levoleucovorin and Soft-Tissue-Neoplasms

Metastatic breast cancer remains an incurable disease and the median overall survival has not significantly improved over the past two decades. Aims of the present randomized phase II trial were to analyse activity and toxicity of chemotherapies with single agent or with combination regimens in previously treated patients with advanced breast cancer. Ninety-nine eligible patients were randomized to receive the following chemotherapies: Arm A - vinorelbine 30 mg/m2 i.v. weekly; Arm B - leucovorin 100 mg/m2 i.v. followed by 5-fluorouracil 370 mg/m2 i.v. days 1 --> 5, q 28 days; Arm C - mitoxantrone 12 mg/m2 i.v. only day 1 + leucovorin 100 mg/m2 i.v. followed by 5-fluorouracil 370 mg/m2 i.v. days 1 --> 3, q 28 days. Patients characteristics are comparable in the three groups. The median number of chemotherapy courses administered was 7, 6 and 5 in arm A, B and C, respectively. Objective responses were 24%, 30% and 21% and the median duration of responses were 2, 2.5 and 5.5 months in the arm A, B and C, respectively. Median overall survivals were 9.5, 9 and 9 months in the three arms. No difference was noted comparing the survivals of responding or non responding patients. General toxicity was not mild, with 27.5% of patients experiencing WHO grade 3-4 toxicities. Our results are similar in the three groups of patients and comparable to those reported by other authors. Chemotherapy applied to patients with second or subsequent recurrence allow objective responses in a small percentage of patients. Moreover responders have a negligible prolongation of survival.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Breast Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Mitoxantrone; Salvage Therapy; Soft Tissue Neoplasms; Survival Rate; Treatment Failure; Vinblastine; Vinorelbine

To assess the activity of paclitaxel in combination with 5-fluorouracil (5-FU) and leucovorin in breast cancer, a phase II trial was conducted in women with metastatic disease. Toxicity, response rate, median survival, median duration of response, and median time to disease progression were measured. Between January 1994 and May 1996, 47 patients with metastatic breast cancer and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) < or = 2 who had previously been treated with chemotherapy received 175 mg/m2 paclitaxel over 3 hours on day 1. After paclitaxel administration, 300 mg intravenous (i.v.) leucovorin over 30 minutes was administered followed by 350 mg/m2 i.v. push 5-FU. Both 5-FU and leucovorin were given on days 1-3. Treatment was repeated every 28 days for a minimum of 6 cycles per patient. Two (4%) patients had a complete response and 21 (45%) patients had a partial response for an overall response rate of 49% (95% confidence interval: 35%-63%). The median survival was 17.7 months, median duration of response was 8.6 months, and median time to disease progression was 6.3 months. There was no statistical difference in survival or time to progression between anthracycline-naive, anthracycline-sensitive, and anthracycline-resistant patients. Nine (19%) patients had grade 3 or 4 neutropenia, and no patient required blood or platelet transfusion. The most frequently observed nonhematologic toxicities were arthralgia and myalgia. Pharmacokinetic data were obtained on 19 patients. Responders had higher peak plasma concentrations of paclitaxel than nonresponders (4.46 vs. 2.9 micrograms/mL; P = 0.02). Paclitaxel/5-fluorouracil/leucovorin is an active, well-tolerated regimen for patients with metastatic breast cancer.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Breast Neoplasms; Disease Progression; Drug Administration Schedule; Drug Monitoring; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Middle Aged; Paclitaxel; Proportional Hazards Models; Soft Tissue Neoplasms; Survival Analysis; Time Factors; Treatment Outcome; Viscera

Because leucovorin increases the antitumor activity of 5-fluorouracil (5-FU) in multiple tumor model systems, we performed a clinical trial to evaluate this combination in women who had received one or no prior chemotherapy regimens for metastatic breast cancer. Thirty-six women with measurable metastatic disease were treated with five consecutive days of i.v. leucovorin, 500 mg/m2/day infused over 30 min, followed 1 h later by i.v. bolus 5-FU, 375 mg/m2/day. Repeat cycles were planned at 4-week intervals. Tumor regression occurred in 10 of 36 patients (28%; 95% confidence interval, 14-45%) with a median time to disease progression (TTP) of 8.7 months (range 3.2-16.8 months) in the responding patients. The median TTP and survival for all patients were 3.0 and 12.4 months, respectively. Among 30 patients who had received prior 5-FU, tumor regressions were seen in seven (23%; 95% confidence interval 10-42%). The major dose-limiting toxicity in this study was mucositis, affecting 89% of the patients. Other toxicities were tolerable in the majority of patients. Although the role of leucovorin in breast cancer clinical practice remains undefined, the data from this trial support the hypothesis that leucovorin enhances the cytotoxic activity of 5-FU against human breast cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Evaluation; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Soft Tissue Neoplasms; Survival Rate

Sixty-five patients with high-grade soft tissue sarcomas of the extremities were treated in a prospective randomized trial evaluating the efficacy of adjuvant chemotherapy with doxorubicin, cyclophosphamide, and high-dose methotrexate. Local therapy was administered using either amputation or wide local resection plus radiation therapy and the chemotherapy was begun in the immediate postoperative period. Actuarial analysis with median follow-up of 653 days revealed an advantage in continuous disease-free and overall survival in the patient group receiving chemotherapy (P = 0.0008 and P = 0.04, respectively, one-sided Mantel-Haenszel test). The continuous disease-free survival at three years is 92% in the chemotherapy group compared to 60% in the no chemotherapy group. Overall survival is 95% and 74% in these two patient groups. Fifty-eight percent of patients had limb-sparing surgery plus radiation therapy and 42% underwent amputation. In both treatment subgroups analyzed separately, chemotherapy resulted in an improvement in disease-free survival compared to randomized controls not receiving chemotherapy (P = 0.006 and P = 0.04 for groups receiving amputation and limb sparing, respectively). There were no local failures in the patients receiving chemotherapy and two local failures in the no chemotherapy group. The results of this trial confirm the historically controlled pilot trial performed in 26 patients between 1975 and 1977. A current update of the patients in the pilot trial, with a minimum four-year follow-up, reveals an improvement in disease-free and overall survival due to chemotherapy (P less than 0.002). Analysis of the previous pilot trial indicates that only few recurrences are seen beyond three years. Thus, it appears that adjuvant chemotherapy should be a part of the treatment adult patients with soft tissue sarcomas of the extremities.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Extremities; Female; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Prospective Studies; Random Allocation; Sarcoma; Soft Tissue Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoid Tumor; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Middle Aged; Rectal Neoplasms; Rectum; Remission Induction; Soft Tissue Neoplasms; Time Factors; Treatment Outcome

Spinal cord compression as first presentation of non-Hodgkin's lymphoma (NHL) is an uncommon event. Diagnosis of NHL usually is performed on a laminectomy specimen. Spinal cord compression has been reported in 5% of patients with solid tumors. Although this clinical picture has been considered as very unusual among NHL patients, some series regarding descompresive laminectomy indicate that NHL was the underlying cause in 15% of these cases. We report two cases of patients with NHL who presented paraparesia secondary to spinal cord compression due to lymphomatous mass in the epidural region which was showed by magnetic resonance imaging. The emergency laminectomy and treatment with chemotherapy allowed the clinical recuperation of both patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Epidural Space; Etoposide; Female; Humans; Laminectomy; Leucovorin; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Mechlorethamine; Methotrexate; Middle Aged; Paresis; Paresthesia; Prednisone; Procarbazine; Soft Tissue Neoplasms; Spinal Cord Compression; Spinal Neoplasms; Thoracic Neoplasms; Thoracic Vertebrae; Urinary Retention; Vincristine

A human lymphoblastoid line (RPMI-1788), a methotrexate-sensitive human fibrosarcoma cell line (HT-1080), and a naturally resistant mixed mesodermal human sarcoma cell line with impaired methotrexate polyglutamylation (HS-42), recently established in our laboratory, were used to compare the ability of leucovorin to prevent trimetrexate cytotoxicity. Growth inhibition and an in situ thymidylate synthesis activity assay showed that inhibitory effects of trimetrexate (1 to 10 microM), 24-h exposure, were prevented by 10 microM leucovorin in the RPMI-1788 and HT-1080 cell lines but not in the HS-42 cell line. Total intracellular reduced folates increased about 2-fold in the three cell lines after exposure to leucovorin (10 microM) for 4 h, and after a 6-hour efflux remained elevated (1.5- and 1.3-fold of control levels) in RPMI-1788 and HT-1080 cells but decreased to 80% of control levels in HS-42 cells. Although uptake of leucovorin and levels of N5,N10-methylenetetrahydrofolate achieved after leucovorin administration were similar in RP-MI-1788 and HS-42 cells, polyglutamylate forms of this coenzyme were less in the HS-42 cells as compared to RPMI-1788 cells. Based on these studies, the combination of trimetrexate with leucovorin should be further investigated as a way to increase the therapeutic index in some patients with soft tissue sarcomas.

Topics: Drug Resistance; Fibrosarcoma; Folic Acid; Humans; Leucovorin; Methotrexate; Pteroylpolyglutamic Acids; Soft Tissue Neoplasms; Trimetrexate; Tumor Cells, Cultured

Topics: Bone Neoplasms; Humans; Leucovorin; Methotrexate; Soft Tissue Neoplasms

Sixty-four adult patients with soft-tissue sarcomas received adjuvant chemotherapy with a six-drug combination regimen after surgery. Seventy percent remain free of disease with a median follow-up of 50 months. Only seven patients have died of their disease, all within the first 24 months after surgery. Most patients experienced severe nausea and vomiting secondary to the actinomycin D and dacarbazine parts of the protocol, and three patients experienced frank Adriamycin cardiomyopathy. Toxicity from this combination was otherwise mild. The 58% recurrence rate of 12 patients who discontinued therapy early because of nausea was significantly greater than the 23% rate for those who completed or relapsed on therapy (P = 0.01). Adjuvant chemotherapy should be considered after surgery for patients with soft-part sarcomas, especially those with high-grade tumors that have a considerable risk of recurrence.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Dacarbazine; Dactinomycin; Doxorubicin; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Sarcoma; Soft Tissue Neoplasms; Vincristine

Seven patients with bone or soft tissue sarcomas but without metastatic CNS disease developed a chronic leukoencephalopathy after high-dose (8000-15,000 mg/m2) iv methotrexate (MTX) chemotherapy with leucovorin (LV) rescue. Approximately 12 MTX-LV treatments were administered over a 3-7 month period. None of the patients had cranial irradiation. The syndrome usually began several months after the initiation of chemotherapy with subtle personality changes followed by a progressive dementia, focal seizures, pseudobulbar palsy, spastic quadriparesis, and stupor. Computerized tomographic scans revealed diffuse white matter hypodensity in five patients and atropic changes in five patients. Serum MTX concentrations were elevated in four of six patients prior to several MTX-LV treatments, suggesting that MTX persisted in tissues for a long time. Abnormally high levels of MTX were detected in the cerebrospinal fluid of all four patients several days after an MTX-LV treatment, at a time when their encephalopathy was most severe. Pathologic brain material was obtained from three patients and revealed a spectrum of abnormalities. The syndrome observed in our patients clinically resembles the one described in children with acute lymphatic leukemia who received cranial irradiation and large cumulative amounts of low-dose (12-20 mg/m2) systemic MTX without LV.

Topics: Adolescent; Adult; Bone Neoplasms; Brain; Child; Female; Humans; Leucovorin; Leukoencephalopathy, Progressive Multifocal; Male; Methotrexate; Soft Tissue Neoplasms; Tomography, X-Ray Computed

A case of inflammatory fibrous histiocytoma arising in soft tissue near the sacrum is presented. The patient's mode of presentation, clinical course, and tumor histology were typical of this disease. The tumor was inoperable, and radiotherapy combined with doxorubicin, cyclophosphamide, and intermediate-dose oral methotrexate produced a dramatic complete response lasting over 27 months. Favorable results with nonsurgical therapy have not previously been reported for this disease. The gratifying result obtained, although of relatively short duration to date, indicates that combined modality therapy may provide significant back-up to aggressive surgery. The use of these agents in an adjuvant setting merits study.

Topics: Adult; Antineoplastic Agents; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Histiocytoma, Benign Fibrous; Humans; Leucovorin; Methotrexate; Radiography; Soft Tissue Neoplasms

Topics: Adolescent; Adult; Antineoplastic Agents; Child; Child, Preschool; Chlorambucil; Cyclophosphamide; Dacarbazine; Dactinomycin; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Leucovorin; Methotrexate; Neoplasm Staging; Sarcoma; Soft Tissue Neoplasms; Urogenital Neoplasms; Vincristine

Surgical extirpation of the primary tumor has traditionally been utilized as initial treatment for sarcomas in children. The present report, however, demonstrates that sarcomas are optimally treated by means of a coordianted multidisciplinary approach. The latter offers the potential for achieving improved survival and preservation of organs and limbs, particularly for structures of the head and neck, for extremities, and in the genitourinary system.

Topics: Adolescent; Age Factors; Antineoplastic Agents; Bone Neoplasms; Child; Child, Preschool; Cyclophosphamide; Dactinomycin; Doxorubicin; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Infant; Leucovorin; Lymphatic Metastasis; Male; Methods; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Rhabdomyosarcoma; Sarcoma; Sarcoma, Ewing; Soft Tissue Neoplasms; Vincristine

In clinical studies performed during 111 infusions of high dose methotrexate (MTX) we have evolved a clinical and laboratory protocol which permits such therapy without prohibitive risk to the patient. The plasma MTX data obtained indicate that pharmacokinetic disposition is dose related during these infusions and that such data are useful in identifying patients at risk from serious toxicity.

Topics: Adolescent; Adult; Aged; Bone Neoplasms; Drug Therapy, Combination; Humans; Leucovorin; Melanoma; Methotrexate; Middle Aged; Neoplasms; Sarcoma; Soft Tissue Neoplasms