levoleucovorin and Hematologic-Diseases

Methotrexate (MTX) is a disease modifying antirheumatic drug (DMARD) used as a first line agent for treating rheumatoid arthritis (RA). Pharmacologically, it is classified as an antimetabolite due to its antagonistic effect on folic acid metabolism. Many patients treated with MTX experience mucosal, gastrointestinal, hepatic or haematologic side effects. Supplementation with folic or folinic acid during treatment with MTX may ameliorate these side effects.. To identify trials of supplementation with folic acid or folinic acid during MTX therapy for rheumatoid arthritis and to assess the benefits and harms of folic acid and folinic acid (a) in reducing the mucosal, gastrointestinal (GI), hepatic and haematologic side effects of MTX, and (b) whether or not folic or folinic acid supplementation has any effect on MTX benefit.. We originally performed MEDLINE searches, from January 1966 to June 1999. During the update of this review, we searched additional databases and used a sensitive search strategy designed to retrieve all trials on folic acid or folinic acid for rheumatoid arthritis from 1999 up to 2 March 2012.. We selected all double-blind, randomised, placebo-controlled clinical trials (RCTs) in which adult patients with rheumatoid arthritis were treated with MTX (at a dose equal to or less than 25 mg/week) concurrently with folate supplementation. In this update of the review we only included trials using 'low dose' folic or folinic acid (a starting dose of ≤ 7 mg weekly).. Data were extracted from the trials, and the trials were independently assessed for risk of bias using a predetermined set of criteria.. Six trials with 624 patients were eligible for inclusion. Most studies had low or unclear risk of bias for key domains. The quality of the evidence was rated as 'moderate' for each outcome as assessed by GRADE, with the exception of haematologic side effects which were rated as 'low'. There was no significant heterogeneity between trials, including where folic acid and folinic acid studies were pooled.For patients supplemented with any form of exogenous folate (either folic or folinic acid) whilst on MTX therapy for rheumatoid arthritis, a 26% relative (9% absolute) risk reduction was seen for the incidence of GI side effects such as nausea, vomiting or abdominal pain (RR 0.74, 95% CI 0.59 to 0.92; P = 0.008). Folic and folinic acid also appear to be protective against abnormal serum transaminase elevation caused by MTX, with a 76.9% relative (16% absolute) risk reduction (RR 0.23, 95% CI 0.15 to 0.34; P < 0.00001), as well as reducing patient withdrawal from MTX for any reason (60.8% relative (15.2% absolute) risk reduction, RR 0.39, 95% CI 0.28 to 0.53; P < 0.00001).We analysed the effect of folic or folinic acid on the incidence of stomatitis / mouth sores, and whilst showing a trend towards reduction in risk, the results were not statistically significant (RR 0.72, 95% CI 0.49 to 1.06)It was not possible to draw meaningful conclusions on the effect of folic or folinic acid on haematologic side effects of methotrexate due to small numbers of events and poor reporting of this outcome in included trials.It does not appear that supplementation with either folic or folinic acid has a statistically significant effect on the efficacy of MTX in treating RA (as measured by RA disease activity parameters such as tender and swollen joint counts, or physician's global assessment scores).. The results support a protective effect of supplementation with either folic or folinic acid for patients with rheumatoid arthritis during treatment with MTX.There was a significant reduction shown in the incidence of GI side effects, hepatic dysfunction (asmeasured by elevated serum transaminase levels) as well as a significant reduction in discontinuation of MTX treatment for any reason. A trend towards a reduction in stomatitis was demonstrated however this did not reach statistical significance.This updated review with its focus on lower doses of folic acid and folinic acid and updated assessment of risk of bias aimed to give a more precise and more clinically relevant estimate of the benefit of folate supplementation for patients with rheumatoid arthritis receiving methotrexate.

Topics: Abdominal Pain; Adult; Antirheumatic Agents; Arthritis, Rheumatoid; Folic Acid; Folic Acid Antagonists; Gastrointestinal Diseases; Hematologic Diseases; Humans; Leucovorin; Methotrexate; Nausea; Vomiting

Capecitabine (Xeloda), Roche Laboratories Inc., Nutley, NJ) is an orally administered fluoropyrimidine carbamate that serves as a prodrug of 5-fluorouracil (5-FU), an integral component of chemotherapy (CT) regimens for metastatic colorectal cancer (mCRC). As the drug is orally administered, capecitabine permits greater convenience and flexibility in dosing by eliminating the need for continuous infusion and its potential complications. In phase 3 trials, capecitabine has been used as an alternative to 5-FU, both as a monotherapy and in combination with agents such as oxaliplatin (as XELOX), with good efficacy and tolerability. Combination therapy with capecitabine and irinotecan (XELIRI), however, has produced more variable results, with some dose combinations and schedules resulting in excessive and/or unexplained treatment-related toxicity. Recent initiatives using lower doses of capecitabine and irinotecan, as well as alternative dosing schedules, have resulted in more favorable outcomes (efficacy and tolerability), even in combination with targeted-agents such as bevacizumab. Dose reduction in elderly populations and in those with moderate renal impairment also appears to be important for minimizing toxicity with XELIRI regimens. Although additional phase 3 studies are needed, XELIRI may be an effective base CT regimen, allowing a greater number of treatment options for tumor control in patients with mCRC.

Topics: Adenocarcinoma; Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Clinical Trials as Topic; Colorectal Neoplasms; Deoxycytidine; Dose-Response Relationship, Drug; Drug Administration Schedule; Fluorouracil; Gastrointestinal Diseases; Hematologic Diseases; Humans; Irinotecan; Leucovorin; Multicenter Studies as Topic; Oxaloacetates; Prodrugs; Randomized Controlled Trials as Topic; Treatment Outcome

Methotrexate is a folic acid antagonist widely used for the treatment of inflammatory disorders for more than 50 years. Methotrexate is a standard systemic therapy for severe psoriasis and rheumatoid arthritis. Folic acid supplementation has been advocated to limit the toxicity of methotrexate on blood cells, gastrointestinal tract and liver. However, there is still controversy regarding the usefulness of folic acid supplementation.. We sought to assess the evidence for the efficacy of folic acid supplementation in patients treated with methotrexate for inflammatory diseases. We also investigated whether folic acid supplementation may decrease the efficacy of methotrexate.. Cochrane and MEDLINE databases were systematically searched. Randomized controlled trials in patients treated with methotrexate for rheumatoid arthritis or psoriasis with or without arthritis were included. Study selection, assessment of methodological quality, data extraction and analysis were carried out by two independent researchers. We selected double-blind randomized placebo-controlled trials. Analysis was performed for each subgroup of side-effects: gastrointestinal, mucocutaneous, haematological and hepatic.. Six randomized controlled trials met the inclusion criteria, with a total sample of 648 patients. There were 257 patients in the placebo group, 198 patients treated with folic acid, and 193 patients treated with folinic acid. The statistical analysis showed a significant reduction of 35.8% of hepatic side-effects induced by methotrexate for patients with supplementation with folic or folinic acid (95% confidence interval -0.467 to -0.248). There was no statistical difference for mucocutaneous and gastrointestinal side-effects although there was a trend in favour of supplementation. The effect of supplementation on haematological side-effects could not be assessed accurately due to a low incidence of these events in the population studied. We were unable to analyse the effect of supplementation on the effectiveness of methotrexate, as markers of activity used in each study were not comparable.. Supplementation with folic acid is an effective measure to reduce hepatic adverse effects associated with methotrexate treatment. There is no difference between folinic acid and folic acid, but the lower cost of the latter promotes its use.

Topics: Arthritis, Rheumatoid; Chemical and Drug Induced Liver Injury; Drug Eruptions; Folic Acid; Gastrointestinal Diseases; Hematologic Diseases; Humans; Immunosuppressive Agents; Leucovorin; Liver Diseases; Methotrexate; Psoriasis; Randomized Controlled Trials as Topic

To assess the effects of folic acid and folinic acid in reducing the mucosal and gastrointestinal (GI) and haematologic side effects of low-dose of Methotrexate (MTX) in patients with Rheumatoid Arthritis (RA) and to determine whether or not folate supplementation alters MTX efficacy.. We searched the Cochrane Controlled Clinical Trial's Register (CCTR), the Cochrane Musculoskeletal Group Specialized Register and Medline up to and including June 1999, using the search strategy developed by the Cochrane Collaboration (Dickersin 1994). We also handsearched the following: (i) bibliographic references; (ii) current contents of the last 6 months; (iii) abstracts of the rheumatology meetings; and (iv) all issues of four journals; Journal of Rheumatology, Arthritis & Rheumatism, Clinical and Experimental Rheumatology, and British Journal of Rheumatology. All languages were included. Principal investigators were also contacted in order to look for unpublished literature.. We selected all double-blind, randomized, placebo-controlled, clinical trials (RCTs), in which adult RA patients were treated with a low dose of MTX (<20 mg / week) concurrently with folate supplementation.. Two observers extracted the data and assessed the quality of the trials. (BS, Z0) The overall treatment effect across trials was calculated using a fixed effect model. Disease activity was evaluated using standardized mean differences to ensure comparability across outcome measures. Results are presented with 95% Confidence Inervals (95% CI). Subgroup analyses were conducted evaluating different doses and sensitivity analysis looking at the quality of the trials. Publication bias was assessed with an inverted funnel plot technique. Heterogeneity of the trials was measured using a standard chi square test. Costs per month in different countries were compared.. Of the 12 trials retrieved, 7 met the inclusion criteria. The total sample included 307 patients, of which 147 were treated with folate supplementation, 80 patients with folinic acid and 67 patients with folic acid. A 79% reduction in mucosal and GI side effects was observed for folic acid [OR = 0.21 (95% CI 0.10 to 0.44)]. For folinic acid, a clinically but non-statistically significant reduction of 43% was found [OR = 0. 57 (95% CI 0.28 to 1.15)]. No major differences were observed between low and high doses of folic or folinic acid. Haematologic side effects could not be analyzed, since details of each haematologic side effect by patients were not provided. No consistent differences in disease activity parameters were observed when comparing placebo and folic or folinic acid at low or high doses, although patients on high dose folinic acid had an increase in the number of tender joints, but not swollen joints. Large differences in costs across countries were found, but folinic acid was more expensive in all.. The results support the protective effect of folate supplementation in reducing MTX side effects related to the oral and GI systems. We could not determine if folic was different from folinic acid. Therefore, for folinic acid to be considered cost-effective it must be found more effective than folic acid at reducing MTX side effects.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Folic Acid; Folic Acid Antagonists; Gastrointestinal Diseases; Hematologic Diseases; Humans; Leucovorin; Methotrexate

The scientific basis for using folinic acid in combination with the antiparasitic drugs prescribed to AIDS patients has been reviewed. In vitro and experimental data are unclear. On the basis of folinic acid metabolism and pharmacology and of clinical experience, we suggest that folinic acid should not be systematically added to the curative treatment of pneumocystosis with cotrimoxazole. Folinic acid may be added to prophylactic regimens using high-dose cotrimoxazole (i.e. 800 mg sulfamethoxazole twice a day) and in malnourished patients. It should be administered as soon as cytopenia occurs in the course of treatment. Concerning toxoplasmosis, the addition of folinic acid is recommended in doses of 10 to 20 mg/day in acute therapy and 5 to 10 mg/day in maintenance therapy. Dosage must be adjusted to the results of blood counts.

Topics: Acquired Immunodeficiency Syndrome; Drug Therapy, Combination; Folic Acid; Hematologic Diseases; Humans; Leucovorin; Opportunistic Infections; Pneumonia, Pneumocystis; Pyrimethamine; Sulfadiazine; Toxoplasmosis, Cerebral; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Abnormalities, Drug-Induced; Bone Marrow; Chemical and Drug Induced Liver Injury; Female; Hematologic Diseases; Humans; Kidney Diseases; Leucovorin; Liver; Methotrexate; Pregnancy; Psoriasis; Skin

Dose modification of chemotherapy for metastatic colorectal cancer (MCRC) is often needed, especially in second-line and later-line treatments due to adverse events of previous treatment and poor patient condition. No study has focused on ramucirumab plus modified dose of FOLFIRI for MCRC, and whether low relative dose intensity (RDI) affects treatment efficacy has not been clarified.. MCRC patients who received ramucirumab plus FOLFIRI, which consisted of 150 mg/m. A total of 43 patients were assessed. Median age was 63 years, and 22 patients (51%) were women. Twenty-six patients (60%) were given ramucirumab plus FOLFIRI as second-line therapy, and 17 (40%) as third or later-line. The median relative dose intensity (RDI) of irinotecan was 60.6%, which is lower than that in the pivotal phase 3 study (RAISE), and other agents showed the same trend. Median progression-free survival was 4.8 [95% confidence interval (CI) 3.2-5.7] months for all patients, 5.4 (95% CI 3.5-7.2) months for second-line patients, and 2.8 (95% CI 1.6-5.8) months for third or later-line patients. Median overall survival was 17.3 (95% CI 11.5-22.4) months for all patients. Patients with irinotecan RDI less than 60% showed similar treatment efficacy. Hematological toxicities of grade 3 or worse were observed in 21 patients, but all were manageable.. Low RDI did not compromise the treatment efficacy of ramucirumab plus modified FOLFIRI for MCRC patients.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Hematologic Diseases; Humans; Leucovorin; Male; Middle Aged; Progression-Free Survival; Ramucirumab; Retrospective Studies; Treatment Outcome

The optimal therapeutic strategy in patients with rectal cancer and synchronous unresectable metastases remains unknown. We evaluated the efficacy of FOLFIRINOX induction therapy in this setting.. Chemotherapy-naïve patients received at least 8 cycles of FOLFIRINOX. The primary end-point was the 4-month disease control (4 m DC) rate. Tumour responses were centrally reviewed and assessed by computed tomography scan for metastases (Response Evaluation Criteria in Solid Tumours criteria) and magnetic resonance imaging for rectal tumorus. With a Simon 2-stage design and a targeted (H1) 4 m DC > 75%, 65 patients were enrolled from July 2012 to February 2015: male, 78%; median age, 61 years; performance status, 0-1, 98%; liver metastases, 92%; ≥2 metastatic sites, 63%.. Fifty-six (85%) of the 65 patients received the 8 planned FOLFIRINOX cycles. The primary objective was achieved (4 m DC rate: 94%; 95% confidence interval [CI], 86.3-97.8). Primary tumour symptoms decreased from 72% at baseline to 10% at 4 months. Response rate was 86%, and a >70% primary tumour volume decrease was seen in 63% of patients. Forty-four patients (68%) had at least one grade 3 side-effect; no toxic deaths occurred. Median follow-up was 35.0 months (95% CI, 31.3-43.7). Median progression-free survival and overall survival were 10.9 m (95% CI, 8.8-12.9) and 33.4 m (95% CI, 22.6-38.2), respectively.. Upfront FOLFIRINOX is feasible and allows good local and distant control. It therefore offers the opportunity to choose the best therapeutic strategy for each patient and to personalise treatment according to the local and distant efficacy results of this induction step.. Clinicaltrials.gov, NCT01674309.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Fatigue; Female; Fluorouracil; Follow-Up Studies; Gastrointestinal Diseases; Hematologic Diseases; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Lung Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Oxaliplatin; Paresthesia; Progression-Free Survival; Rectal Neoplasms; Remission Induction; Tomography, X-Ray Computed; Treatment Outcome

In the phase 3 randomised NAPOLI-1 clinical study, a 45% increase in median overall survival (OS) was shown with liposomal irinotecan, 5-fluorouracil and leucovorin (nal-IRI+5-FU/LV) versus 5-FU/LV in patients with metastatic pancreatic cancer progressing after gemcitabine-based therapy. Here, we report data from a pre-specified, expanded analysis of outcomes in the per-protocol (PP) population.. The PP population comprised patients receiving ≥80% of planned treatment during the first 6 weeks, with no major protocol violations. A post-hoc analysis of the non-PP population was also performed.. For PP patients, median OS was 8.9 (95% confidence interval: 6.4-10.5) months with nal-IRI+5-FU/LV (n = 66) vs 5.1 (4.0-7.2) months with 5-FU/LV (n = 71; unstratified hazard ratio [HR] 0.57, p = 0.011). For non-PP patients, it was 4.4 (3.3-5.3) months with nal-IRI+5-FU/LV (n = 51) vs 2.8 (1.7-3.2) months with 5-FU/LV (n = 48; unstratified HR 0.64, p = 0.0648).. A statistically significant survival advantage was observed with nal-IRI+5-FU/LV vs 5-FU/LV in the PP patient population.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Deoxycytidine; Drug Resistance, Neoplasm; Fluorouracil; Gastrointestinal Diseases; Gemcitabine; Hematologic Diseases; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Liposomes; Middle Aged; Pancreatic Neoplasms; Polyethylene Glycols; Progression-Free Survival; Proportional Hazards Models

Adverse events associated with 5-fluorouracil (5FU) based adjuvant therapy in colorectal cancer (CRC) patients may predict survival. We studied whether haematological (leucopenia, neutropenia, thrombocytopenia) or non-haematological (mucositis, diarrhoea, nausea/vomiting, hand-foot syndrome or other toxicity) adverse events were associated with disease-free survival (DFS) or overall survival (OS) in a large patient material treated with 5-fluorouracil based adjuvant chemotherapy.. Data from two prospective randomised adjuvant trials were combined to achieve a dataset of 1033 radically operated stage II and III CRC patients treated with either monthly 5FU and leucovorin (LV) as bolus injections (Mayo or modified Mayo) or bi-monthly with bolus and continuous infusion (LV5FU2 or simplified LV5FU2). Toxicities were recorded at each treatment cycle according to NCI-C CTC (the Common Toxicity Criteria of the National Cancer Institute of Canada). The worst toxicity grade was taken into account. The median follow-up time of patients was 6.05 years.. 47% of patients developed neutropenia, 54% nausea/vomiting and 43% mucositis. Any grade neutropenia was associated with improved DFS (hazard ratio (HR) 0.81), any grade nausea/vomiting with improved DFS (HR 0.79) and OS (HR 0.62) and mucositis with improved DFS (HR 0.74) and OS (HR 0.72). Patients experiencing no predefined toxicity had the worst outcome.. Specific adverse events related to adjuvant fluorouracil chemotherapy are associated with improved DFS and OS in early stage CRC patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Diarrhea; Disease-Free Survival; Female; Fluorouracil; Hand-Foot Syndrome; Hematologic Diseases; Humans; Leucovorin; Male; Middle Aged; Mucositis; Nausea; Prospective Studies; Treatment Outcome; Vomiting

Pancreatic endocrine carcinomas are rare and heterogeneous. Published results concerning treatment of advanced tumours are inconsistent and responses to standard chemotherapy remain unsatisfactory.. To investigate the ability of the FOLFIRI regimen to manage progressive unresectable metastatic well-differentiated endocrine carcinomas of the pancreas as first-line chemotherapy.. 20 patients with metastatic or advanced well-differentiated endocrine carcinomas of the pancreas and progressive disease were enrolled in a prospective multicentre phase II trial to receive chemotherapy with FOLFIRI schedule (irinotecan 180mg/m(2) infusion combined with simplified LV5FU2) every 14 days. The primary end point was the non-progression rate at 6 months.. The 6-month non-progression rate was 80% (95% confidence interval [56-94%]), with stabilisation in 15 patients and 1 objective response. Overall survival at 24 months was 65% [40-82%]. Median progression-free survival was 9.1 months [6.5-17.3 months]. The median number of administered cycles was 12 [range 1-28]. Grade 3/4 haematologic toxicity occurred in 5 patients (25%) and grade 3 digestive toxicity in 11.. The FOLFIRI regimen, as first-line chemotherapy, achieved stabilisation in most patients whose tumours had been progressing and was well-tolerated. It could be an alternative therapy for advanced well-differentiated endocrine carcinomas of the pancreas.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Disease-Free Survival; Female; Fluorouracil; Gastrointestinal Diseases; Hematologic Diseases; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neuroendocrine Tumors; Pancreatic Neoplasms; Treatment Outcome

The aim of the study was to assess the toxicity and the clinical activity of biweekly oxaliplatin (OXA) in combination with continuous infusional 5-fluorouracil (5-FU) and leucovorin (LV) administered every 2 weeks (modified FOLFOX-4 regimen) in elderly patients with advanced gastric cancer (AGC).. A total of 44 previously untreated AGC patients aged 65 or older were treated with OXA 85 mg m-2 on day 1, LV 200 mg m-2 as a 2-hour infusion followed by a 22-hour infusion of 5-FU 1000 mg m using a multichannel programmable pump, repeated for 2 consecutive days every 2 weeks.. All patients were assessable for toxicity and 40 patients for response. Median age was 69 years (65-83). The response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria was 52.5% (95% confidence interval: 44.6%-68.0%) with 3 complete responses, 18 partial responses, 11 stable diseases, and 8 progressions. Median time to progression was 6.5 months and median overall survival was 10.0 months. Toxicity was generally mild. Grade 3 hematologic toxicities of neutropenia, anemia, and thrombocytopenia were in 6.8%, 2.3%, and 4.5% of the patients, respectively. No grade 4 hematologic toxicities occurred. Grade 1 peripheral neuropathy was a common event (34.1%), whereas grade 3 peripheral neuropathy was recorded in only 1 (2.3%) patient. An acute hypersensitivity reaction was observed in 1 patient during administration.. The modified FOLFOX-4 regimen is an active and well-tolerated chemotherapy for elderly patients aged > or =65 years with AGC. OXA may occasionally cause mild hypersensitivity.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Drug Hypersensitivity; Female; Fluorouracil; Follow-Up Studies; Granisetron; Hematologic Diseases; Humans; Infusions, Intravenous; Leucovorin; Male; Organoplatinum Compounds; Oxaliplatin; Peripheral Nervous System Diseases; Premedication; Stomach Neoplasms; Survival Rate; Treatment Outcome

The aim of this study was to investigate the efficacy and safety of the combination chemotherapy of paclitaxel, infusional 5-fluorouracil (5-FU) and leucovorin (FLT regimen) in advanced gastric cancer. The primary end point was the time to progression (TTP).. Patients with evaluable disease with or without measurable lesions received 175 mg/m2 paclitaxel on day 1 followed by 20 mg/m2 leucovorin and 24-h infusion of 5-FU 1,000 mg/m2 (day 1-3) repeated every 3 weeks.. Sixty patients were enrolled. The median TTP and overall survival duration were 13 and 60 weeks, respectively. One-year survival rate was 53.3%. Of the 50 patients with measurable lesion, the overall response rate was 31.7%. The most common grade 3-4 adverse event was neutropenia (61.7%).. The FLT regimen showed an efficacy comparable to other regimens of cisplatin or anthracycline combinations with the advantage of remarkably low non-hematological toxicity. These data about the efficacy of this regimen need confirmation in a phase III trial.

Topics: Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Hematologic Diseases; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Paclitaxel; Prognosis; Stomach Neoplasms; Survival Analysis

The aim of this study was to evaluate the effects of a combination of folinic acid, 5-fluorouracil (5FU) and irinotecan (FOLFIRI 1) administered every 2 weeks in a population of elderly subjects with advanced colorectal cancer.. Patients with metastatic colorectal cancer included in this study were aged at least 70 years, with a performance status of 0/1, without geriatric syndrome and without previous palliative chemotherapy. They received irinotecan [180 mg/m(2) intravenous (iv) infusion over 90 min] followed by folinic acid (400 mg/m(2) iv over 2 h), then 5FU (400 mg/m(2) iv bolus) and 5FU (2,400 mg/m(2) continuous iv infusion for 46 h) every 2 weeks.. Forty eligible patients were included. The median age was 77.3 years (range 70-84.7). The objective response rate was 40% and the stabilisation rate was 45%. Median progression-free survival was 8 months, overall survival was 17.2 months and cancer-related specific survival was 20.2 months. In total, 300 cycles of chemotherapy were administered with a median number of eight cycles per patient (range 1-18). Tolerance was good; grade 3/4 toxicities included diarrhoea (15%), asthenia (15%), nausea/vomiting (7.5%) and neutropenia (7.5%). One toxic death was observed due to grade 4 diarrhoea.. The FOLFIRI 1 regimen is a valid therapeutic option for elderly patients in good clinical condition.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Combined Modality Therapy; Diarrhea; Disease-Free Survival; Fluorouracil; Hematologic Diseases; Humans; Leucovorin; Myocardial Ischemia; Organoplatinum Compounds; Oxaliplatin; Palliative Care; Patient Compliance; Prospective Studies; Quality of Life; Radiotherapy, Adjuvant; Survival Analysis

Complete surgical resection of gastric cancer is potentially curative, but long-term survival is poor.. Patients with histologically proven adenocarcinoma of the stomach of stages IB, II, IIIA and B, or IV (T4N2M0) and treated with potentially curative surgery were randomly assigned to follow-up alone or to intravenous treatment with four cycles (repeated every 21 days) of PELF (cisplatin [40 mg/m(2), on days 1 and 5], epirubicin [30 mg/m(2), days 1 and 5], L-leucovorin [100 mg/m(2), days 1-4], and 5-fluorouracil [300 mg/m(2), days 1-4] in a hospital setting. Frequencies and severity of adverse events were determined. Overall survival (OS) and disease-free survival (DFS) were compared between the treatment arms using Kaplan-Meier analysis and a Cox proportional hazards regression model. All statistical tests were two-sided.. From January 1995 through September 2000, 258 patients were randomly assigned to chemotherapy (n = 130) or surgery alone (n = 128). Patient characteristics were well balanced between the two arms. Among those who received chemotherapy, grade 3 or 4 toxic effects including vomiting, mucositis, and diarrhea were experienced by 21.1%, 8.4%, and 11.8% of patients, respectively. Leucopenia, anemia, and thrombocytopenia of grade 3 or 4 were experienced by 20.3%, 3.3%, and 4.2% of patients, respectively. After a median follow-up of 72.8 months, 128 patients (49.6%) experienced recurrence and 139 (53.9%) deaths were observed, one toxicity-related. Relative to treatment with surgery alone, adjuvant chemotherapy did not increase disease-free survival (hazard ratio [HR] of recurrence = 0.92; 95% confidence interval [CI] = 0.66 to 1.27) or overall survival (HR of death = 0.90; 95% CI = 0.64 to 1.26).. Our results failed to provide proof of an effect of adjuvant chemotherapy with PELF on overall survival or disease-free survival. The estimated effect of chemotherapy (10% reduction in the hazard of death or relapse) is modest and consistent with the results of meta-analyses of adjuvant chemotherapy without platinum agents.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Chemotherapy, Adjuvant; Cisplatin; Diarrhea; Disease-Free Survival; Epirubicin; Female; Fluorouracil; Gastrectomy; Hematologic Diseases; Humans; Immunohistochemistry; Italy; Kaplan-Meier Estimate; Leucovorin; Lymph Node Excision; Lymphatic Metastasis; Male; Middle Aged; Mucositis; Neoplasm Staging; Patient Compliance; Prognosis; Proportional Hazards Models; Stomach Neoplasms; Treatment Outcome; Vomiting

To test the efficacy and safety of pharmacokinetic modulating chemotherapy combined with cisplatin (PMC-cisplatin) as induction chemotherapy (ICT) before definitive treatment in patients with respectable locally advanced head and neck squamous cell carcinoma (HNSCC).. Patients with stage III-IV resectable locally advanced HNSCC were enrolled. All eligible patients received PMC-cisplatin regimen as ICT containing intravenous leucovorin 250 mg/m(2) and 5-FU 600 mg/m(2) on day 1, oral tegafur-uracil (UFUR) 250 mg/m(2)/day on days 1-5, repeated every week for six courses. Cisplatin 100 mg/m(2 )was given during the first and fourth courses of PMC. For ICT responders, concurrent chemoradiotherapy (CRT) with cisplatin/tegafur-uracil/70 Gy radiotherapy was performed. Salvage surgery plus postoperative CRT was given to ICT non-responders.. The overall response rate of PMC-cisplatin as ICT was 76%, including a complete remission rate of 23%. The overall organ preservation rate of the multimodality treatment was 75%, with 97% in ICT responders. At a median follow-up of 25 months, 47% of the patients were still alive and disease-free. The superiority of disease-free survival was demonstrated in ICT responders. The 3-year overall survival rate was 67%. The toxicity of treatment was acceptable.. Application of PMC-cisplatin as the induction chemotherapy before definitive treatment provides a promising result in treatment response and survival of advanced HNSCC. This regimen is effective and safe, and further studies considering the combination of PMC with other chemotherapeutics such as taxanes to improve the clinical outcome of advanced HNSCC is warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Gastrointestinal Diseases; Head and Neck Neoplasms; Hematologic Diseases; Humans; Leucovorin; Male; Middle Aged; Radiotherapy, Adjuvant; Remission Induction; Salvage Therapy; Survival Analysis; Tegafur; Treatment Outcome; Uracil

Preoperative radiochemotherapy is a cornerstone in patients with non- resectable locally advanced rectal cancer (LARC). To improve outcome (number of R0 resections and survival) high-dose radiotherapy (RT) was combined with oral UFT/l-leucovorin to allow tumour regression before radical intended surgery.. Pelvic RT was delivered with megavoltage photons using a 5 field technique. RT was CT-based, given 5 days a week through one posterior field and two lateral fields (48.6 Gy/27 fractions) to encompass the primary tumour and the regional lymph nodes. In addition, the tumour bed received a concurrent boost (5.4 Gy/27 fractions) and a final boost (6 Gy/3 fractions); thus GTV received 60 Gy/30 fractions. Concurrent with RT patients received a daily dose of oral UFT 300 mg/m(2) plus l-leucovorin 22.5 mg 5/7 days (divided in three doses).. From September 2000 to November 2004, 52 patients (median age 60 years (32-83); median PS 0 (0-2)) with LARC (36 primary, 16 recurrent) were included in this phase II study. All but three patients received the planned 60 Gy, median duration of RT was 42 days (25-49). Toxicity was very modest; only four patients had a dose reduction of UFT. No hematological toxicity of clinical significance was seen. Non-hematological toxicity grade 1 (GI-toxicity, fatigue and/or dysuria) was frequently observed but only four patients experienced grade 3 toxicity (diarrhoea and/or nausea/vomiting). Forty patients (77%) were operated (30 R0, 5 R1, 5 R2) median 55 days (27-112) after completion of RT. Seven (13%) patients had a pathological complete response (pCR). Thirty-one patients (60%) died after median 25.4 months (1.6-45.2 months). Twenty-one patients (40%) are still alive June 2007.. Preoperative high-dose RT and concomitant UFT produces major regression in most patients with non-resectable LARC and thus a good chance of cure.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Dose Fractionation, Radiation; Drug Combinations; Female; Gastrointestinal Diseases; Hematologic Diseases; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Preoperative Care; Radiotherapy, Adjuvant; Radiotherapy, High-Energy; Rectal Neoplasms; Survival Analysis; Tegafur; Treatment Outcome; Uracil

This study aimed at evaluating the feasibility and toxicity of a salvage therapy with mitomycin C (MMC), 5-fluorouracil (5-FU), leucovorin, and oxaliplatin in patients with cisplatin-resistant advanced gastric cancer.. A 3-patient cohort dose-escalating study design was used. The patients received FLO: oxaliplatin 85 mg/m2, 5-FU 2,600 mg/m2 (24 h), leucovorin 200 mg/m2 on days 1, 15, and 29 plus MMC on day 1 (FLOM). The MMC dose was escalated from 6 to 12 mg/m2 in 2- mg/m2 steps. Cycles were repeated every 6 weeks.. Twenty patients were enrolled in 4 treatment cohorts. The treatment was well tolerated with grade 3 or 4 nonhematological toxicities affecting less than 5% of patients. Grade 3 or 4 neutropenia, anemia, and thrombocytopenia were observed in 9 (45%), 7 (35%), and 5 (25%) of 20 patients, respectively. Mild but prolonged thrombocytopenia was dose limiting, requiring treatment discontinuation or a treatment delay >or=2 weeks in 8 (40%) of 20 patients. MMC 10 mg/m2 every 6 weeks was considered as the optimal dose in combination with FLO. Objective responses were observed in 7 (35%) of 20 patients, and 7 further patients (35%) had stable disease. Median time to progression and overall survival were 4.1 and 8 months, respectively.. Prolonged cumulative myelotoxicity was dose limiting in the therapy with MMC, 5-FU, and oxaliplatin. This combination chemotherapy seems to overcome cisplatin resistance in patients with advanced gastric cancer.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Feasibility Studies; Female; Fluorouracil; Hematologic Diseases; Humans; Leucovorin; Male; Middle Aged; Mitomycin; Organoplatinum Compounds; Oxaliplatin; Salvage Therapy; Stomach Neoplasms; Terminal Care; Treatment Outcome

Our objectives were to determine response rate, time to progression, overall survival and tolerability of novel combination chemotherapy, consisting of irinotecan, high-dose 24-h continuous intravenous infusion of floxuridine and leucovorin in advanced previously untreated colorectal cancer. Thirty-eight patients with advanced colorectal cancer were treated at Sylvester Comprehensive Cancer Center, University of Miami, from 2000 to 2004, and received weekly intravenous infusion of irinotecan at 110 mg/m with a combination of 120 mg/kg floxuridine and 500 mg/m leucovorin administered as a 24-h continuous intravenous infusion. The treatment cycle consisted of 4 weeks of consecutive therapy followed by 2 weeks of rest. Five (13%) patients achieved complete response, 10 (26%) patients achieved partial response, 17 (45%) patients attained stable disease and six (16%) patients progressed. The overall response rate was 39% in this study. This chemotherapy regiment was well tolerated; the most common grade 3 toxicities were neutropenia (16%), anemia (16%), vomiting (24%), diarrhea (16%), and hand-and-foot syndrome (26%). The median time to progression was 11.5 months (347.5 days) with 95% confidence intervals of 6.8-12.9 months (206-389 days). The time to progression ranged from 1.8 to 34 months. The median survival of the patients in this trial was 31.28 months (952 days) with a confidence interval of 20.9-38.0 months (629-1141 days). Intravenous infusion of floxuridine and leucovorin is beneficial as first-line therapy in advanced colorectal cancer, demonstrating a prolonged time to progression and overall survival with acceptable tolerability and manageable toxicity profile.

Topics: Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease Progression; Female; Floxuridine; Hematologic Diseases; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Survival Rate

This phase II study was designed to assess the safety and efficacy of a modified FOLFIRI regimen (irinotecan with bi-weekly, low dose leucovorin (ldLV) and bolus and continuous infusion with 5-fluorouracil (5-FU)) as a salvage therapy for patients with advanced or metastatic gastric cancer.. Patients were treated with irinotecan 150 mg/m(2) on day 1 and received ldLV 20 mg/m(2) followed by 5-FU 400 mg/m(2) (bolus) and 5-FU 600 mg/m(2) (22 h continuous infusion) on days 1 and 2 every 14 days.. A total of 36 patients were assigned to treatment. The median patient age was 55 years (range 31-70), and 55.6% (20/36) of the patients had performance status (ECOG) of 0 or 1. The median follow-up duration was 15.5 (range 2.6-36.4) months. Of the 30 patients evaluated for their tumor response, three achieved a partial response, with an overall response rate of 10.0% (95% CI 0.0-21.0%). Eleven patients (36.7%) showed stable disease. The median time to progression was 3.3 (95% CI 2.0-4.6) months, and the median overall survival time was 10.9 (95% CI 6.1-15.7) months. The median number of cycles of modified FOLFIRI treatment was 3 (range 1-9 cycles). Grade III or IV neutropenia was observed in 23 cycles (17.6%), and febrile neutropenia occurred in three cycles (2.3%). Grade III nausea/vomiting was found in one patient (2.8%). There was one episode of UGI bleeding, but there were no treatment-related deaths.. The modified FOLFIRI regimen described here appears a safe and feasible salvage therapy in advanced gastric cancer patients.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Female; Fluorouracil; Follow-Up Studies; Hematologic Diseases; Humans; Leucovorin; Male; Middle Aged; Nausea; Salvage Therapy; Stomach Neoplasms; Stomatitis; Survival Rate; Treatment Outcome

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Because HCC usually presents as an advanced disease and occurs in the background of liver cirrhosis, most patients are not suitable for treatment with curative intent, thus effective systemic chemotherapy is required. However, the outcome of systemic chemotherapy has been disappointing in advanced HCC. This study was conducted to test the efficacy and toxicity of the combined regimen of epirubicin, cisplatin, and UFT moderated by leucovorin in advanced or recurrent HCC.. All 53 patients received epirubicin (50 mg/m2 i.v.) on day 1 and cisplatin (60 mg/m2 i.v.) after epirubicin administration. Oral UFT 400-600 mg/day, determined by body surface area, and leucovorin 75 mg/day were administered for 21 consecutive days, followed by a 7-day drug free interval.. Nine had a partial response, representing 16.9% of response rate (95% confidence interval rate; 7.0-26.8%) with median response duration of 17.1 weeks (95% CI; 5.0-29.3 weeks, range; 7.1-51.7 weeks). Fifteen patients had stable disease and the disease progressed in 26 patients. The median overall survival for the patients was 24.6 weeks (95% CI; 17.3-31.9 weeks, range; 3.0-131.3 weeks). The main toxicities were hematologic toxicities including neutropenia, which reached grade 3/4 in 17 patients (38.5%), and grade 3 or 4 thrombocytopenia in five patients (9.4%).. The combination of epirubicin, cisplatin, and UFT moderated by leucovorin showed modest anti-tumor activity with relatively tolerable toxicities. However, a randomized phase III trial based on this regimen is warranted to clarify its survival benefit in patients with advanced HCC.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antidotes; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cisplatin; Dose-Response Relationship, Drug; Epirubicin; Female; Hematologic Diseases; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Survival Analysis; Tegafur; Tomography, X-Ray Computed; Treatment Outcome; Uracil

oxaliplatin in combination with folinic acid (FA) and infusional 5-fluorouracil (5-FU) has shown significant anti-tumor activity in gastric cancer patients (FOLFOX). Previous studies have shown that gemcitabine (GEM), a new fluorinated anti-metabolite, enhances the individual anti-tumor activity of either 5-FU or oxaliplatin. We have therefore designed a multi-center phase II trial in order to test a novel GEM+FOLFOX-4 regimen in patients with metastatic gastric cancer.. we enrolled 36 patients, 28 males and 8 females, with an average age of 64.4 years (range 37-78), who received bi-weekly treatment with GEM (1,000 mg/m2 on day 1), levo-FA (100 mg/m2 on days 1 and 2), a 5-FU (400 mg/m2) bolus injection followed by 22-h continuous infusion (800 mg/m2) on days 1 and 2, and oxaliplatin 85 mg/m2 in a 4-6 h intravenous (i.v.) infusion before the second FUFA administration on day 2.. the most frequent side effect was grade 1-2 hematological toxicity and late sensorial neurotoxicity. Two patients developed hypersensitivity to oxaliplatin while another developed an aseptic eosinophilic pneumonitis. Two patients refused to continue the treatment after two cycles of chemotherapy and were lost at the follow-up. Among the remaining 34 patients four achieved a complete response, 15 a partial response, 12 had a stable disease and three progressed.. these results may grant the rationale to evaluate this multi-drug combination in randomized phase III trials in advanced gastric cancer.

Topics: Adenocarcinoma; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gastrointestinal Diseases; Gemcitabine; Hematologic Diseases; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Staging; Neurotoxicity Syndromes; Organoplatinum Compounds; Stomach Neoplasms; Survival Rate

UFT (BMS-200604, Uftoral) is an oral fluoropyrimidine that combines uracil and the 5-fluorouracil (5-FU) prodrug, ftorafur, in a 4:1 molar ratio with single-agent activity in breast and gastrointestinal cancers. In vitro studies have shown that irinotecan downregulates thymidylate synthase (TS) expression in tumour cells, leading to synergy between irinotecan and 5-FU that is maximal when irinotecan is given 24 h prior to 5-FU. Given this observed synergy and the confirmatory clinical activity of combination therapy with 5-FU, leucovorin (LV) and irinotecan, we performed a phase I trial to determine the maximum tolerated doses (MTD) of UFT, LV, and irinotecan. Treatment consisted of irinotecan administered as a 90-min intravenous (i.v.) infusion on day 1 followed by twice daily oral UFT/LV on days 2-15, repeated every 21 days. Initial doses were irinotecan 200 mg/m(2) and UFT 200 mg/m(2)/day, with LV dose fixed at 60 mg/day. 31 patients received a total of 130 cycles of UFT/LV and irinotecan. 3 of 9 patients experienced grade 3/4 diarrhoea at the highest dose level of irinotecan 310 mg/m(2) and UFT 300 mg/m(2)/day. Other toxicities included neutropenia, anaemia, alopecia, nausea/vomiting and fatigue. Further dose escalation was not pursued since this level of toxicity was appropriate for future phase II study. One patient with colorectal cancer experienced a partial response and 9 patients with non-small cell lung, colorectal and gastro-oesophageal junction carcinomas had disease stabilisation lasting 4-26 (median 6) cycles. Methylenetetrahydrofolate reductase (MTHFR) C677T genotype was analysed in peripheral mononuclear cells (PMNs) obtained from 24 patients. 2 patients had the homozygous TT polymorphism and 1 of them had grade 3 diarrhoea at the first dose level. Irinotecan on day 1 followed by a 14-day course of oral UFT/LV beginning on day 2 is well tolerated, and suitable for testing in several tumour types. Doses recommended for further study on this schedule are irinotecan 310 mg/m(2) and UFT 300 mg/m(2)/day, with LV 60 mg/day.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Dose-Response Relationship, Drug; Female; Genotype; Hematologic Diseases; Humans; Irinotecan; Leucovorin; Male; Methylenetetrahydrofolate Dehydrogenase (NADP); Middle Aged; Neoplasms; Polymorphism, Genetic; Tablets; Tegafur; Treatment Outcome; Uracil

The objectives of this study were: (1) to analyze the relation of serum methotrexate (MTX) concentration with creatinine clearance, (2) to compare the leucovorin rescue dose administered to the patients based on creatinine clearance, with the one calculated according to serum MTX levels, and (3) to determine MTX-related toxicity.. Thirty children with high-risk non-B acute lymphoblastic leukemia (ALL) treated according to the national protocol (PINDA 92) based on ALL BFM 90, were randomized to receive consolidation with four doses of either 1 or 2 g/m(2) MTX as a 24-hr infusion, at 2-week intervals (group M1 and M2, respectively). Serum MTX concentrations were measured at 24, 42, and 48 hr after beginning the infusion and were analyzed retrospectively. The creatinine clearance was calculated after 12-hr intravenous hydration prior to each MTX dose. Leucovorin dosage was adjusted according to creatinine clearance.. Serum MTX concentrations at 24, 42, and 48 hr after starting the infusion were not related to creatinine clearance in both treatment groups. Leucovorin rescue administered according to creatinine clearance was excessive in 43% in group M1 and in 51% in group M2, as compared to the dose calculated according to serum MTX levels. No serious clinical complications were observed.. These results suggest that creatinine clearance is not a good parameter to calculate leucovorin rescue. MTX-related toxicity in this group of patients receiving a dose of 1 or 2 g/m(2) and rescued with leucovorin without monitoring serum MTX levels was acceptable.

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Chile; Creatine; Disease-Free Survival; Drug Monitoring; Female; Hematologic Diseases; Humans; Infant; Leucovorin; Male; Metabolic Clearance Rate; Methotrexate; Mouth Mucosa; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Stomatitis

This multicentre phase I/II study was designed to determine the maximum tolerated dose of irinotecan when combined with 5-fluorouracil and folinic acid according to the Mayo Clinic schedule and to evaluate the activity of this combination as first-line therapy in patients with advanced colorectal cancer.. Sixty-three patients received irinotecan (250 or 300 mg/m2, 30- to 90-minute intravenous infusion on day 1), immediately followed by folinic acid (20 mg/m2/day) and 5-fluorouracil (425 mg/m2, 15-minute bolus infusion) days 1 to 5, every four weeks.. Diarrhoea was dose limiting at 300 mg/m2 irinotecan in combination with 5-fluorouracil and folinic acid, and this was determined to be the maximum tolerated dose. Grade 3-4 neutropenia was the most frequently reported toxicity. The recommended dose of irinotecan for the phase II part of the study was 250 mg/m2. The response rate for the evaluable patient population was 36% (13/36), and 44% (16 patients) had stable disease (including 19% of minor response). For the intention-to-treat population, the response rate was 29% (14/49) and 35% (17 patients) stable disease (including 14% of minor response). The median time to progression was 7.0 months and the median survival was 12.0 months. Grade 3-4 non-haematological drug-related toxicities included delayed diarrhoea, stomatitis, fatigue, and nausea/vomiting. There were three deaths due to septic shock that were possibly or probably treatment-related.. This regimen of irinotecan in combination with the Mayo Clinic schedule of bolus 5-fluorouracil/folinic acid every four weeks showed activity as first-line therapy in patients with advanced colorectal cancer. In keeping with other published results of studies using bolus 5-fluorouracil combined with irinotecan, the use of this regimen is limited by a relatively high rate of grade 3-4 neutropenia, and the combination of irinotecan and infusional 5-fluorouracil / folinic acid should remain the regimen of first choice.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Diarrhea; Fatigue; Female; Fluorouracil; Hematologic Diseases; Humans; Irinotecan; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Nausea; Shock, Septic; Stomatitis; Survival Rate

Combination therapy of irinotecan, folinic acid (FA) and 5-fluorouracil (5-FU) has been proven to be highly effective for the treatment of metastatic colorectal cancer. However, in light of safety and efficacy concerns, the best combination regimen for first-line therapy still needs to be defined. The current study reports on the bimonthly FOLFIRI protocol consisting of irinotecan with continuous FA/5-FU in five German outpatient clinics, with emphasis on the safety and efficiency, quality of life, management of delayed diarrhea, and secondary resection of regressive liver metastases.. A total of 35 patients were treated for metastatic colorectal cancer. All patients received first-line treatment according to the FOLFIRI regimen, consisting of irinotecan (180 mg/m2), L-FA (200 mg/m2) and 5-FU bolus (400 mg/m2) on day 1, followed by a 46-h continuous infusion 5-FU (2400 mg/m2). One cycle contained three fortnightly administrations. Staging was performed after 2 cycles. Dosage was reduced at any time if toxicity NCI CTC grade III/IV was observed. Chemotherapy was administered only to diarrhea-free patients.. The FOLFIRI regimen was generally well tolerated. It was postponed for one-week in 51 of 415 applications (12.3%). Dose reduction was necessary in ten patients. Grade III/IV toxicity was rare, with diarrhea (14%), nausea/vomiting (12%), leucopenia (3%), neutropenia (9%) and mucositis (3%). The overall response rate was 31% (4 CR and 7 PR), with disease control in 74%. After primary chemotherapy, resection of liver metastases was achieved in three patients. In one patient, the CR was confirmed pathologically. Median progression-free and overall survival were seven and 17 months, respectively.. The FOLFIRI regimen proved to be safe and efficient. Outpatient treatment was well tolerated. Since downstaging was possible, combinations of irinotecan and continuous FA/5-FU should further be investigated in neoadjuvant protocols.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colorectal Neoplasms; Diarrhea; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Hematologic Diseases; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Nausea; Quality of Life; Remission Induction; Treatment Outcome

5-Fluorouracil (5-FU) and gemcitabine are the major active drugs in the treatment of pancreatic cancer.. Twenty-two patients with advanced pancreas cancer were treated with a new chemotherapy regimen consisting of infusional 5-FU and high-dose leucovorin with gemcitabine (GEMFUFOL).. A total of 200 cycles of chemotherapy were administered. The response rate was 27.3%, all responses being partial. The median survival time and 1-year survival rate were, respectively, 13 months and 60.4%. The toxicity was very low and severe hematological toxicity was exceptional.. The GEMFUFOL regimen can be an active regimen for the treatment of advanced pancreatic cancer and has a low toxicity.

Topics: Adenocarcinoma; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Hematologic Diseases; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Survival Rate

Second- and third-line treatments remain a challenge in advanced colorectal cancer. Studies of bimonthly regimens of high-dose leucovorin (LV) and 5-fluorouracil (5-FU) by continuous infusion combined with oxaliplatin (L-OHP) have shown encouraging response rates in patients not responding to a bimonthly LV/5-FU regimen. Hyperthermic enhancement of L-OHP efficiency by increased DNA adduct formation has been demonstrated in vitro. This study was designed to address feasibility, toxicity and efficacy issues of whole-body hyperthermia (WBH) as an adjunct to L-OHP/LV/5-FU in pretreated patients after progression to first- and second-line treatments with LV/5-FU by continuous infusion and irinotecan.. Forty-four patients with advanced colorectal cancer, who had progressed during or within 3 months after completion of chemotherapy with LV/5-FU 24-h infusion (LV/5-FU(24h)) (eight patients) or irinotecan combined with or after LV/5-FU(24h )(36 patients), were treated with L-OHP 85 mg/m(2), 2-h intravenous (i.v.) infusion, followed by LV 200 mg/m(2), 1-h i.v. infusion, and 5-FU 3 g/m(2), 48-h continuous infusion. Every second cycle of the biweekly regimen was combined with WBH, thus allowing a comparison of toxicity with and without WBH in the same patient. Whole-body hyperthermia was administered by a humidified radiant heat device. The target temperature of 41.8 degrees C was maintained for 60 min. L-OHP (2-h infusion) was started at a core body temperature of 39 degrees C.. All patients could be evaluated for toxicity, and 41 patients were evaluable for response. A total of 273 L-OHP-containing regimens were administered, 130 with and 143 without WBH. Hyperthermic treatment combined with L-OHP/LV/5-FU showed no unexpected toxicities. WHO grade 3 toxicities were rare and evenly balanced between cycles given with or without WBH. One early death occurred due to sepsis and tumor lysis. The overall response rate was 20%, with two complete and six partial responses. Twenty-three patients (56%) had stable disease and nine patients (22%) progressive disease. With a median observation time of 70 weeks, the median time to progression was 21 weeks [95% confidence interval (CI) 17-25 weeks] and the median survival was 50 weeks (95% CI 39-61 weeks) from the start of therapy.. This trial suggests some advantage of combining L-OHP/LV/5-FU with WBH. Results compare favorably with the activity of similar regimens without WBH in less extensively pretreated patients. These data support further evaluation and warrant phase III studies.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Gastrointestinal Diseases; Hematologic Diseases; Humans; Hyperthermia, Induced; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome

To determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of both docetaxel and 5-fluorouracil (5-FU) when administered weekly in a regimen of docetaxel, 5-FU/leucovorin and cisplatin (DFLP) for 2 consecutive weeks every 3 weeks.. A total of 31 patients with chemo-naive, advanced adenocarcinoma of the stomach were enrolled in the study. Cisplatin and leucovorin dosages were fixed throughout the study at 30 and 300 mg/m2, respectively. 5-FU dosage was fixed at 1,600 mg/m2 while docetaxel was evaluated at weekly 1-hour infusion dosages of 30, 40 and 50 mg/m2 to determine the MTD. Cisplatin, 5-FU and leucovorin were administered together as a 24-hour continuous infusion following docetaxel. Weekly 5-FU dosages of 1,600, 2,000 and 2,400 mg/m2 were then evaluated after setting the docetaxel dosage at the MTD.. A total of 95 chemotherapy cycles were administered, with a median of three cycles per patient. The MTD of docetaxel was defined at 40 mg/m2. At a docetaxel dosage of 50 mg/m2 per week, the dose-limiting events of grade 4 febrile neutropenia and grade 3 hypomagnesemia occurred. With fixation of docetaxel to 40 mg/m2, the DLT for 5-FU was found at 2,400 mg/m2 per week. This incurred grade 4 neutropenia such that the MTD of 5-FU was defined at 2,000 mg/m2. Grade 3/4 neutropenia occurred in 14 patients (45%), with 2 patients developing febrile neutropenia. Grade 2 and 3 hypomagnesemia and hypokalemia occurred in 9 (41%) and 4 (18%) patients, respectively, of the first 22 patients treated with a 24-hour infusion of cisplatin and 5-FU/leucovorin immediately following docetaxel. Following a change in the cisplatin administration schedule to a 3-hour infusion after 5-FU/leucovorin infusion, no such complications were observed in 9 subsequently treated patients. Grade 2 diarrhea was recorded in 11 patients (35%). Grade 2/3 asthenia occurred in 9 patients (30%), which resolved after correction of electrolyte disorders. Twenty-six patients were assessable for response analysis. There were 2 (7.8%) complete and 14 (53.8%) partial responses, with the overall response rate being 61.5% (95% confidence interval, 41.5-81.6%). Responses were observed at all dose levels.. Two consecutive weeks of DFLP infusions every 3 weeks appear to be an active regimen with a tolerable toxicity profile in advanced gastric cancer. For further phase II studies, the recommended dose for this combination is 40 mg/m2 of docetaxel and 2,000 mg/m2 of 5-FU per week.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Docetaxel; Dose-Response Relationship, Drug; Female; Fluorouracil; Gastrointestinal Diseases; Hematologic Diseases; Humans; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neutropenia; Paclitaxel; Stomach Neoplasms; Taxoids

Cisplatin (CDDP) is among the most active single agents against squamous cell carcinoma of the head and neck (SCCHN), and it is still the reference drug in the induction chemotherapy setting, when used in combination with infusional 5-fluorouracil (5-FU). Raltitrexed has been shown to be devoid of clinical activity against SCCHN when used alone; however, both preclinical and early clinical data regarding the combination raltitrexed-CDDP hold promise. Thymidylate synthase is the target enzyme of both raltitrexed and 5-FU; however, the two drugs have distinct sites of action on the enzyme and the combination of the two agents may be synergistic. We have previously shown that the combination of raltitrexed, levofolinic acid (LFA) and 5-FU has clinical activity against SCCHN; in a subsequent phase I study, cisplatin was added, and the combination of CDDP plus raltitrexed on day 1, followed by LFA and 5-FU on day 2, was judged feasible and active, since a 67% response rate was shown across all dose levels, with a 100% response rate at the recommended dose for phase II.. Patients with inoperable locally advanced or metastatic SCCHN, not pretreated with chemo- or radiotherapy were randomized to receive either CDDP 60 mg/m2 and raltitrexed 2.5 mg/m2 on day 1 and LFA 250 mg/m2 and 5-FU 900 mg/m2 on day 2 (arm A) or CDDP 65 mg/m2 and methotrexate 500 mg/m2 on day 1, and LFA 250 mg/m2 and 5-FU 800 mg/m2 on day 2 (arm B). Both treatments were repeated every 2 weeks. Evaluation for tumor response was performed after four cycles. According to Simon two-stage design, with a target complete response (CR) rate (p1) of 35%, at least 7 CR among the first 31 treated patients and 16 CR among the final sample size of 52 patients were required.. An interim analysis was performed when 36 patients were evaluable in each arm. In arm A, 10 CR (28%) and 19 partial responses (PR) (53%) were observed, for an overall response rate of 81%. In arm B, 3 CR (8%) and 12 PR (34%) were observed, for an overall response rate of 42%. The difference in both CR and overall response rate between the two arms was statistically significant (p = 0.03 and <0.001, respectively). Therefore, the accrual was stopped in arm B and continued only in arm A. Overall, 13 CR (21%) and 34 PR (56%) were observed among the 61 patients who were accrued in arm A, for an overall response rate of 77% (95% confidence interval 64-87%). Neutropenia was the main side effect in both arms (grade 3-4 in 45 and 23 patients in arm A and B, respectively). Extrahematologic toxicity was mild in both arms; however, 2 patients in arm B died due to toxicity (grade 4 mucositis in one case, grade 4 renal toxicity in the other).. Although response data for our experimental treatment look encouraging, the hypothesis of a 35% activity, expressed as capability to induce a CR, cannot be accepted. The results obtained in this study are not substantially different from those of other trials of CDDP-5-FU-based regimens, and our combination is unlikely to represent a major breakthrough when used in this setting.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Dose-Response Relationship, Drug; Female; Fluorouracil; Head and Neck Neoplasms; Hematologic Diseases; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Neutropenia; Quinazolines; Thiophenes; Treatment Outcome

The aim of this study was to evaluate the toxicity and efficacy of combination chemotherapy with weekly 24-h continuous infusion of 5-fluorouracil (5-FU)/folinic acid, weekly paclitaxel and 3-weekly cisplatin in patients with unresectable, locally advanced or metastatic gastric adenocarcinoma. Between November 1999 and November 2001, 29 chemotherapy-naive patients (13 male and 16 female) with a median age of 56 years (range 22-72) were consecutively enrolled at three centers. 5-FU 2 g/m2 was given weekly over 24 h i.v. preceded by folinic acid 500 mg/m2 as a 2-h infusion. Paclitaxel 80 mg/m2 was administered as a 1-h infusion weekly and cisplatin 50 mg/m2 as 1-h infusion on days 8 and 29. Six weeks of therapy (days 1, 8, 15, 22, 29 and 36) followed by 1 week of rest was considered one cycle. A median of 3 cycles (range 1-5) was administered to 29 patients with a total of 73 cycles applied. All patients were assessable for toxicity and survival, 28 patients were assessable for response (one patient received less than one complete cycle and could not be evaluated for response). Four patients (14%) obtained a complete response and 10 patients (34%) a partial response (overall response rate 48%, 95% CI 29-68%). Seven patients (24%) had stable disease. Seven patients (24%) had progressive disease during or within 4 weeks after treatment. The median progression-free and overall survival times were 8 months (range 1-23) and 11 months (range 1-23), respectively. Overall toxicity was acceptable. Hematological toxicity was favorable with only one patient (3%) experiencing WHO grade 3/4 leukocytopenia and one patient (3%) WHO grade 3/4 anemia. Non-hematologic WHO grade 3/4 toxicities included alopecia in 19 (66%), nausea/vomiting in six (21%), diarrhea in six (21%), neurotoxicity grade 3 in three (10%) and infection in three (10%) patients. A total of 42 applications (10%) (range 0-5) had to be postponed and dose reductions of at least one drug was necessary in 37% of applications. In three patients (10%) treatment was stopped because of toxicity. All patients were treated on an outpatient basis. Thus, the combination of weekly paclitaxel, cisplatin and continuously infused 5-FU/folinic acid appears to be a highly active regimen for the treatment of patients with advanced gastric cancer. Compared with our previous experience with the same combination of drugs but using paclitaxel at 175 mg/m2 given every 3 weeks, the protocol with weekly application of paclitaxel 80

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Cisplatin; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Gastrointestinal Diseases; Hematologic Diseases; Humans; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Paclitaxel; Stomach Neoplasms; Survival Rate; Time Factors

We have reported a 33% partial response rate with acceptable toxicity using weekly 24-h infusion of high-dose 5-fluorouracil (5-FU) and leucovorin (LV) in patients with far advanced biliary tract cancers (BTC). In this study, we added mitomycin (MMC) to 5-FU and LV in an attempt to improve the response rate and survival. From July 1997 to September 1999, 25 chemotherapy-naive patients with pathology-proven far advanced BTC and periampullar cancers were enrolled. The regimen consisted of MMC 10 mg/m(2) every 8 weeks combined with 5-FU 2600 mg/m(2) and LV 150 mg at a schedule of 24-h infusion weekly for 6 weeks followed by a 2 week break. There were 10 males and 15 females with a median age of 57 years (range 40-76). The sites of primary tumor were 15 intrahepatic cholangiocarcinomas (CC), one perihilar CCs, three distal BTC, three gallbladder cancers (GB) and three periampullar cancers. A total of 148 sessions of chemotherapy were given with a mean of 8 (range 2-18). Nineteen patients were evaluable for response. The response rate was: 26% (five of 19) partial response, 42% (eight of 19) stable disease and 32% (six of 19) progressive disease. All of the patients were evaluable for toxicity. Toxicities more than grade III-IV were thrombocytopenia 16% (four of 25), leukopenia 12% (three of 25) and vomiting 4% (one of 25). There were four treatment-related deaths. The median time to disease progression was 3 months. The median survival was 6 months. A combination of MMC with weekly high-dose 5-FU and LV in patients with BTC did not improve the response rate, but produced more toxicity than weekly high-dose 5-FU and LV alone.

Topics: Adenocarcinoma; Adult; Aged; Ampulla of Vater; Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Cholangiocarcinoma; Digestive System Neoplasms; Disease Progression; Drug Administration Schedule; Female; Fluorouracil; Hematologic Diseases; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Mitomycin; Survival Rate; Treatment Outcome

Oxaliplatin is a novel platinum derivative, which, combined with 5-fluorouracil (5-FU), and folinic acid (FA), demonstrates synergistic activity in metastatic colorectal cancer (MCC). The HeCOG performed a multicenter phase II study of a weekly oxaliplatin administration schedule in patients with previously treated MCC to evaluate the antitumor efficacy and toxicity of this combination.. Eligible patients included those who relapsed after or during chemotherapy with 5-FU and FA and/or irinotecan. Prior radiotherapy was accepted provided that measurable disease was outside the radiation fields. Other eligibility criteria included written informed consent, a WHO performance status < or = 2 and adequate bone marrow, liver and renal function. Treatment consisted of Oxaliplatin 50 mg/m2 by two-hour intravenous (i.v.) infusion followed by FA 500 mg/m2 (two-hour i.v. infusion) and 5-FU 2,500 mg/m2 (24-hour continuous i.v. infusion) on days 1, 8, 15, 22, 29, 36. The regimen was repeated every 50 days.. Thirty-two patients (Median age 61 years, range 25-76) entered the trial. The majority (75%) had progressed after receiving first-line chemotherapy. Diarrhea was the main non-hematologic toxicity. More than half of the patients (53%) developed grades 3 or 4 diarrhea. Due to this side effect only 29% of cycles were given with at least 90% of the planned dose of 5-FU. Hematologic toxicity included grade 3 neutropenia and thrombocytopenia (10% for each), and grade 4 thrombocytopenia (3%). Two patients (6%) died of sepsis, one related to neutropenia and one due to urinary tract sepsis. Sixteen patients (50%) developed grades 1 and 2 neurotoxicity in the form of sensory neuropathy, which was mild and transient. The objective response rate was 13% (95% CI: 3%-29%). All four responses were partial. Twelve patients (38%) had stable disease and 8 (25%) progressive disease. The median time to progression was three months and the median survival was nine months from the start of therapy. The Kaplan-Meier estimated probability of one-year survival for the group as a whole was 32%.. The weekly administration of oxaliplatin with 5-FU and FA was associated with considerably less neurotoxicity than other schedules. However, the high percentage of diarrhea suggests that a dose reduction of 5-FU in this regimen may result in better therapeutic synergy.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Schedule; Feasibility Studies; Female; Fluorouracil; Hematologic Diseases; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Prognosis; Salvage Therapy; Survival Rate; Treatment Outcome

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

5-Fluorouracil (5-FU) has been widely used for over 30 years. Recently, investigators have described interactions between toxicity with 5-FU and age and gender. Pharmacokinetics of infusional 5-FU are known to be gender dependent, with drug clearance being lower in females. The full impact of age and gender on both toxicity and response has not been fully explored and is worthy of further investigation. 439 patients were entered into a phase III trial comparing a novel thymidylate synthase (TS) inhibitor Tomudex (raltitrexed, formerly ZD1694) with 5-FU and leucovorin (LV) for the treatment of advanced colorectal cancer. Approximately 20-24% of patients in each treatment group were aged 70 years or older and 41% of the patients were female. In a multiple regression analysis, female patients receiving 5-FU + LV experienced significantly more grade 3/4 leucopenia, whilst those receiving raltitrexed had more rises in transaminase levels. Grade 3/4 leucopenia and mucositis were significantly correlated with age (especially > 70 years) only in patients receiving 5-FU + LV. Patients receiving 5-FU + LV were significantly more at risk of experiencing grade 3/4 haematological and non-haematological toxicity in the first three cycles than patients receiving raltitrexed. Female gender and increased age predict for increased grade 3/4 toxicity in patients receiving modulated 5-FU. Further studies with modulated 5-FU which utilise a modified dose reduction schema for female patients, or patients aged 70 years or over, may be appropriate.

Topics: Adult; Age Factors; Aged; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Hematologic Diseases; Humans; Leucovorin; Male; Middle Aged; Quinazolines; Sex Factors; Thiophenes

To determine the feasibility of ambulatory infusional administration 24 hours per day, 7 days per week of a three-drug regimen of cisplatin or carboplatin, leucovorin, and 5-fluorouracil (5-FU) (PLF) utilizing an alternating weekly sequential design and to introduce infusional etoposide as PLEF to the regimen.. Forty-three patients with diverse malignancies received a sequential infusion of 5-FU 200 mg/M2/day on days 1 to 14 and 21 to 35 with leucovorin admixed for day 1 to 7 and 21 to 28. Cisplatin (20 patients) or carboplatin (23 patients) infusion was administered at a dose of 10 mg/M2/day or 30 mg/M2/day, respectively, day 7 to 14 and 35 to 42. Cycles were planned to be repeated consecutively in the absence of toxicity in patients with stable or responding disease. Sixteen patients also received etoposide 30 mg/M2/day as an admixture concomitant with administration of the platinum analogue. Therefore, the distribution of therapies was PLF 19, CLF 8, PLEF 14, and CLEF 2.. A total of 63 courses of PLF +/- E was administered as outlined above. Hematologic toxicity was minimal with or without the addition of etoposide. Sixteen percent of patients developed an elevated creatinine with a median of 1.6 and a range of 1.6 to 3.2 mg %. Tumor responses were observed in seven of fourteen evaluable patients with squamous cell carcinoma of the lung (all of whom received concomitant etoposide). In addition, one patient with metastatic gallbladder cancer achieved a complete clinical response.. Ambulatory infusional PLF with carboplatin or cisplatin using sequentially alternating delivery of the component antineoplastic agents is feasible and active with minimal toxicity. The addition of infusional etoposide to the PLF regimen does not substantially increase hematologic toxicity. Extended phase II studies in aerodigestive cancers are ongoing and a phase III trial comparing this ambulatory regimen to short-term PLF infusion (5-day) may be justified to compare the relative cost and benefits of the two schedules.

Topics: Adult; Aged; Aged, 80 and over; Ambulatory Care; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Drug Administration Schedule; Etoposide; Female; Fluorouracil; Gastrointestinal Neoplasms; Hematologic Diseases; Humans; Infusions, Intravenous; Leucovorin; Lung Neoplasms; Male; Middle Aged

Etoposide, leucovorin and 5-fluorouracil (ELF) chemotherapy has been reported to be less toxic yet effective (response rates of 50%) in patients with advanced gastric cancer. A phase II study of ELF in 25 patients (11 males, 14 females, median age 53 years) with advanced adenocarcinoma of the stomach is reported. Patients received outpatient intravenous etoposide 120mg/m2 over 2 hours, folinic acid 300 mg/m2 over 2 hours, 5-fluorouracil 500 mg/m2 boluses daily for 3 days every 21 days. Of 17 measurable patients, there was one complete response (CR), 4 partial responses (PR) for a total response rate of 29.4%. Non-hematologic toxicity was modest (grade 0 vomiting 11/21, stomatitis 16/21, diarrhea 17/21). Grade 3/4 neutropenia was seen in 14/23, thrombocytopenia in 2/23, anemia in 5/23 patients. Median progression-free and overall survival was 4.1 and 7.1 months, respectively. In conclusion, ELF chemotherapy shows only modest activity in patients with advanced gastric cancer and is associated with severe hematologic toxicity.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Etoposide; Female; Fluorouracil; Hematologic Diseases; Humans; Leucovorin; Levoleucovorin; Male; Middle Aged; Remission Induction; Stomach Neoplasms; Survival Rate

To evaluate prospectively the efficacy of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the reduction of chemotherapy-induced oral mucositis.. Twenty patients with stage IV squamous cell carcinoma of head and neck were studied. Two-cycles (periods) of identical doses of cisplatin, fluorouracil (5-FU), and leucovorin (PFL) chemotherapy with cisplatin 20 mg/m2/d, 5-FU 800 mg/m2/d, leucovorin 90 mg/m2/d by 96-hour continuous intravenous infusion every 3 weeks were given to each patient. After PFL chemotherapy, GM-CSF 4 micrograms/kg subcutaneously from days 5 to 14 or no therapy was given by a randomized self-controlled crossover study design. Oral mucositis was graded with modified Radiation Therapy Oncology Group criteria.. In the first cycle of PFL chemotherapy, GM-CSF significantly reduced the incidence, mean duration, and mean area under the curve (AUC) of severe oral gross mucositis (grade > or = 3) compared with no therapy. These beneficial effects continued into the second cycle of PFL chemotherapy after crossover to no GM-CSF. The incidence of severe mucositis was reduced when GM-CSF was given in the second cycle of PFL. Analysis of variance indicated significant direct GM-CSF treatment effects on the mean AUC of gross/functional scores and duration of moderate gross mucositis (grade > or = 2) over both periods. There was a significant period effect in favor of giving GM-CSF in the first cycle of chemotherapy.. GM-CSF can significantly reduce the severity and duration of chemotherapy-induced oral mucositis after PFL chemotherapy.

Topics: Adult; Aged; Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Cross-Over Studies; Female; Fluorouracil; Granulocyte-Macrophage Colony-Stimulating Factor; Head and Neck Neoplasms; Hematologic Diseases; Humans; Leucovorin; Male; Middle Aged; Mouth Mucosa; Prospective Studies; Stomatitis

A prospective, randomized study was conducted to evaluate the role of vitamin B12 and folinic acid supplementation in preventing zidovudine (ZDV)-induced bone marrow suppression. Seventy-five human immunodeficiency virus (HIV)-infected patients with CD4+ cell counts < 500/mm3 were randomized to receive either ZDV (500 mg daily) alone (group I, n = 38) or in combination with folinic acid (15 mg daily) and intramascular vitamin B12 (1000 micrograms monthly) (group II, n = 37). Finally, 15 patients were excluded from the study (noncompliance 14, death 1); thus, 60 patients (31 in group I and 29 in group II) were eligible for analysis. No significant differences between groups were found at enrollment. During the study, vitamin B12 and folate levels were significantly higher in group II patients; however, no differences in hemoglobin, hematocrit, mean corpuscular volume, and white-cell, neutrophil and platelet counts were observed between groups at 3, 6, 9 and 12 months. Severe hematologic toxicity (neutrophil count < 1000/mm3 and/or hemoglobin < 8 g/dl) occurred in 4 patients assigned to group I and 7 assigned to group II. There was no correlation between vitamin B12 or folate levels and development of myelosuppression. Vitamin B12 and folinic acid supplementation of ZDV therapy does not seem useful in preventing or reducing ZDV-induced myelotoxicity in the overall treated population, although a beneficial effect in certain subgroups of patients cannot be excluded.

Topics: Adult; Anemia; Bone Marrow Diseases; CD4 Lymphocyte Count; Female; Folic Acid; Hematologic Diseases; HIV Infections; Humans; Leucovorin; Male; Neutropenia; Prospective Studies; Vitamin B 12; Zidovudine

Cancer chemotherapy with folate antimetabolites has been traditionally targeted at the enzyme dihydrofolate reductase and is based on the requirement of dividing tumor cells for a supply of thymidylate and purines. However, a new compound, 5,10-dideazatetrahydrofolate (DDATHF, whose 6R diastereomer is also known as Lometrexol), has become available that prevents tumor cell growth by inhibiting the first of the folate-dependent enzymes involved in de novo purine synthesis, glycinamide ribonucleotide formyltransferase.. We investigated the toxicity and therapeutic activity of DDATHF in a phase I clinical trial.. DDATHF was given at one of the following dose levels to 33 patients (16 females and 17 males) with malignant solid tumors: 3.0 mg/m2 per week (level A) to 10 patients, 4.5 mg/m2 per week (level B) to 13 patients, or 6.0 mg/m2 per week (level C) to 10 patients. Each drug cycle consisted of three weekly injections of DDATHF followed by a 2-week rest prior to redosing in the next cycle.. Of 33 patients, 27 received at least one full cycle of DDATHF. Thrombocytopenia was the major dose-limiting toxicity, and it was severe in one of 10 patients during the first cycle and in two of four patients during the second cycle. Because of cumulative toxicity at 6.0 mg/m2, second or later cycles were abbreviated to two weekly doses. Stomatitis was generally mild, but it was dose-limiting in one patient. Neutropenia was infrequent and mild, and normocytic anemia requiring blood transfusion was common with repeat dosing. Leucovorin was given for grade 2 or greater thrombocytopenia and resulted in hematologic recovery within 1 week in all eight patients so treated. Without leucovorin, the thrombocytopenia lasted from 7 to 49 days in three patients. A partial response was noted in one patient with non-small-cell lung cancer and a minor response in one patient with breast cancer. Three patients with colorectal cancer achieved stable disease for greater than 3 months with improvement in carcinoembryonic antigen levels in one patient.. DDATHF has an unusual pattern of toxicity with repetitive dosing, and humans with advanced cancer are considerably more sensitive than would be predicted from previous animal studies. Although doses of 6.0 mg/m2 per week on our schedule have been determined to be safe, repeated cycles require careful monitoring because of cumulative toxic effects.. Additional phase I studies of DDATHF that relate toxicity to folate intake and tissue folate pools appear warranted.

Topics: Adult; Aged; Drug Administration Schedule; Female; Folic Acid Antagonists; Hematologic Diseases; Humans; Leucovorin; Male; Middle Aged; Neoplasms; Purines; Tetrahydrofolates; Treatment Outcome

Topics: Adolescent; Adult; Child; Child, Preschool; Clinical Trials as Topic; Dehydration; Drug Therapy, Combination; Female; Hematologic Diseases; Humans; Hydrogen-Ion Concentration; In Vitro Techniques; Infant; Kidney Diseases; Kidney Function Tests; Leucovorin; Liver Diseases; Liver Function Tests; Male; Methotrexate; Neoplasms; Pleural Effusion; Prognosis; Time Factors; Vomiting

We aimed to compare the efficacy and the safety of the FOLFOX and the FLOT regimens in metastatic gastric cancer (mGC) as first-line treatment. It was a retrospective multicenter observational study. The comparisons between groups were conducted in terms of progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and hematologic adverse events. Seventy-nine patients, diagnosed with mGC between March 2012 and December 2019, treated with FOLFOX (n = 43) or FLOT (n = 36) regimens as first-line treatment were included in the study. The mPFS was 10.9 months [95% confidence interval (CI), 5.8-16.1] in the FLOT arm and 7.1 months (95% CI, 5.1-9.1) in the FOLFOX arm (P < 0.001). The ORR was 63.9% in the FLOT arm and 30.2% in the FOLFOX arm (P = 0.003). The mOS was 13.3 months (95% CI, 11.3-15.4) in the FLOT arm and 10.9 months (95% CI, 8.2-13.5) in the FOLFOX arm (P = 0.103). The hematologic adverse events in all grades were 88.4% (n = 38) in the FOLFOX arm compared with 80.6% (n = 29) in the FLOT arm (P = 0.335). The FLOT regimen might be a preferred option in mGC with an improved PFS and ORR compared with the FOLFOX regimen.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Esophagogastric Junction; Female; Fluorouracil; Hematologic Diseases; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies; Stomach Neoplasms; Survival Analysis

FOLFIRINOX has been shown to significantly increase both overall survival (OS) and progression-free survival (PFS) in metastatic pancreas cancer. There is limited data regarding the treatment of locally advanced pancreatic cancer. We present a retrospective study of patients with both locally advanced and metastatic pancreas cancer using FOLFIRINOX as first-line therapy in our centre.. This is a retrospective review of patients treated with FOLFIRINOX for pancreatic cancer at Princess Margaret Cancer Centre, between December 2011 and July 2014. The primary objective was to evaluate the efficacy and safety of FOLFIRINOX when used with dose modifications.. One hundred two patients were identified; 66 metastatic and 36 locally advanced. Sixty-eight per cent of patients initiated treatment with a dose reduction. The median (95% CI) OS in the metastatic group was 13.1 (6.3-16.1) months with full dose and 12.9 (10.3-30.1) months with modified dose. The median (95% CI) OS in the locally advanced group was 11.1 (6.1-not reached) months with full dose and 23 (not reached-not reached) months with modified dose. The median (95% CI) PFS in the metastatic group was 6.2 (4.9-15.2) months with full dose and 8.7 (5.7-12.9) months with modified dose. The median (95% CI) PFS in the locally advanced group was 11.1 (3.1-not reached) months with full dose and 10.4 (6.8-not reached) months with modified dose. Grade 3/4 haematologic adverse events were observed in 43% of patients. Grade 3/4 non-haematologic adverse events were observed in 28% of patients. Patient well-being significantly improved from baseline to cycle 4 (P=0.002).. Efficacy was achievable with dose-modified FOLFIRINOX in daily setting. The safety of FOLFIRINOX remains a concern with a high rate of grades 3 and 4 neutropaenia despite dose reduction.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; CA-19-9 Antigen; Camptothecin; Carcinoma, Pancreatic Ductal; Cisplatin; Combined Modality Therapy; Deoxycytidine; Disease-Free Survival; Drug Substitution; Female; Fluorouracil; Gastrointestinal Diseases; Gemcitabine; Hematologic Diseases; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Ontario; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Quality of Life; Sepsis; Treatment Outcome

Results concerning the side effects of oxaliplatin associated with fluorouracil and leucovorin (FOLFOX) in older patients are controversial. The objective of this study was to assess the use and the toxicity of FOLFOX in patients aged 70 years and older as administered in current practice.. Among 305 stage III colon cancers registered in a well-defined population in Burgundy between 2004 and 2009, 210 had adjuvant chemotherapy, including 156 with FOLFOX. The cumulated rates of toxicity were calculated by using the Kaplan-Meier method. The risks of overall toxicity and of severe toxicity (grade 3 or 4) in patients less than 70 years and in older patients were compared by using a Cox model.. There was no difference between the group of the patients less than 70 years and the older age group for the cumulative incidence of hematologic, neurologic, digestive, and general toxicity. There was also no difference between the two groups for the severity of side effects (grade 3 or 4, 31.4 vs. 39.0 %; p = 0.576). The multivariate analysis indicated after adjustment on sex and the Charlson comorbidity score that there was no difference between the two age groups for toxicity (hazard ratio = 1.28; 95 % CI 0.68-2.41; p = 0.439).. Cancer registries can be used to evaluate the toxicity of chemotherapy at the population level. Tolerance to the FOLFOX regimen among elderly patients did not significantly differ from that in younger patients. This treatment should be considered regardless of patients' age alone, but consideration should be given to the capacity of patients to tolerate adverse events.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Colonic Neoplasms; Digestive System Diseases; Female; Fluorouracil; Follow-Up Studies; France; Hematologic Diseases; Humans; Incidence; Leucovorin; Male; Neoplasm Staging; Nervous System Diseases; Organoplatinum Compounds; Oxaliplatin; Prognosis; Survival Rate

The aim of this retrospective study was to show the efficacy and safety of modified FOLFOX6 plus high-dose bevacizumab (10 mg/kg/2 weeks) in the second-line or later treatment of metastatic colorectal cancer.. A total of 24 consecutive patients treated between August 2007 and August 2009 were included in this retrospective study. None of the patients had received bevacizumab as part of prior treatment.. All 24 patients received modified FOLFOX6 plus high-dose bevacizumab and were followed for a median of 36.9 months. Overall response rate was 29%. Median progression-free survival was 7.5 months, and median overall survival was 17.3 months. Grade 3/4 adverse events were: neutropenia (54.2%), leukopenia (25.0%), neuropathy (12.5%), hypertension (12.5%), thrombocytopenia (8.3%), and decreased haemoglobin, gastrointestinal haemorrhage, wound complications, nausea, diarrhoea, mucositis and fatigue (each 4.2%).. Modified FOLFOX6 plus high-dose bevacizumab may be useful in the second-line treatment of patients with metastatic colorectal cancer who have not received bevacizumab.

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Diarrhea; Disease-Free Survival; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluorouracil; Hematologic Diseases; Humans; Leucovorin; Male; Middle Aged; Mucositis; Nausea; Neoplasm Metastasis; Organoplatinum Compounds; Retrospective Studies; Severity of Illness Index; Treatment Outcome; Young Adult

Patients with advanced gastric carcinoma have still had bad prognosis despite advances in the modern treatment era. Docetaxel, cisplatin, 5-fluorouracil (DCF) is effective, but highly toxic regimen for advanced cases. In this study, we modified the standard doses of DCF (mDCF) to evaluate the effectiveness and side effects. From July 2005 to July 2008, 37 advanced gastric cancer patients treated with at least one course of mDCF protocol as first-line treatment were included. The mDCF protocol included 60 mg/m(2) docetaxel and cisplatin for 1 day and 600 mg/m(2)/day, 5-flourouracil infusion for 5 days, repeated every 3 weeks. No patients used prophylactic granulocte -colony stimulating factor. Of the patients, 28 were male and nine were female; the median age was 53 (23-65) years. Of them, 83.8% received at least four courses of chemotherapy and 64.9% completed the preplanned six courses of treatment. Eleven (29.7%) of those patients who received mDCF in the first-line treatment used the FOLFIRI (5-FU, folinic acit, irinotekan) regimen for the second-line treatment. Response rates were evaluated according to RECIST criteria in 30 out of 37 patients. The median follow-up time was 7.1 months. The longest follow-up time was 19.9 months. Two patients (5.4%) had complete response, nine (21.6%) had partial response, and 14 (37.9%) had stabilized disease; overall, the disease was controlled in 25 patients (64.9%) whereas five patients (13.5%) had progression. Median time to progression was 6.7 months and overall survival was 10 months. The assessment of patients for grade 3-4 toxicity revealed that while 5.4% had anemia and 8.1% had neutropenia, 5.4% nausea and 5.4% diarrhea. Neutropenic fever developed in two patients, requiring hospitalization. G-CSF was used in three patients. Two patients with neutropenic fever and two with severe anemia (total number 4; 10.8%) received delayed chemotherapy. Dose reduction was required in four patients (10.8%), one due to neutropenia, one due to nephrotoxicity, and two due to nausea. No patient died due to chemotherapy toxicity. This retrospective study suggested that mDCF might have comparable efficacy with classical DFC, with better toxicity profile. However, its small size and retrospective nature should be considered when interpreting the results.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cisplatin; Disease-Free Survival; Docetaxel; Dose-Response Relationship, Drug; Female; Fever; Fluorouracil; Follow-Up Studies; Gastrointestinal Diseases; Granulocyte Colony-Stimulating Factor; Hematologic Diseases; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neutropenia; Retrospective Studies; Stomach Neoplasms; Taxoids; Young Adult

Dihydropyrimidine dehydrogenase (DPD) plays a pivotal role in the metabolism of 5FU. The prognostic significance of DPD activity in peripheral blood mononuclear (PBM) cells and buccal mucosa cells with respect to toxicity was investigated in 44 patients treated with 5FU-leucovorin. Grade III/IV haematological and grade III/IV gastrointestinal toxicity were observed in 25% and 21% of the patients, respectively. No association was observed between the DPD activity in buccal mucosa cells and toxicity. In contrast, the mean DPD activity in PBM cells proved to be increased in patients experiencing grade I/II neutropenia when compared to patients without neutropenia and those suffering from grade III/IV neutropenia (P=0.002). Patients with a high-normal DPD activity proved to be at risk of developing mild toxicity upon treatment with 5FU-leucovorin, suggesting an important role of DPD in the aetiology of toxicity associated with catabolites of 5FU.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Colorectal Neoplasms; Dihydrouracil Dehydrogenase (NADP); Female; Fluorouracil; Hematologic Diseases; Humans; Leucovorin; Leukocytes, Mononuclear; Male; Middle Aged; Mouth Mucosa

Common methylenetetrahydrofolate reductase gene variants (MTHFR C677T and A1298C) have been described to have opposite effects on cancer patients. They may reduce cancer susceptibility and increase drug-related toxicity when folate antagonists (e.g. methotrexate) are utilized. We analyzed 110 patients with high-grade non-Hodgkin's lymphoma (NHL), 68 of whom were eligible for a chemotherapy combination containing methotrexate (MACOP-B) and 42 for chemotherapy without methotrexate (CHOP).. Patients were genotyped by polymerase chain reaction and stratified by MTHFR variants. These data were related to the toxicity (WHO grade GO-4) that the patients suffered and their survival. Overall 64 cases (58.2%) developed some form of toxicity and 23 (20.9%) had grade 3/4 toxicity.. When considering toxicity of any grade (grade 1-4), the 677TT genotype was significantly over-represented among cases with mucositis (OR=4.85; 95% CI, 1.47-15.97; p=0.009) and those with hepatic toxicity (OR=3.43; 95% CI, 0.99-11.86; p=0.052). Sub-analyses in the group treated with MACOP-B showed a slight increase in the risk of developing mucositis (OR=5.22; 95% CI, 1.20-27.27; p=0.03), and a strong increase in the risk of hepatic toxicity (OR=7.08; 95% CI, 1.38-36.2; p=0.019) and thrombocytopenia (OR=7.69, 95% CI 1.0-58.94; p=0.05). Interestingly, compared to the risk of developing toxicity of any grade, the risk of developing severe (grade 3/4) mucositis was almost doubled in the whole group of cases with 677TT (OR=8.13; 95% CI 1.61-41.04; p=0.011) and dramatically increased in the MACOP-B-treated cases with this gene variant (OR=24.6; 95% CI 2.49-87.41; p=0.001). There were significant results for 1298CC cases exclusively for mucositis (any grade, OR=5.33; 95% CI, 1.25-22.70; p=0.023 and OR=9.15; 95% CI, 1.14-73.41; p=0.037; for the whole group and the MACOP-B-treated group, respectively). Similarly, the risk of 1298CC patients developing severe mucositis increased (OR=9.24; 95% CI, 1.47-58.0; p=0.017 and OR=11.53; 0.93-143.18; p=0.057; in the whole group and in the MACOP-B-treated group, respectively). Event-free survival analysis revealed a lower probability of event-free survival at 5 years for 677T-carriers (log-ranks, p=0.05 and p=0.07 in the whole group and in the MACOP-B-treated group, respectively). More significant results were obtained when 1298CC cases were excluded from the reference group (log-ranks, p=0.03 and p=0.04, respectively). No significant associations were found in the CHOP-treated group.. Our data suggest that MTHFR gene variants play a critical role in NHL outcome, possibly by interfering with the action of methotrexate with significant effects on toxicity and survival. Genotyping of folate pathway gene variants might be useful to enable reduction of chemotherapy toxicity and/or to improve survival by indicating when dose adjustments or alternative treatments are necessary.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amino Acid Substitution; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Chemical and Drug Induced Liver Injury; Cyclophosphamide; Doxorubicin; Female; Genotype; Hematologic Diseases; Humans; Kaplan-Meier Estimate; Leucovorin; Lymphoma, Large B-Cell, Diffuse; Male; Methotrexate; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Mucositis; Neoplasm Proteins; Polymorphism, Single Nucleotide; Prednisone; Risk; Survival Analysis; Treatment Outcome; Vincristine

The aim of this study was to evaluate and compare the clinical characteristics of the B-cell non-Hodgkin lymphoma (NHL) patients and therapeutic efficacy of modified NHL BFM-90 and NHL BFM-95 protocols in the authors' center. From January 1993 to December 2003, 61 newly diagnosed children with B-NHL were enrolled to the study. The patients were stratified by risk factors and treated either with a modified B-NHL BFM-90 or BFM-95 protocols. The use of 1 or 3 g/m2 of methotrexate instead of 5 g/m2/24 h was the only important modification in BFM-90 protocol. Sixty-one children (12 girls, 49 boys) with a median age of 6.5 years (range: 2.5-16) were treated in the center. There were 14 patients in stage II, 28 in stage III, and 19 in stage IV. The most common initial primary tumor sites were abdomen, head, and neck. Forty-five patients were treated with modified B-cell BFM-90 and 16 patients were treated with B-cell BFM-95 regimens. The 5-year overall survival (OS) for all patients was 85.8%, and event-free survival (EFS) was 82.8%. The 5-year OS rates in modified BFM-90 and in BFM-95 protocols were 85.2 and 87.5%; the 5-year EFS rates in these 2 protocols were 84.6 and 70%, respectively (p >.05). Factors associated with lower EFS by univariate analysis were bulky disease, risk groups, and LDH level > or = 500 IU/L. By multivariate analysis only LDH level was significant. In conclusion, the treatment results in this study were similar to those of BFM group.

Topics: Adolescent; Allopurinol; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Disease-Free Survival; Diuretics; Female; Fluid Therapy; Hematologic Diseases; Humans; Kaplan-Meier Estimate; L-Lactate Dehydrogenase; Leucovorin; Lymphoma, B-Cell; Male; Methotrexate; Mucositis; Neoplasm Proteins; Risk Assessment; Sodium Bicarbonate; Survival Analysis; Survival Rate; Treatment Outcome; Tumor Burden; Tumor Lysis Syndrome; Turkey; Vincristine

This study was performed to determine the prognostic factors of 102 nonresectable locally advanced or metastatic gastric cancer patients prospectively treated with a multimodulation of 5-fluorouracil (5FU), hydroxyurea, leucovorin, and cisplatin. Response rate in 85 patients with measurable disease was 62.4% (95% confidence interval 51.9% to 72.9%). A weight increase (5% or more) was observed in 47% of patients, performance status improved in 70.6%, and symptoms disappeared in 69%. Median times for progression-free survival and overall survival were eight and 11 months, respectively. Liver metastases, more than two involved sites, and increased carcinoembryonic antigen (CEA) were found to be univariate adverse prognostic factors for survival. In a multivariate analysis, only the presence of liver metastasis was found to be an independent prognostic factor. Response rate and survival in patients with gastric linitis or diffuse forms were in the same range as in patients with intestinal forms of gastric adenocarcinoma.

Topics: Adenocarcinoma; Adult; Aged; Alopecia; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoembryonic Antigen; Cisplatin; Disease-Free Survival; Drug Evaluation; Female; Fluorouracil; Gastrointestinal Diseases; Hematologic Diseases; Humans; Hydroxyurea; Karnofsky Performance Status; Kidney Diseases; Leucovorin; Life Tables; Liver Neoplasms; Male; Middle Aged; Nervous System Diseases; Prognosis; Proportional Hazards Models; Quality of Life; Risk Factors; Stomach Neoplasms; Survival Analysis; Treatment Outcome; Weight Gain

Small-noncleaved-cell (SNC) lymphoma is a high-grade, biologically aggressive neoplasm notable for poor response to therapy, high relapse rate, and less than a 20% long-term survival. We treated 20 patients with SNC lymphoma with a novel chemotherapeutic regimen using intensive doses of chemotherapy at frequent intervals in the inpatient setting. All patients were previously untreated. Sixteen patients (80%) had stage IV disease. Most patients (95%) had at least one other characteristic associated with poor prognosis (bulky [greater than 10 cm] disease, multiple extranodal sites, poor performance status), and 85% had two or more characteristics associated with poor prognosis. Seventeen patients (85%) achieved a complete response (CR) to therapy, including all three patients with human immunodeficiency virus (HIV)-associated disease. There have been three relapses, all occurring less than 18 months after treatment, and two of three relapses occurred in patients who were unable to complete therapy. At a median follow-up of 29 months, 13 patients (65%) remain disease-free; the calculated 5-year actuarial disease-free survival is 60%. Toxicity, chiefly myelosuppression, was severe but manageable. There were two treatment-related deaths, both in elderly patients with poor performance status and advanced-stage disease. These data suggest that such a dose-intensive approach improves the response and survival of patients with SNC lymphoma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cyclophosphamide; Doxorubicin; Etoposide; Female; Follow-Up Studies; Hematologic Diseases; Humans; Leucovorin; Lymphoma, Non-Hodgkin; Male; Methotrexate; Middle Aged; Neoplasm Staging; Prednisone; Prognosis; Survival Rate; Vincristine

The effect of leucovorin (LV) given in various doses and schedules on the in vivo antitumor activity and toxicity of 5-fluorouracil (5FU) was studied in two murine colon cancer lines, i.e., Colon 26 (relatively resistant to 5FU) and Colon 38 (5FU sensitive), maintained in Balb-c and C57B1/6 mice, respectively. Mice were treated weekly with 5FU at the maximum tolerated dose, alone and in combination with LV. In Colon 26, neither simultaneous administration of 5FU and LV nor 5FU combined with delayed administration of LV potentiated the antitumor activity of 5FU. LV given twice - 1 hr before (50 mg/kg) and then together (50 mg/kg) with 5FU (100 mg/kg) - gave significantly better delay of tumor growth of both tumor lines than 5FU did alone (100 mg/kg). No differences were found after a total LV dose of 100 or 200 mg/kg. Delayed administration of uridine (3500 mg/kg) allowed the use of higher 5FU doses, which improved the antitumor effect on Colon 26. Systemic toxicity led to moderate weight loss in treated mice, but was comparable for mice treated with 5FU alone or combined with LV. Hematological toxicity consisted of moderate leukopenia (nadir 40%), which was observed with the most active schedule and was less severe than with 5FU alone. This schedule did not cause thrombocytopenia, but after discontinuation the thrombocyte count showed an overshoot. Addition of uridine to this schedule reduced hematological toxicity only slightly. It is concluded that LV potentiated the antitumor activity of 5FU against two solid tumor lines, i.e., a relatively resistant and a sensitive murine colon carcinoma, and that toxicity was moderate.

Topics: Animals; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Fluorouracil; Hematologic Diseases; Leucovorin; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Time Factors; Uridine

Twenty-three patients with advanced colorectal cancer were treated with folinic acid (200 mg/m2/day 1-5 IV bolus injection) and 5-fluorouracil (400 mg/m2/day 1-5 IV in 15 minutes) every 28 days. Only three patients were pretreated. Objective response was observed in 6 (30%) of 20 evaluable patients (three complete and three partial responses). The median duration of response was 9 months (range 5-15) and time to disease progression ranged from 2 to 12 months (median 6 months). Median survival was 21 months (range 12-23+) for responders. Another 6 (30%) patients had stabilization of disease. Toxicity was generally gastrointestinal (mucositis, diarrhea, nausea); moderate leukopenia was noted. The response rate found in this study indicates that folinic acid administered in high doses enhances the effectiveness of 5-FU administered concomitantly in colorectal cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Fluorouracil; Gastrointestinal Diseases; Hematologic Diseases; Humans; Infusions, Intravenous; Injections, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Rectal Neoplasms

12 AIDS/ARC patients with or suspected of Pneumocystis carinii pneumonia were treated with co-trimoxazole and received supplementary folic or folinic acid to avoid peripheral blood cytopenia. Most patients developed decreased numbers of neutrophils and hemoglobin while receiving co-trimoxazole. Supplementary folate/folinate could not abolish the drug-induced cytopenia. Routine prescription of folinic acid is not recommended. Folic acid is cheap and may be beneficial and should be prescribed.

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Complex; Anemia; Drug Combinations; Folic Acid; Hematologic Diseases; Humans; Leucovorin; Leukopenia; Pneumonia, Pneumocystis; Prospective Studies; Sulfamethoxazole; Thrombocytopenia; Time Factors; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Drug Combinations; Hematologic Diseases; Humans; Leucovorin; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

A regimen of high-dose methotrexate with leucovorin rescue, vinblastine, and bleomycin with or without tamoxifen was administered to 34 patients with metastatic renal cell carcinoma. No complete remissions were observed, but ten patients (30%) achieved partial remission and an additional 13 patients (39%) had stabilization of disease. The median survival of responding patients (110 weeks) was significantly longer than that of nonresponding patients. The addition of tamoxifen did not influence response or survival. This regimen was tolerated without significant toxicity. A prospective randomized study of the vinblastine and high-dose methotrexate regimen compared to the respective single agents seem to be indicated.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Drug Evaluation; Female; Hematologic Diseases; Humans; Kidney Neoplasms; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Metastasis; Random Allocation; Tamoxifen; Time Factors; Vinblastine

Topics: Drug Therapy, Combination; Hematologic Diseases; Humans; Leucovorin; Trimethoprim

Fifty-one patients with metastatic adenocarcinoma received Folinic Acid (FA) combined with 5-Fluorouracil (5FU) in a Phase I-II clinical trial. Two different schedules were used: (a) bolus infusion--5FU 7-12 mg/kg/d I.V. d1-5, FA 1.6 mg/kg/d I.V. d1-5; (b) continuous infusion--5FU 600-1200 mg/m2/d I.V. d1-4, FA 60 mg/m2/d I.V. d1-4. Mucositis and myelosuppression were dose-limiting, with recommended dose levels of 5FU for further trials being 10 mg/kg/d I.V. d1-5 and 1000 mg/m2/d I.V. d1-4 on the bolus and continuous infusion schedules, respectively. Forty-one evaluable patients with measurable disease were treated. Thirty-six had metastatic colorectal carcinoma, and 14/36 patients responded (CR-1, PR-13), including responses in three patients who had previously failed 5FU treatment alone. In the two patients with unknown primary sites and three with gastric cancer, no response were seen. 5FU and FA have activity equivalent to 5FU alone, and the responses in patients receiving prior 5FU suggest it may be superior. The possibility that toxicity may be enhanced does exist. Further trials of these two agents are warranted.

Topics: Adenocarcinoma; Adult; Aged; Drug Administration Schedule; Drug Evaluation; Female; Fluorouracil; Gastrointestinal Diseases; Gastrointestinal Neoplasms; Hematologic Diseases; Humans; Infusions, Parenteral; Injections, Intravenous; Leucovorin; Male; Middle Aged

Fifteen patients with advanced or recurrent gynecologic malignancy were treated with high-dose methotrexate (HDMTX) (1-8 g/M2) and citrovorum factor rescue (10-100 mg/M2). One complete response (13%) and two improved responses occurred in eight patients (25%) with squamous cell carcinoma and one of seven patients (14%) with nonsquamous nontrophoblastic carcinoma had stable disease for 7 months. The median duration of survival in the squamous group was 9 months and in the nonsquamous groups 6.5 months. Mean serum MTX concentrations were proportional to the doses administered and typical two compartment plasma disappearance curves were seen. Adverse toxic reactions were not observed at serum MTX levels less than 7.8 X 10(-7) M at 24 hr and 1 X 10(-7) M at 48 hr post-MTX. Hematopoietic toxicity occurred most frequently with leukopenia observed in 19.5% of courses. Hepatic, renal, gastrointestinal, and dermatologic toxicities were observed infrequently. Drug-induced nephrotoxicity occurred in one patient and possibly related leukoencephalopathy occurred in another patient. On the basis of the relatively low response rate observed in this trial and the high expense of HDMTX therapy, the value of such therapy may be limited in advanced nontrophoblastic gynecologic cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemical and Drug Induced Liver Injury; Drug Evaluation; Female; Genital Neoplasms, Female; Hematologic Diseases; Humans; Kidney Diseases; Kinetics; Leucovorin; Methotrexate; Middle Aged; Nausea; Time Factors

Thirty-one patients with unresectable non-small cell carcinoma of the lung (19 adenocarcinoma, 7 large cell carcinoma, 4 squamous cell carcinoma, 1 mixed histology) were treated with one of two intravenous infusion schedules of high dose methotrexate with leucovorin rescue. First, 14 patients received methotrexate in escalating doses from 1.5 to 12 g/m2 over 6 hours followed immediately with leucovorin 15 mg/m2 for 12 doses every 6 hours; there were no complete or partial responses among these 14 patients. Then, 17 patients were treated with a loading bolus of 50 mg/m2 intravenous methotrexate followed by a 30-hour continuous infusion of 1.5 g/m2. Leucovorin 15 mg/m2 every 6 hours for 12 doses was begun at the end of the infusion. There were 3 partial responses among the 17 patients in this group. The results demonstrate that both 6- and 30-hour infusions of high-dose methotrexate regimens can be given safely to middle aged adult patients, but the overall 10% response rate does not appear to be significantly different than the results with standard-dose methotrexate.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Aspartate Aminotransferases; Creatinine; Drug Administration Schedule; Female; Hematologic Diseases; Humans; Leucovorin; Lung Neoplasms; Male; Methotrexate; Middle Aged

A regimen consisting of two courses of methotrexate (MTX) with leucovorin rescue followed 1 week later by cyclophosphamide, vincristine, and prednisone (MTX-COP) was studied in ten patients with disseminated diffuse non-Hodgkin's lymphoma who had had no prior chemotherapy. A similar regimen with the addition of doxorubicin (MTX-CHOP) was used for patients who had had previous chemotherapy: 11 with diffuse non-Hodgkin's lymphoma and two with Hodgkin's disease. The response rate to initial MTX administration was 55%, and the clinical onset of effect was usually observed within 48 hours. Responses were observed in previously treated and untreated patients. The remission rate was 100% with both regimens. There were seven complete remissions with MTX-COP and six with MTX-CHOP. The median durations of remission were 23 and 13 months, respectively; median survival was not reached in either group. MTX was well-tolerated by both groups of patients without serious toxic effects. Overall, significantly more hematologic toxicity was observed in previously treated patients; however, no life-threatening toxic effects were observed in either group. The incorporation of MTX and other antimetabolites into schedules of chemotherapy for previously treated and untreated patients with non-Hodgkin's lymphoma is well tolerated and deserved further exploration.

Topics: Adult; Aged; Antineoplastic Agents; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Hematologic Diseases; Humans; Leucovorin; Lymphoma; Male; Methotrexate; Middle Aged; Prednisone; Vincristine

Fifty-one patients with nonmetastatic gestational trophoblastic neoplasms (NMGTN) were treated with either 4 or 6 mg/kg methotrexate (MTX) and citrovorum factor (CF) rescue to determine if the higher dosage could reduce the number of courses of chemotherapy required to achieve remission. Thirty-six of 41 patients treated with 4 mg/kg MTX achieved complete remission with 1 course of chemotherapy. Increasing the initial dose of MTX to 6 mg/kg in 10 patients did not reduce the need for subsequent courses of chemotherapy but did increase associated toxicity. The rate of fall in the human chorionic gonadotropin (hCG) titer following the initial course of MTX-CF was found to be an accurate predictor of therapeutic response. The need for further chemotherapy may be anticipated if the hCG titer has not fallen by 1 log within 18 days.

Topics: Adolescent; Adult; Chemical and Drug Induced Liver Injury; Chorionic Gonadotropin; Drug Administration Schedule; Drug Therapy, Combination; Female; Hematologic Diseases; Humans; Leucovorin; Liver; Methotrexate; Middle Aged; Pregnancy; Risk; Trophoblastic Neoplasms; Uterine Neoplasms

Topics: Antineoplastic Agents; Drug Administration Schedule; Drug Therapy, Combination; Folic Acid; Hematologic Diseases; Humans; Leucovorin; Middle Aged; Pyrimethamine

Hematological and histological studies of the rabbit brachydactyly mutant were made to clarify the question of the blood abnormality that had previously been implicated in the teratogenic process leading to congenital amputation. The hemoglobin of fetal and adult br/br rabbits, studied by electrophoresis and cyanmethemoglobin assay, exhibited no differences from that of controls. The br/br fetuses were polycythemic and severely macrocytic. Fetal limb vessels showed thrombosis leading to hemorrhages in the extremities. The hepatic tissue was abnormal, being particularly poor in hematopoietic cells; blood cell macrocytosis was attributed to impaired erthropoiesis. Treatment of pregnant rabbits with folic acid plus vitamin B12 or with folinic acid was able simultaneously to prevent the fetal blood cell macrocytosis and the congenital abnormalities.

Topics: Abnormalities, Multiple; Animals; Blood Cell Count; Drug Therapy, Combination; Electrophoresis, Cellulose Acetate; Erythrocytes, Abnormal; Erythropoiesis; Extremities; Female; Folic Acid; Hematologic Diseases; Hemoglobinometry; Homozygote; Inbreeding; Leucovorin; Limb Deformities, Congenital; Liver; Maternal-Fetal Exchange; Pregnancy; Rabbits; Vitamin B 12

Topics: Gastrointestinal Diseases; Hematologic Diseases; Humans; Leucovorin; Tritium