C (100–200 mg/m 2 daily for 5 to 7 days) can be induced into clinical remissions with high dose ara‐C (HiDAC). The interaction between HiDAC and asparaginase is schedule‐dependent; pharmacologic synergy and an improvement in the therapeutic index occurring with sequential HiDAC→Asparaginase. This combination has been applied in clinical trial: ara‐C 3 g/m 2 as a 3 hr IV infusion was given every 12 hrs for 4 doses. At the end of the 4th infusion, 6000 IU/m 2 asparaginase was given IM. This therapy was given on days 1 and 8. Refractory/ relapsed patients had a 68% complete remission rate. Treatment of 49 patients with previously untreated ANLL was associated with an 80% and 40% complete remission rate in patients <60 and >60 years of age, respectively. Median time to complete remission for both age groups was 30 days. The lower complete remission rate in older patients reflects higher induction deaths (ID) (50%), not innate drug resistance. Laboratory investigations have focused on the biochemical pharmacology of HiDAC in an attempt to explain the unique therapeutic utility of this mode of drug administration. These data suggest that human leukemia cells transport ara‐C across the cell membrane relatively less efficiently than experimental leukemia cells. The systemic metabolite of ara‐C, ara‐U, may also influence the drug's effect. In the murine leukemia L5178Y, both in vitro and in vivo, high concentrations of ara‐U are cytostatic in S‐phase. the phase of the cell cycle wherein ara‐C cytotoxicity is increased. In vivo, high concentrations of ara‐U also retard systemic deamination of ara‐C as well as its renal excretion. These features increase the terminal half‐life of HiDAC in the plasma and thus prolong cellular exposure to the drug. The interactions between ara‐U and ara‐C thus invoke selfpotentiation of HiDAC.

One hundred twenty-four patients with recurrent or metastatic breast cancer were randomized to receive megestrol acetate 40 mg orally, four times daily, or tamoxifen 10 mg orally twice daily. If therapy failed patients were crossed over to the alternate treatment. Eligibility required that either the estrogen or progesterone receptor be positive or that both values be unknown, and that patients be at least 2 years postspontaneous menopause or over 50 years of age. Pretreatment characteristics were similar for both groups. Three patients had had previous hormonal therapy while one third had had chemotherapy. Objective response for evaluable patients based on strict UICC criteria was 29% with megestrol acetate and 31% with tamoxifen. Responses in patients with bone and soft tissue disease were similar for both regimens; however, 7 of 19 (37%) patients with visceral disease responded to tamoxifen but none of 18 (0%) responded to megestrol acetate. Response did not correlate with amount of estrogen or progesterone receptor. Unadjusted analysis of time to progression and survival showed no significant differences between regimens. With adjustment for pretreatment characteristics, patients on tamoxifen had a statistically significant prolongation of both of these parameters. Crossover data show 3 of 24 patients responding to tamoxifen after failure on megestrol acetate and 1 of 24 responding to megestrol acetate after failure on tamoxifen. However, crossover data should be viewed cautiously, as patients who are currently responding to initial treatment are those who would be most likely to respond to crossover therapy.

A phase 2 trial of vincristine infusion was conducted in a group of 21 patients with refractory multiple myeloma. Patients were generally heavily pretreated with radiotherapy and chemotherapy. Vincristine was given intravenously (IV) as a 0.5 mg bolus and followed immediately by infusion of 0.25 to 0.50 mg/m2/d for 5 days. Courses were repeated every 3 weeks in the absence of disease progression or prohibitive toxicity. Objective responses (partial) were noted in two patients (10%), both of whom were administered 0.5 mg/m2/d infusions. Response durations were brief (2.2 and 1.2 months). Toxicity consisted of neurotoxicity and myelosuppression. In addition to the occurrence of paresthesias and myalgias, ileus (two cases) and moderately severe loss of motor function (two cases) were observed. The mean lowest WBC count following treatment was 2.67 X 10(3)/microL v 3.96 X 10(3)/microL pretreatment (P = .008). The mean lowest platelet count was 75.0 X 10(3)/microL v 106.8 X 10(3)/microL pretreatment (P = .008). Vincristine infusion appears to have limited activity in the treatment of refractory multiple myeloma. Additionally, response durations were short lived and toxicity, both neurologic and hematologic, was appreciable.

The records of 87 patients with small cell lung cancer were reviewed. Patients were clinically staged with bone marrow aspirate and biopsy as well as radionuclide scans of bone, liver, and brain. Extrathoracic spread was noted in 54% (47/87) and limited disease in 46% (40/87). The bone marrow evaluation was positive in 13/62 patients (21%) and seven of these thirteen patients had normal bone scans (54%). Of these seven patients, five had no other evidence of distant metastases and their survival was 7-10 months, considerably shorter than patients found to have limited disease. Bone marrow examination appears to complement radionuclide scanning in the initial staging of patients with small cell carcinoma of the lung and provides important prognostic information.

The role of etoposide epipodophyllotoxin (VP-16-213) in a combined modality treatment program incorporating local chest irradiation and combination chemotherapy with cyclophosphamide, Adriamycin (Adria Laboratories, Columbus, Ohio), and vincristine has been evaluated in a randomized trial of 165 patients with small-cell lung cancer. The overall response rate (complete response [CR] plus partial response [PR]) was significantly greater in the VP-16-213 arm (85% v 64%, P = .005) primarily as a consequence of improved response in patients with extensive disease (85% v 38%, P = .002 and 30% v 8% for CR only, P = .045). No differences in the response rates were observed in limited disease. The duration of response (months) was greater in the VP-16-213 arm (8.6 v 7.0 overall and 14.4 v 11.5 for CR) but not significantly so. Median survival times (months) were consistently greater in the group receiving VP-16-213 when analyzed according to extent of disease and response (10.6 v 9.5 overall; 15.0 v 13.6 for limited disease; 9.0 v 6.7 for extensive disease; 18.5 v 16.2 for CR overall; and 18.6 v 16.1 for CR in limited disease); the results were not statistically significant. The median survival of extensive disease patients attaining a CR was 15.3 months (range 3.2 to 34.3 + months) in the VP-16-213 arm and 7.4+ and 8.1+ months for the two patients with CR in the other group. Anemia and leukopenia occurred to a greater degree in the four-drug regimen, but no unusual or significant compounding toxicity (ie, neurotoxicity) was observed otherwise. Further investigation of this agent in combination chemotherapy programs for small-cell lung cancer appears to be warranted.

Twenty-five patients with a variety of histologic types of advanced non-Hodgkin's lymphoma refractory to previous chemotherapy were entered into a trial of vincristine infusion. Patients received 5-day courses of vincristine 0.25 mg/m2/day by continuous intravenous infusion after an initial 0.5 mg intravenous bolus injection. Courses were repeated every 3 weeks. Objective responses were observed in nine patients (36%), all of whom had previously received vincristine given by conventional bolus injection. A complete response occurred in a patient with diffuse mixed histiocytic lymphocytic lymphoma, and partial responses were observed in eight patients with the following histologic types: diffuse poorly differentiated lymphocytic (4); nodular poorly differentiated lymphocytic (2); diffuse mixed histiocytic lymphocytic (1); and diffuse histiocytic (1). Duration of response lasted from 1.2 to 16.2 months (mean, 4.4 months). The principal complication of therapy was mild-to-moderate neurotoxicity; this occurred in 12 patients (48%) who received a total of 54 courses of vincristine infusion. Hematologic toxicity was minimal and nausea/vomiting did not occur. Vincristine infusion may afford palliation for patients with advanced non-Hodgkin's lymphomas who have become refractory to standard chemotherapeutic regimens even if they have received prior vincristine by conventional bolus injection. These data suggest the possibility of enhancing the therapeutic efficacy of vincristine in the treatment of non-Hodgkin's lymphoma by use of an infusion technique.

Forty-nine patients with advanced carcinoma of the breast who had received no prior chemotherapy were randomized to receive either high-dose cyclophosphamide (C) 1250 mg/M2 intravenously on day 1 and 5-fluorouracil (F) 600 mg/M2 intravenously on days 1 through 5 (CF), or vincristine (V) 1.5 mg/M2, doxorubicin (A) 50 mg/M2 and cyclophosphamide (C) 500 mg/M2 (VAC), all intravenously on day 1. Both regimens were repeated at 3-week intervals. Nine of 25 patients (36%) treated with CF and ten of 21 patients (48%) treated with VAC showed a complete or partial response as defined by the (UICC) guidelines. The estimated median time to progression for all patients was 3.5 months for CF and 6.0 months for VAC, with the median time to progression for responding patients being 8.5 months on CF and 6.3 months on VAC. Estimated survival is also similar for the two regimens. Ten of the patients treated with high-dose CF experienced septic episodes and four died. Toxicity on the CF arm necessitated premature closure of the study, and thus full statistical comparison of the efficacy of the two regimens cannot be made.

Thirty-three patients with advanced breast cancer were treated with a recombinant alpha interferon (rIFN-alpha 2). All patients were ambulatory (performance status greater than or equal to 50 Karnofsky scale) and almost all had received previous chemotherapy. Large intravenous dosages of 30 to 50 X 10(6) IU/m2 were given for five consecutive days every two to three weeks to 22 patients and smaller subcutaneous dosage of 2 X 10(6) IU/m2 three times a week to 11 patients. No complete or partial responses were seen. Two patients had stable disease and the remainder progressed. Flu-like syndromes were seen in all patients. Nausea, vomiting, and anorexia were frequent. Hypotension and confusion were noted in six and five patients, respectively. Life-threatening leukopenia was noted in two patients receiving intravenous dosage and thrombocytopenia was noted in one; no sepsis or bleeding complications were noted. In this study, a highly purified and biologically active rIFN-alpha 2 was not associated with activity in previously treated women with metastatic breast cancer.