Interferon alpha consolidation after intensive chemotherapy does not prolong the progression-free survival of patients with low-grade non-Hodgkin's lymphoma: results of the Southwest Oncology Group randomized phase III study 8809.

PURPOSE: S8809 is a randomized phase III trial determining whether intensive cytoreductive treatment, followed by interferon consolidation at the time of minimal residual disease, prolongs the progression-free survival (PFS) or overall survival (OS) of indolent lymphoma patients. PATIENTS AND METHODS: Five hundred seventy-one patients with previously untreated stage III or IV low-grade non-Hodgkin's lymphoma were registered. Patients received six to eight cycles of prednisone, methotrexate, doxorubicin, cyclophosphamide, and etoposide/mechlorethamine, vincristine, procarbazine, and prednisone (ProMACE[day 1]-MOPP[day 8]) chemotherapy or chemotherapy plus radiotherapy. Responding patients were randomized to observation alone or to interferon consolidation. Interferon alpha-2b 2 mU/m(2) was given subcutaneously three times weekly for 2 years. RESULTS: Two hundred sixty-eight eligible patients were randomized to interferon alpha consolidation (n = 144) or observation alone (n = 124). With a median follow-up time from randomization among patients still alive of 6.2 years, the median PFS time was 4.1 years for patients who received interferon consolidation therapy and 3.2 years for patients who were observed after ProMACE-MOPP induction (P =.25). The adjusted hazard ratio for relapse for observation to interferon was 0.83 (95% confidence interval [CI], 0.61 to 1.13). The median OS has not been reached in either group. At 5 years, OS is 78% for the interferon group and 77% for the observation group (P =.65). The adjusted hazard ratio for survival for observation to interferon is 1.11 (95% CI, 0.69 to 1. 79). CONCLUSION: Interferon alpha consolidation therapy after intensive treatment with anthracycline-containing combination chemotherapy and involved-field radiation therapy does not prolong the PFS or OS of patients with low-grade non-Hodgkin's lymphoma.

Toxicity and efficacy of carboplatin and etoposide in conjunction with disruption of the blood-brain tumor barrier in the treatment of intracranial neoplasms.

CARBOPLATIN AND ETOPOSIDE have been investigated in preclinical studies and a limited toxicity study in 13 patients; these studies have established carboplatin and etoposide as a tolerable combination when administered with blood-brain barrier disruption. The studies also found a predictable dose-limiting toxicity of myelosuppression. Subsequently, a broad efficacy trial of this regimen was carried out. A total of 34 patients, ranging in age from 7 to 72 years, underwent a combination chemotherapy regimen of carboplatin (200 mg/m2 administered intra-arterially) and etoposide (200 mg/m2 administered intravenously) administered with blood-brain barrier disruption on each of 2 consecutive days every 28 days. The diagnoses included glioblastoma multiforme (n = 3), malignant astrocytoma (n = 8), malignant astrocytoma-oligodendroglioma (n = 1), primitive neuroectodermal tumor (n = 4), disseminated germ cell tumor of the central nervous system (CNS) (n = 6), CNS lymphoma (n = 7), and metastatic carcinoma (n = 5). The major toxicity observed in patients treated with multiple courses of this regimen was the expected reversible myelosuppression and an unexpected, irreversible high-frequency hearing loss. Of these 34 patients, 22 had measurable disease, and 9 radiographic responses (50% or more decrease in enhancing tumors) were observed in these patients. Carboplatin and etoposide with blood-brain barrier disruption is an active regimen in the treatment of malignant astrocytomas and has shown dramatic responses in primitive neuroectodermal tumors and CNS lymphoma. Additionally, the durability of responses in patients with disseminated CNS germ cell tumors is encouraging. However, such therapy is associated with unexpected high-frequency hearing loss; even so, on the basis of the favorable responses in patients with primitive neuroectodermal tumors, germ cell tumors, and lymphomas, the study of this regimen for those tumors is being extended in a multiinstitutional trial that also includes cytoxan to further evaluate the potential enhanced drug delivery.

Primary penile lymphoma presenting as a penile ulcer.

Primary penile lymphoma is rare. The clinical manifestations can be quite subtle, which may lead to misdiagnosis. Treatments have included radical surgery, chemotherapy and radiation. We report on an 18-year-old man with primary penile lymphoma whose lesion caused prolonged diagnostic uncertainty. He was treated with chemotherapy alone, and he has had no tumor recurrence for 27 months.

Trimethoprim-sulfamethoxazole prophylaxis in granulocytopenic patients with acute leukemia: evaluation of serum antibiotic levels in a randomized, double-blind, placebo-controlled Department of Veterans Affairs Cooperative Study.

Despite widespread use of trimethoprim-sulfamethoxazole (TMP-SMZ) for prophylaxis in neutropenic patients, questions remain regarding its efficacy, toxicity, the risk of selection of resistant isolates, and the relation of its activity to selective decolonization vs. the attainment of direct inhibitory levels within blood and tissues. We evaluated the effect of TMP-SMZ (160/800 mg orally every 12 hours) in 42 adult granulocytopenic patients (< 100 absolute neutrophils/mm3, mean duration 13.3 days) undergoing chemotherapy for acute leukemia at 11 participating Veterans Administration Medical Centers in a randomized, double-blind, placebo-controlled trial. No significant differences in survival, frequency of bacteremia, overall infections, use of systemic antimicrobial therapy, or adverse effects, including myelosuppression, were observed between patients receiving TMP-SMZ vs. those receiving placebo. All patients acquired trimethoprim-resistant organisms. Concentrations of trimethoprim in serum were significantly lower before febrile episodes than when patients were afebrile. These results suggest that the purported activity of TMP-SMZ may be related to the serum concentration achieved. Moreover, the results highlight the need for additional study of the value of antibiotic prophylaxis in neutropenic patients.

Long-term follow-up of patients with low-grade malignant lymphomas treated with doxorubicin-based chemotherapy or chemoimmunotherapy.

PURPOSE: We reviewed survival data of patients with low-grade lymphoma entered on Southwest Oncology Group (SWOG) lymphoma trials in 1972 to 1983 to determine the utility of doxorubicin-containing therapy (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP]) in such patients. PATIENTS AND METHODS: We identified all patients with low-grade lymphoma, no prior therapy, and stage III or IV disease who were treated with full-dose CHOP induction therapy on any arm of SWOG studies 7204, 7426, or 7713. Survival data for this group of patients were correlated with pretreatment prognostic factors, including histology, patient age, sex, symptom status, performance status, bone marrow or extranodal involvement, and the number of disease sites. The effect of maintenance treatment was also assessed. RESULTS: Four hundred fifteen patients met criteria for inclusion in the study group. With median follow-up periods of 12.8 years (maximum, 19.8 years), the median survival duration was 6.9 years. Survival was significantly shorter in patients with follicular mixed or small lymphocytic histology, age greater than 40 years, male sex, B-symptom status, and SWOG performance status greater than 1. Multivariate regression analysis showed histology, age, and sex to be independent predictors of survival. There was no definite survival plateau of cured patients in any subgroup, although the survival curve for follicular mixed histology patients showed long-term survival of approximately 25%. Maintenance therapy did not prolong survival. CONCLUSION: Doxorubicin-containing treatment did not prolong the overall median survival of low-grade lymphoma patients compared with results with less-aggressive programs.

Activity of esorubicin in recurrent malignant lymphoma: a Southwest Oncology Group study.

A phase II trial of esorubicin (4' deoxydoxorubicin) was conducted by the Southwest Oncology Group in 88 assessable patients with non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD) at the time of first relapse. Esorubicin was administered at two dose levels: 25 mg/m2 for patients at risk for excessive myelosuppression, and at 30 mg/m2 for all others at 21-day intervals. Overall, 33 of 88 patients (38%) responded to treatment including three complete remissions (CRs; 3%) and 30 partial remissions (PRs; 34%), with the median duration of response lasting 6.2 months. Response rates did not differ significantly by histologic subtype: 31% of 26 patients with favorable NHL, 33% of 43 patients with unfavorable NHL, and 58% of 19 patients with HD. Twelve of 33 responding patients (36%) had relatively durable remissions lasting from 1 to more than 4 years. Leukopenia (less than 3,000 cells per microliter) was seen in 65 of 88 patients (74%) and was severe (less than 1,000 cells per microliter) in 20 of 88 patients (23%). Clinical signs or symptoms of congestive heart failure were not seen and the ejection fraction (EF) fell 10% to 20% in three patients. Esorubicin is an active agent in patients with NHL or HD at the time of first relapse.

m-BACOD treatment for intermediate- and high-grade malignant lymphomas: a Southwest Oncology Group phase II trial.

One hundred six eligible patients with advanced intermediate- or high-grade malignant lymphoma were treated with methotrexate with leucovorin rescue, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD) in a Southwest Oncology Group phase II trial. Patients were stratified by estimated bone marrow reserve, and impaired marrow reserve patients received reduced doses of cyclophosphamide and doxorubicin. The complete remission rate for normal marrow reserve patients was 65%, while the complete remission rate for impaired marrow reserve patients was 29%. With a median follow-up period of 41 months, 64% of complete responders in the normal marrow group are disease-free 3 years after their response. Three-year survival is 61% in the normal marrow reserve group and is 29% in the impaired marrow reserve group. Eighty-seven percent of treatment courses were given in accordance with protocol dosing and schedule. For doxorubicin, relative dose intensities were 0.75 and 0.61 (normal and impaired marrow reserve arms, respectively), for cyclophosphamide, 0.76 and 0.61, and for methotrexate, 0.55 and 0.45. Serum lactic dehydrogenase (LDH) level was the only pretreatment characteristic found to have a significant effect on overall survival. Severe or greater toxicity occurred in 97% and 89% of the normal and impaired marrow reserve groups, respectively, with granulocytopenia the principal toxicity. Treatment-related fatalities occurred in 8% of patients. m-BACOD is an effective but toxic treatment program for intermediate- and high-grade malignant lymphomas.

Aclacinomycin A in the treatment of multiple myeloma: a Southwest Oncology Group study.

Fifty-two patients with progressive resistant multiple myeloma were entered in this Southwest Oncology Group Phase II study, using weekly intravenous Aclacinomycin A. Of forty-three evaluable patients for response, there was one partial remission of 2 years duration and two sustained clinical improvements with 25% reduction in paraprotein. Major toxicity seen was severe myelosuppression and significant nausea and vomiting requiring dose reduction and delay of the scheduled treatment. Cardiac arrhythmia was seen in one patient. Chronic daily schedule or continuous IV infusion is recommended for future study.

Treating malignancies with curative intent: understanding growth and differentiation.

Cancer is due to changes in the genes that normally regulate cellular growth and differentiation. These genetic changes cause cells to grow without normal regulation. Strategies for curative cancer treatment based on these new understandings are discussed.

Southwest Oncology Group clinical trials for intermediate- and high-grade non-Hodgkin's lymphomas.

The Southwest Oncology Group (SWOG) began testing doxorubicin-containing combination chemotherapy in 1972 using the cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) regimen. Subsequent studies, including 350 patients followed for up to 13.3 years, demonstrated that CHOP was curative in 32% of advanced stage, diffuse large cell lymphomas. More recently, promising results from several institutions suggest that new combinations including methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone (m-BACOD), prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, methotrexate (ProMACE-CytaBOM), and methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin (MACOP-B) may be superior to CHOP as gauged by complete response (CR) rates. Consequently, the SWOG developed a strategy to compare these regimens directly with CHOP. In 1984 the SWOG began testing these regimens in sequential group-wide phase II trials to confirm therapeutic activity, establish feasibility with regard to toxicity in a cooperative group setting, and gain experience using the complex schedules and dose-modification schemes. Those phase II studies have been completed, and preliminary results indicate that these regimens are active (CR rates, 53% to 65%) and feasible to administer in a cooperative group setting (fatal toxicity, 2% to 6%). We conclude that these three drug regimens can be administered safely in a cooperative group setting, and the CR rates support the current SWOG comparative trial using CHOP as the standard treatment arm.

A randomized trial of high dose bolus metoclopramide versus low-dose continuous infusion metoclopramide in the prevention of cisplatin-induced emesis.

We compared the antiemetic efficacy of metoclopramide in a bolus low-dose infusion schedule to that of metoclopramide given in a conventional high-dose bolus schedule in a randomized crossover trial. Thirty-two treatment courses in 16 patients receiving cisplatin chemotherapy were evaluable. The metoclopramide regimen was either 2 mg/kg i.v. bolus, then 20 mg/h by infusion for 4 h, or 2 mg/kg i.v. bolus every 2 h for three doses. Dexamethasone 20 mg i.v. and diphenhydramine 50 mg i.v. were also given. Antiemetic efficacy was assessed by a questionnaire. There were no differences in antiemetic efficacy between the metoclopramide regimens. With either program, 75% of patients were emesis-free, 13% had mild symptoms, and 13% had moderate symptoms (greater than two emetic episodes). The infusion metoclopramide regimen was 30% less expensive than the bolus schedule in our pharmacy. Thus, we recommend low-dose metoclopramide infusion as a less expensive, equally effective alternative to high-dose bolus regimens for antiemetic treatment.

Southwest oncology group clinical trials for intermediate- and high-grade non-Hodgkin's lymphomas.

Previous studies have established CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) as the standard of comparison for treatment programs for patients with advanced stages of aggressive non-Hodgkin's lymphomas. Three sequential CHOP studies conducted by the Southwest Oncology Group (SWOG) showed a complete remission (CR) rate of 53% for 418 patients. This rate did not vary among the three studies. Median age was over 55 years. Relapse-free survival of CRs plateaued at 4 to 5 years. Approximately 21% of all patients in the first study and 33% of all patients in the following two studies are long-term survivors and presumed cured. Survival was clearly a function of patient age. Approximately 45% of all patients under age 55 at the time of treatment are cured by CHOP chemotherapy. To determine the toxicity, CR rate, and patient survival of m-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone), ProMACE-CytaBOM (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, methotrexate), and MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin), SWOG initiated a series of phase II studies. Of 118 eligible patients in the m-BACOD study, the median age of 85 patients treated with the full-dose regimen was 54 years, while the median age of 33 patients who started therapy at reduced doses was 67 years. Fatal toxicity was observed in 6% of patients receiving full doses and 13% of those receiving reduced doses. Life-threatening toxicity occurred in 31% of patients on the full-dose regimen and 34% on the reduced-dose regimen. CR was 65% for full-dose treatment, but 27% for reduced doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Methylthioadenosine phosphorylase deficiency in human leukemias and solid tumors.

5'-Methylthioadenosine (MTA) is a naturally occurring nucleoside which is degraded by MTA phosphorylase (MTAase) to adenine and methylthioribose-1-phosphate in all normal mammalian cells. These products of the phosphorylytic cleavage of MTA are recycled to the nucleotide pool and methionine, respectively. Thus, supplemental MTA could theoretically be utilized by MTAase-containing cells as a source of methionine and adenine. In fact, in vitro experiments have shown that MTAase-containing cells proliferate normally in methionine-free medium if MTA is added to the cultures (M. K. Riscoe and A. J. Ferro, J. Biol. Chem., 259: 5465-5471, 1984). In contrast, MTAase-deficient malignant cell lines do not proliferate under these conditions. In light of these observations and the recent demonstration (N. Kamatani et al., Blood, 60: 1387-1391, 1982) that a proportion of acute lymphoblastic leukemias lack MTAase, we wished to determine if this enzyme deficiency occurs in a variety of human neoplasms. Accordingly, malignant cells from eight patients with acute nonlymphocytic leukemia and ten patients with various solid tumors were assayed for MTAase activity. Samples from one of the eight acute nonlymphocytic leukemia patients and three of the 10 solid tumor patients (one with melanoma, one with squamous cell lung cancer, and one with adenocarcinoma of the rectum) had undetectable MTAase activity. In contrast, erythrocytes, neutrophils, and monocytes isolated from normal subjects and from patients with immunodeficiency syndromes or cancer all contained enzyme activity. In addition, the methods of preservation, storage, and cell disruption did not affect MTAase activity. These observations confirm and extend the findings of Kamatani et al. (Blood, 60: 1387-1391, 1982) by demonstrating that MTAase deficiency occurs in a variety of human malignancies including acute nonlymphocytic leukemia and solid tumors. This metabolic difference between normal and malignant cells may be therapeutically exploitable.

Salvage treatment of unfavorable non-Hodgkin's lymphoma with cisplatin, amsacrine, and mitoguazone: a Southwest Oncology Group Pilot Study.

We tested the combination of cisplatin, amsacrine, and mitoguazone as salvage treatment for patients with advanced unfavorable non-Hodgkin's lymphomas. An objective response rate of 43% was noted in 30 evaluable patients, but all responses were partial and the median duration of response was only 2 months. Toxicity included life-threatening and fatal leukopenia and severe gastrointestinal intolerance. We conclude that this combination chemotherapy regimen is not a valuable salvage treatment for patients with non-Hodgkin's lymphoma.

Dexamethasone vs. placebo for cisplatin-induced emesis. A randomized cross-over trial.

A randomized cross-over trial of dexamethasone (10 mg I.V. before therapy, and 4 mg I.V. q 4 h X 6 doses) vs. placebo as antiemetic therapy was conducted in 19 patients receiving high-dose cisplatin. Sixteen patients and 32 treatment courses were fully evaluable. There was no significant difference between regimens in the number of emesis-free patients or the number of emetic episodes, though the duration of nausea symptoms may have been reduced. We conclude that dexamethasone as used in our trial is not an effective antiemetic in patients receiving cisplatin.

Combination chemoimmunotherapy for advanced renal carcinoma with Adriamycin, bleomycin, vincristine, cyclophosphamide, plus BCG.

Fourteen patients with advanced renal carcinoma were treated with Adriamycin 40 mg/m2 I.V., bleomycin 15 U/m2 I.V., vincristine 2 mg I.V., cyclophosphamide 200 mg/m2 p.o. x 4 days, and BCG by scarification every 4 weeks. Of 13 evaluable patients, three (23%) achieved partial remissions on therapy, five (39%) were improved, and three were stable. Responding disease sites included lung and pleural metastases, and an abdominal mass. Median duration of response was 4 months. Median survival was 8.5 months, but the partial responders survived for 13, 17, and 19 months. Toxicity included nausea and vomiting (31%), leukopenia (8%), thrombocytopenia (8%), diarrhea (15%), alopecia (8%), stomatitis (8%), and paresthesias (8%). This well-tolerated stomatitis (8%), and paresthesias (8%). This well-tolerated chemoimmunotherapy regimen has moderate activity in renal carcinoma and deserves further evaluation.

Concomitant administration of granulocyte transfusions and amphotericin B in neutropenic patients: absence of significant pulmonary toxicity.

One hundred and ninety-five series of granulocyte transfusions in 144 patients were evaluated with respect to possible severe pulmonary toxicity from concomitant administration of granulocytes and amphotericin B. Dyspnea as a side effect of granulocyte transfusion was equally common among patients receiving amphotericin B and those in a matched control group not receiving amphotericin B. Granulocyte transfusions and amphotericin B were given simultaneously in 35 transfusion series, involving 32 patients. Respiratory deterioration, defined as the appearance of new pulmonary infiltrates on chest x-ray, occurred in 11 of these 35 episodes. Patients developing respiratory deterioration were similar to those not developing respiratory deterioration in age, diagnosis, disease status, duration of concomitant therapy, and outcome, but more often had positive fungal cultures as an indication for treatment (91% versus 58%; p = 0.1). In 8 patients, the episodes of respiratory deterioration were readily explained by congestive heart failure, by simultaneous bacteremia or fungemia, or by fungal pneumonia discovered at autopsy. One patient had a leukoagglutinin reaction (responsive to steroids) and the other 2 had unexplained, but reversible respiratory deterioration. We concluded that concomitant administration of granulocyte transfusions and amphotericin B is not associated with unexpected or rapidly fatal pulmonary toxicity and when appropriate, can be safely accomplished.