levoleucovorin and Mesothelioma

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; Carboplatin; Combined Modality Therapy; Cystadenofibroma; Diagnosis, Differential; Female; Fluorouracil; Humans; Hyperthermia, Induced; Infusions, Parenteral; Irinotecan; Leucovorin; Mesothelioma; Middle Aged; Neoplasm Recurrence, Local; Neoplasms, Second Primary; Organoplatinum Compounds; Ovarian Neoplasms; Ovariectomy; Oxaliplatin; Paclitaxel; Pemetrexed; Peritoneal Neoplasms

Malignant pleural mesothelioma is associated with a poor prognosis because of its resistance to treatment. The authors conducted a Phase II trial in which two drugs (etoposide and 5-fluorouracil) were added to the Cancer and Leukemia Group B cisplatin-mitomycin regimen in an effort to define a more effective chemotherapy.. Forty-five patients with confirmed Stage II malignant pleural mesothelioma were prospectively enrolled in the study. Thirty-one patients received cisplatin 60 mg/m2 on Day 1, 5-fluorouracil 600 mg on Days 1-4, folinic acid 100 mg/m2 on Days 1-4, mitomycin C 10 mg/m2 on Day 3, and etoposide 100 mg/m2 i.v. on Days 1-3, with prophylactic hematopoietic growth factors. Fourteen patients received cisplatin, 5-fluorouracil, folinic acid, and mitomycin C with the protocol unchanged, and oral etoposide 50 mg on Days 1-21 without growth factors (1 cycle every 28 days). Histology included epithelial (in 33 cases), sarcomatous (in 6), mixed (in 3), and unspecified type (in 3).. Two hundred eleven cycles were administered. Treatment was well tolerated and the major toxicity was hematologic: anemia in 30% of cases, neutropenia in 24%, and 2 probable cases of mitomycin-induced pneumonitis. The objective response rate was 38% (17 of 45 were partial responses), and the median response duration was 12 months. The median survival time was 16 months. There were no differences in response or survival between the 31 patients treated with growth factors and the 14 patients treated without them. Survival was slightly better for responders than for nonresponders who had stable disease or progression (20 vs. 10 months, P < 0.05).. This four-drug combination was effective, with a notably high response rate, acceptable toxicity, and good adherence to protocol doses. The impact on survival was limited.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Asbestos; Cisplatin; Combined Modality Therapy; Etoposide; Female; Filgrastim; Fluorouracil; Granulocyte Colony-Stimulating Factor; Hematologic Diseases; Humans; Immunotherapy; Leucovorin; Male; Mesothelioma; Middle Aged; Mitomycin; Pleural Neoplasms; Prospective Studies; Recombinant Proteins; Remission Induction; Survival Analysis; Treatment Outcome

The Cancer and Leukemia Group B (CALGB) conducted sequential Phase II multicenter trials to evaluate the activity of edatrexate alone (E) or with leucovorin rescue (EL) in patients with malignant pleural mesothelioma (CALGB Protocol 9131).. Twenty patients were accrued to the E portion of the study and received edatrexate, 80 mg/m(2), intravenously over 20-30 minutes weekly. After a protocol amendment precipitated by excessive toxic events with E, 40 patients were enrolled in the EL arm and received the same dose of edatrexate with leucovorin, 15 mg orally, every 6 hours for 4 doses beginning 24 hours after edatrexate. Eligibility criteria included a CALGB performance status of 0-2 and no prior chemotherapy. A central pathology review was performed. Of the 58 patients included in this analysis (20 receiving E and 38 receiving EL), 36 had epithelial cell type and 22 had mixed or sarcomatous cell types. There were 31 patients with measurable disease and 27 with evaluable disease.. The overall response rate was 25% for E (95% confidence interval [95% CI], 9-49%) and 16% for EL (95% CI, 6-31%). There was a 5% complete response [CR] rate, a 10% partial response [PR] rate, and a 10% regression [R] rate for E and a 0% CR rate, a 3% PR rate, and a 13% R rate for EL. The median survival duration from study entry was 9.6 months and 6.6 months, respectively, for E and EL; 1-year survival was 50% and 32%, respectively, for E and EL. There were four early deaths with the E regimen (including two from neutropenic sepsis) and one early death with the EL regimen (from progressive disease). Principal toxicities included mu cositis, myelosuppression, and rash, which were less frequent with leucovorin rescue.. Moderate antitumor activity has been observed with both regimens. Leucovorin rescue ameliorated the mucosal, hematologic, and dermatologic toxicities of edatrexate, but also may have reduced its efficacy.

Topics: Aminopterin; Antineoplastic Agents; Dose-Response Relationship, Drug; Female; Humans; Leucovorin; Leukemia; Male; Mesothelioma; Middle Aged; Pleural Neoplasms; Survival Rate; Treatment Failure

To investigate the ability of leucovorin (LV) to abrogate dose-limiting toxicities of pralatrexate (PDX) while maintaining efficacy, in vivo.. H2052 mesothelioma cells were treated with the antifolates methotrexate (MTX), PDX and pemetrexed, with and without LV rescue 24 h later. Cell killing was evaluated 48 h later. Female nude mice bearing H2052 xenografts were treated with varying doses and schedules of the antifolate PDX and LV.. In vitro, H2052 cells were more sensitive to PDX as compared to MTX and pemetrexed. Administration of LV 24 h after antifolate treatment reduced efficacy of antifolates MTX and pemetrexed, but not PDX. In vivo, LV was found to reduce toxicity of PDX at the maximum tolerated dose without sacrificing efficacy. Lethal doses of PDX were rescued by LV, and mice bearing the H2052 tumor demonstrated prolonged and enhanced tumor regression.. High-dose PDX with subsequent LV rescue may be a viable treatment strategy in mesothelioma and other cancers. The inclusion of LV rescue into new and existing PDX treatment protocols should be explored as a way to expand the tolerability and effectiveness of PDX in the clinic.

Topics: Aminopterin; Animals; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Drug Synergism; Female; Folic Acid Antagonists; Glutamates; Guanine; Humans; Leucovorin; Mesothelioma; Methotrexate; Mice, Nude; Pemetrexed; Time Factors; Tumor Burden; Vitamin B Complex; Xenograft Model Antitumor Assays

Topics: Adolescent; Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Fluorouracil; Gastrointestinal Hemorrhage; Humans; Leucovorin; Male; Mesothelioma; Organoplatinum Compounds; Telangiectasia, Hereditary Hemorrhagic; Vascular Endothelial Growth Factor A

Topics: Antineoplastic Agents; Cisplatin; Cortisone; Drug Therapy, Combination; Humans; Leucovorin; Mesothelioma; Pleural Neoplasms; Time Factors

The incidence of malignant mesothelioma has increased greatly in the last 40 years. Current and recent past exposure to asbestos is expected to substantially increase this incidence. We report nine cases of malignant mesothelioma which temporarily responded to treatment with high-dose methotrexate-citrovorum rescue and vincristine. Further clinical trials of high-dose methotrexate with citrovorum rescue appear indicated in this disease.

Topics: Adult; Aged; Asbestos; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Leucovorin; Leukopenia; Male; Mesothelioma; Methotrexate; Middle Aged; Peritoneal Neoplasms; Pleural Neoplasms; Time Factors; Vincristine