Phase II study of theophylline in chronic lymphocytic leukemia: a study of the Eastern Cooperative Oncology Group (E4998).

The Eastern Cooperative Oncology Group (ECOG) performed a phase 2 study in B-cell chronic lymphocytic leukemia (CLL) of oral theophylline, a methylxanthine that inhibits cyclic nucleotide phosphodiesterases, thereby inducing the intracellular accumulation of cyclic adenosine monophosphate (cAMP). In 25 patients with Rai stages 0-I, theophylline, 200 mg given orally every 12 h was well tolerated. There was one complete response after 22.5 months of treatment, which continues at 27+ months, and 18 other patients had stable disease. In vitro exposure of patients' lymphocytes to aminophylline (75-250 microg/ml), the soluble form of theophylline, resulted in dose- and time-dependent induction of apoptosis in 9/20 patients studied. Apoptosis was documented flow-cytometrically by monitoring the expression of bcl-2 and bax, forward light scatter, fluorescence intensity of binding of CD45 antibody, and the binding of annexin. Patients whose leukemic lymphocytes were susceptible to apoptosis induction by aminophylline in vitro experienced a significantly longer progression-free survival than patients whose cells were resistant to the drug in culture (P=0.025). This suggests that in a CLL population treated with theophylline, induction of an apoptotic response to the drug in vitro is prognostic for absence of clinical progression.

Epoetin treatment of anemia associated with cancer therapy: a systematic review and meta-analysis of controlled clinical trials.

Epoetin treatment offers an attractive but costly alternative to red blood cell transfusion for managing anemia associated with cancer therapy. The goal of this review is to facilitate more efficient use of epoetin by 1) quantifying the effects of epoetin on the likelihood of transfusion and on quality of life in patients with cancer treatment-related anemia and 2) evaluating whether outcomes are superior when epoetin treatment is initiated at higher hemoglobin thresholds. Two independent reviewers followed a prospective protocol for identifying studies. Outcomes data were combined with the use of a random-effects meta-analysis model. Double-blind, randomized, controlled trials that minimized patient exclusions were defined as higher quality for sensitivity analysis; randomized but unblinded trials and trials with excessive exclusions were included in the meta-analysis but were defined as lower quality. Twenty-two trials (n = 1927) met inclusion criteria, and 12 (n = 1390) could be combined for estimation of odds of transfusion. Epoetin decreased the percentage of patients transfused by 9%-45% in adults with mean baseline hemoglobin concentrations of 10 g/dL or less (seven trials; n = 1080), by 7%-47% in those with hemoglobin concentrations greater than 10 g/dL but less than 12 g/dL (seven trials; n = 431), and by 7%-39% in those with hemoglobin concentrations of 12 g/dL or higher (five trials; n = 308). In sensitivity analysis, the combined odds ratio for transfusion in epoetin-treated patients as compared with controls was 0.45 (95% confidence interval [CI] = 0.33 to 0.62) in higher quality studies and 0.14 (95% CI = 0.06 to 0.31) in lower quality studies. The number of patients needed to treat to prevent one transfusion is 4.4 for all studies, 5.2 for higher quality studies, and 2.6 for lower quality studies. Only studies with mean baseline hemoglobin concentrations of 10 g/dL or less reported statistically significant effects of epoetin treatment on quality of life; quality-of-life data were insufficient for meta-analysis. No studies addressed epoetin's effects on anemia-related symptoms. We conclude that epoetin reduces the odds of transfusion for cancer patients undergoing therapy. Evidence is insufficient to determine whether initiating epoetin earlier spares more patients from transfusion or results in better quality of life than waiting until hemoglobin concentrations decline to nearly 10 g/dL.

Phase II trial of menogaril in patients with previously treated multiple myeloma or chronic lymphocytic leukemia.

Menogaril is a semisynthetic anthracycline with relative lack of cardiotoxicity. Ten patients with multiple myeloma (MM), seven patients with chronic lymphocytic leukemia (CLL), and one patient with diffuse well-differentiated lymphocytic lymphoma (DWDL) were treated with menogaril, 160 mg/m2 (for MM) or 200 mg/m2 (for CLL/DWDL), given as a 2-hour intravenous infusion, repeated every 28 days. All patients except one with CLL had been previously treated with one chemotherapy regimen and had either not responded or had relapsed after a response to prior treatment. There were no objective responses to treatment. Among the six evaluable patients with MM, two had stable disease with subjective improvement in symptoms for five to 25 cycles, and among the eight patients with CLL/DWDL, five patients remained stable for two to eight cycles on treatment. The remainder of the patients had progressive disease after one to two cycles of chemotherapy. Five grade 4 hematologic toxicities were observed. There was one fatal neutropenic sepsis. Menogaril, as administered in this study, does not appear to have significant activity in patients with previously treated MM or CLL.

Phase II trial of weekly intravenous gemcitabine with continuous infusion fluorouracil in patients with metastatic renal cell cancer.

PURPOSE: To determine the clinical response rate of the combination of weekly intravenous (IV) gemcitabine with continuous infusion fluorouracil (5-FU) in patients with metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS: Between June 1998 and February 1999, 41 patients with metastatic RCC were enrolled onto this multi-institutional phase II study of gemcitabine 600 mg/m(2) over 30 minutes on days 1, 8, and 15 and 5-FU 150 mg/m(2)/d via continuous IV infusion through a permanent catheter on days 1 to 21 of a 28-day cycle. Patients had a Cancer and Leukemia Group B performance status of 0 or 1, with a median time since diagnosis of metastatic disease of 10 months (range, 0 to 129 months). Thirty-three patients (80%) had multiple metastatic sites, and 34 patients (83%) had prior chemotherapy or immunotherapy. RESULTS: Of the 39 assessable patients, there were no complete responses but seven partial responses (objective response rate = 17%; 95% confidence interval, 8% to 34%). Five minor responses (25% to 50% decreased tumor size) were also observed. The duration of response for the seven partial responders was 2, 3, 7, 8, 10, 11, and 14 months. Median progression-free survival for the gemcitabine/5-FU group was 28.7 weeks versus 8 weeks for a similar cohort of patients treated on previous phase II studies at the University of Chicago (P =.008). The regimen was well tolerated, with fatigue, mucositis, nausea/vomiting, and grade 2 hematologic toxicities being most common. CONCLUSION: Weekly gemcitabine with continuous infusion 5-FU is an active combination in patients with metastatic RCC. Therapy was well tolerated and produced an improvement in progression-free survival over historical controls.

Evaluation of topotecan in resistant and relapsing multiple myeloma: a Southwest Oncology Group study.

PURPOSE: Topotecan is a topoisomerase I inhibitor with antitumor activity against hematologic and solid tumor malignancies. We evaluated its activity in refractory and relapsing multiple myeloma patients who had received one prior chemotherapeutic regimen. PATIENTS AND METHODS: Toptecan 1.25 mg/m2/d was administered as a 30-minute infusion for 5 days repeated every 3 weeks. Granulocyte colony-stimulating factor (G-CSF) 5 microg/kg/d subcutaneously was administered after the first course of treatment if neutropenia was dose-limiting. RESULTS: Forty-six patients entered the study, with 43 patients eligible. The major toxicity was granulocytopenia with grade 3 or better occurring in 40 of 43 patients treated; 21 of 43 patients developed grade 3 or greater thrombocytopenia. Other significant toxicity included mild nausea in 23 patients and mild vomiting in 13 patients. The overall response rate (partial response or better) was 16% (95% confidence interval, 7% to 31%), with responses occurring in both relapsed and refractory patients. Responses have lasted 70 to 477+ days, with a median progression-free survival duration of 13 months and median survival time of 28 months. CONCLUSION: Topotecan has activity in refractory and relapsing multiple myeloma. Future investigation of topotecan in multiple myeloma including combination therapy and the study of other topoismerase I inhibitors is warranted.

A phase II trial of interferon-alpha and 5-fluorouracil in patients with advanced renal cell carcinoma. A Southwest Oncology Group study.

BACKGROUND: Renal cell carcinoma is a common neoplasm that is often refractory to treatment. It is occasionally responsive to immunomodulating agents including interferon-alpha, which enhances the effects of 5-fluorouracil upon cells. Combinations of these two drugs have been most frequently tested in patients with gastrointestinal cancers, with some promising results. Because interferon-alpha has activity for renal cell carcinoma, a trial of this combination in patients with this malignancy was undertaken. METHODS: The Southwest Oncology Group performed a Phase II clinical trial of the combination of 5-fluorouracil and interferon-alpha for recurrent or metastatic renal cell carcinoma. Eligibility criteria included no prior treatment with medications for cancer, a performance status of 2 or better, and bidimensionally measurable disease. The regimen studied consisted of 5-fluorouracil, 750 mg/M2/day, by continuous intravenous infusion on Days 1-5, and interferon-alpha-2b (Intron A), 5 x 10(6)U/M2/day, subcutaneously on Days 1, 3, and 5, repeated every 21 days. RESULTS: Forty eligible patients were treated; twenty of the 40 underwent a nephrectomy. The regimen was tolerable: 3 patients had Grade 4, and 17 had Grade 3 toxicity. There were 5 partial responses (13% with 95% confidence limits of 4-27%). Median progression free survival for all 40 patients was 4 months and median overall survival was 15 months from the time of registration. CONCLUSIONS: The combination of 5-fluorouracil and interferon-alpha given by this schedule, although tolerable and occasionally yielding responses, is not an improvement over existing therapies.

Doctor-hospital integrated practice.

The doctor-hospital integrated practice is one possible strategy oncologists may wish to employ in order to stay financially solvent in the current unstable health-care environment. Before entering into an arrangement with a particular hospital, the physician should compare the institution's financial health with that of similar hospitals. The practitioner also should review the hospital's current managed-care contracts to ensure that he or she will have access to new patients. Another crucial issue is whether the patients will belong to the physician or to the hospital, in particular whether patients can "follow" the physician if he or she leaves the hospital. Finally, the physician needs to consider whether the arrangement will provide the level of intellectual satisfaction he or she desires. The next step is to explore the various possible doctor-hospital relationships. These include a simple purchase of the practice by the hospital, renting space in a hospital-financed cancer center, or a hybrid of these two arrangements.

Randomized phase III study of 5-fluorouracil plus high dose folinic acid versus 5-fluorouracil plus folinic acid plus methyl-lomustine for patients with advanced colorectal cancer.

BACKGROUND: Metastatic colorectal cancer is generally incurable. The most active regimen available, 5-fluorouracil (5-FU) and folinic acid (Leucovorin), produces response rates of approximately 25% to 30%. Methyl-lomustine is a nitrosourea with modest activity against colorectal cancer. A randomized trial was undertaken to evaluate the impact the addition of methyl-lomustine would have on response, duration of survival, and survival rates in patients with advanced colorectal cancer. METHODS: The methyl-lomustine/5-FU/Leucovorin (MFL) regimen consisted of methyl-lomustine (110 mg/m2), administered on Day 1 of each 8-week cycle with six weekly boluses of 5-FU (600 mg/m2), and Leucovorin (500 mg/m2). The FL treatment arm consisted of the administration of 5-FU and Leucovorin as described above. Patients were evaluated for response and toxicity after each 8-week cycle. RESULTS: Of 319 patients included in this trial, 297 (93.1%) had disease evaluable for response and toxicity: 145 received MFL, and 152 received FL. In this trial, 526 courses of MFL and 529 courses of FL were administered. Methyl-lomustine/5-FU/Leucovorin treatment resulted in 4 complete and 30 partial responses (response rate, 21.9%), and FL treatment resulted in 9 complete and 33 partial responses (response rate, 26.4%). There was no significant difference in median survival duration between patients in the two arms (MFL = 48 weeks, FL = 51 weeks). However, MFL was significantly more toxic with greater myelosuppression than was FL (Grade 3-4 neutropenia: MFL = 56 patients, FL = 27 patients, P < 0.001; Grade 3-4 thrombocytopenia: MFL = 49 patients, FL = 2 patients, P < 0.001; Grade 3-4 anemia: MFL = 15 patients, FL = 6 patients, P < 0.001; and more prolonged median duration of granulocytopenia: MFL = 9 days, FL = 7 days, P < 0.001; and thrombocytopenia: MFL = 14 days, FL = 7.5 days, P < 0.001). CONCLUSION: Because the addition of methyl-lomustine in the MFL schedule markedly increased the toxicity of the regimen and because the FL regimen was as effective as MFL, the authors recommend that Leucovorin and 5-FU remain the treatment choice for treating patients with metastatic colorectal cancer.

A phase II trial of piroxantrone in advanced ovarian carcinoma after failure of platinum-based chemotherapy: Southwest Oncology Group Study 8904.

A phase II trial of the new anthrapyrazole piroxantrone was conducted by the Southwest Oncology Group in advanced ovarian carcinoma. The objective were to evaluate its response rate and toxicity in patients who had disease persistence, progression, or recurrence either during or after platinum-containing chemotherapy. A two-stage statistical design targeted accrual to 15 eligible patients if no responses were observed. The piroxantrone starting dose was 120 mg/m2, with the provision to escalate to 150 and 180 mg/m2. There were 16 eligible patients, all of whom had received either one (12 patients) or two (4 patients) prior platinum-containing regimens; one patient had received doxorubicin. Fourteen of the 16 patients were enrolled either at the time of disease persistence/progression during initial chemotherapy or with recurrence or progression within 6 months of the previous platinum-based remain. One to 5 cycles of piroxantrone were given. Dose escalation was feasible in 7 patients but was prevented in the other 9 by neutropenia. Maximum toxicity for all cycles was none or grade 1 in 2 patients; grade 2, 5; grade 3, 8; and grade 4, 1. All but one of the grade 3 or 4 events was from myelosuppression; there were no adverse cardiac events. No responses were observed. Thus, piroxantrone appears inactive in patients with persistent, progressive, or recurrent ovarian cancer who recently had received a platinum-based regimen.

Reducing duplicate hand and wrist series in the emergency room: experience at Madigan Army Medical Center.

OBJECTIVE: To demonstrate that repetitive hand or wrist series could be minimized with minor refinements of triage. POPULATION: 2,119 consecutive trauma patients requiring hand or wrist series. METHOD: In baseline phase I, radiographs were ordered by triage corpsmen. In phase II, RNs or physicians performed triage and ordered films. Phase III followed inservice training on strategies to minimize duplicate studies. Phase IV required the RN or physician to provide written justification for duplicate studies. The number of duplications in each phase were compared to baseline using the chi-square test of homogeneity. RESULTS: The phase I duplication rate was 10.8%. In phase II, the percentage of duplicate studies was 8.1% (p = 0.12). Phase III decreased duplication to 6.2% (p < 0.01). Phase IV decreased duplicate studies to 5.8% (p < 0.01). CONCLUSION: In an emergency room generating over 180 hand and wrist studies monthly, minor changes in ordering practices reduced the duplication rate from 10.8% to 5.8%.

Phase II trial of edatrexate in patients with advanced pancreatic adenocarcinoma.

BACKGROUND: The methotrexate analogue 10-ethyl-10-deazaaminopterin (10-EdAM, or edatrexate) has shown antitumor activity in preclinical testing and clinical studies of patients with breast, lung and head and neck carcinomas. A phase II study was conducted in patients with advanced pancreatic adenocarcinoma. PATIENTS AND METHODS: Forty patients were enrolled on the clinical trial. Edatrexate was administered intravenously at a dose of 80 mg/m2 weekly for 5 weeks. The treatment course was repeated every 6 weeks. RESULTS: Two partial responses were observed. Both of these patients had partial responses which lasted 2 and 3.5 months. The median survival for all patients was 3.5 months. Serious (grade 3 or 4) toxic effects were primarily mucosal, hematologic, and dermatologic. Two patients experienced severe pulmonary toxic reactions. CONCLUSION: At the dose and schedule used, edatrexate was poorly tolerated and did not demonstrate significant antitumor activity.

Phase II study of fludarabine phosphate for gastric adenocarcinoma. An Illinois Cancer Center trial.

In an Illinois Cancer Center phase II trial, fludarabine phosphate was administered to a total of 14 patients (9 men, 5 women) with advanced, measurable, gastric adenocarcinoma. Fludarabine phosphate was given as a rapid intravenous (IV) bolus at a starting dose of 20 mg/m2/d for the first 5 days of a 28-day cycle. For subsequent cycles, the dose was escalated in increments of 2 mg/m2/d, provided that no toxicities greater than grade 1 were noted. In cases of grade 3 toxicity, dose reductions of 2 mg/m2/d were required, and patients who experienced grade 4 toxicities were removed from study. Receiving one complete 5-day course of fludarabine phosphate and surviving for 4 weeks on study were required for a patient to be evaluable for response. None of the patients responded to treatment. Although fludarabine phosphate was ineffective against gastric adenocarcinoma in this study, toxicity was acceptable at the 20 mg/m2/d times 5 every 28 days dose and schedule.

Phase II study of amonafide in gastric adenocarcinoma. An Illinois Cancer Center trial.

Twelve patients with recurrent, metastatic, or inoperable gastric adenocarcinoma were enrolled in an Illinois Cancer Center phase II trial of amonafide (nafidimide), a novel compound that acts as a DNA intercalator. Treatment consisted of a 60-minute infusion of amonafide which was administered daily for 5 consecutive days every 3 weeks at a starting dose of 300 mg/m2/d. Doses were modified according to the grade of toxicity experienced and eight patients underwent dose escalations. All 12 patients were evaluable for response and toxicities were predominantly hematologic. Stabilization of disease for at least 28 days was observed in seven patients and disease progression was noted in five. The median survival was 7.4 months. Doses were sufficient to produce severe bone marrow toxicity in one-third of the patients treated. None of the patients responded to therapy, implying a true response rate less than .221. Based on the results of this study, amonafide showed no activity against gastric adenocarcinoma; however toxicity appeared acceptable at the 300 mg/m2/d x 5 consecutive days every 3 weeks dose and schedule.

Phase I/II trial of tamoxifen with or without fenretinide, an analog of vitamin A, in women with metastatic breast cancer.

PURPOSE: Considerable attention has been focused on the chemopreventive properties of fenretinide against carcinogen-induced rodent mammary cancer. Less is known about its direct antitumor effects. The combination of tamoxifen and fenretinide is more effective than tamoxifen or fenretinide alone in prevention of rat mammary cancer. However, the combined toxicity of tamoxifen plus fenretinide in humans is unknown. Therefore, we performed a phase I/II trial in women with estrogen receptor (ER)-positive or progesterone receptor (PR)-positive, previously untreated metastatic breast cancer. PATIENTS AND METHODS: Groups of three patients received tamoxifen 20 mg/d, or tamoxifen plus fenretinide 100, 200, 300, or 400 mg/d. Patients who received fenretinide enjoyed a 3-day "drug holiday" every 4 weeks. Serum levels of fenretinide and its major metabolites were monitored. Patients were monitored for known toxicities of tamoxifen and vitamin A analogs, as well as for response. RESULTS: There were no significant adverse effects on renal, hepatic, hematologic, or lipid values. Nyctalopia, photophobia, cheilitis, and pruritus were not observed. Improvement or stabilization of disease occurred in 12 of 15 patients. CONCLUSION: We conclude that tamoxifen administered with fenretinide is nontoxic. Phase III trials of tamoxifen versus tamoxifen plus fenretinide are warranted.

In vivo incorporation of [14C]leucine into brain protein of mice treated with methylmercury and thiol complexes of methylmercury.

The effect of methylmercury and thiol complexes of methylmercury on inhibition of protein synthesis was evaluated. Mice were injected (i.p.) with the following treatments: methylmercuric chloride, methylmercury-glutathione, methylmercury-cysteinylglycine and control (vehicle) for 10 days. Ten animals from each group were injected with [14C]leucine 90 min prior to death. The brains were removed and the extracted protein was subjected to liquid scintillation analysis. Mice receiving the methylmercury and methylmercury-glutathione treatments exhibited significantly greater weight loss than the control while the methylmercury-cysteinylglycine treatment was not significantly different than the control. Incorporation of [14C]leucine into brain protein was significantly depressed in the methylmercury (81% of control) and the methylmercury-glutathione (79% of control) treatments. Protein synthesis in mice receiving the methylmercury-cysteinylglycine complex although not significantly different than the methylmercury treatments was only 92% of the control mice.

Toxicity, distribution, and elimination of thiol complexes of methylmercury after intracerebral injection.

Intracerebral injection of CH3Hg and CH3Hg complexed with glutathione (GSH), cysteine (cys), cysteinylglycine (cys-gly), and homocysteine (homocys) resulted in differences in toxicity. Criteria based on neurological indices, mortality, and weight loss indicated that the cys-gly complex of CH3Hg was significantly less toxic than CH3Hg or the other complexes. The other complexes of CH3Hg (GSH, homocys, and cys) were also found to be less toxic than CH3Hg. The selenium status of the animal did not seem to significantly influence the toxicity of CH3Hg and the complexes. While CH3Hg complexed to cys-gly was significantly less toxic than CH3Hg alone, there were no differences observed in the CH3Hg half-life values or in the distribution of these compounds in the kidneys, brain, liver, and blood. It was observed, however, that the CH3Hg--cys-gly complex had higher fecal excretion on d 3 and 4 following intracerebral injection.

Treatment of malignant pheochromocytoma with combination chemotherapy.

Three patients with rapidly progressive, disseminated malignant pheochromocytoma were treated with a combination chemotherapeutic regimen consisting of cyclophosphamide, vincristine, and dacarbazine in repeated 21- to 28-day cycles. All three patients had a marked decrease in blood pressure and an improvement in performance status within the first few cycles of treatment. At a follow-up of 6 to 13 months all patients continue to receive chemotherapy with further regression of tumor in two and stable disease in one. Their blood pressure is normal with minimal or no antiadrenergic therapy. Therapy has been well tolerated; moderate reversible granulocytopenia, neurotoxicity, and one episode of pneumonitis have been the major toxicities encountered. Thus, combination chemotherapy appears to be effective for symptomatic malignant pheochromocytoma.