levoleucovorin and Mucositis

: High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m. High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m

Topics: Acute Kidney Injury; Antimetabolites, Antineoplastic; Bone Marrow; Chemical and Drug Induced Liver Injury; Crystallization; gamma-Glutamyl Hydrolase; Humans; Leucovorin; Methotrexate; Mucositis

To evaluate the efficiency and safety profile of raltitrexed-based chemotherapy in the treatment of advanced colorectal cancer.. An electronic search was undertaken to identify randomized controlled trials comparing raltitrexed-based regimen to 5-fluorouracil-based regimen in patients with advanced colorectal cancer. The outcomes included overall survival, overall response rate and toxicities.. This meta-analysis included 11 studies with 4622 patients. Overall, there were no significant differences between the two regimens in terms of overall survival (HR=1.06, 95% CI: 0.96-1.17, P=0.23) or overall response rate (RR=1.09, 95% CI: 0.86-1.38, P=0.47). In subgroup analysis, patients in raltitrexed/oxaliplatin group had significantly higher partial response (RR=1.53, 95% CI: 1.17-2.00, P=0.002), overall response rate (RR=1.42, 95% CI: 1.10-1.82, P=0.006), disease control rate (RR=1.16, 95% CI: 1.04-1.29, P=0.009) and lower progressive disease (RR=0.61, 95% CI: 0.45-0.84, P=0.002) when compared to 5-fluorouracil/leucovorin/oxaliplatin group. Occurrence of severe anemia (RR=2.23, 95% CI: 1.38-3.59, P=0.0001), asthenia (RR=2.29, 95% CI: 1.36-3.84, P=0.002), hepatic disorders (RR=7.51, 95% CI: 1.30-43.56, P=0.02), and nausea/vomit (RR=1.70, 95% CI: 1.03-2.81, P=0.04) were significantly higher with the raltitrexed arm treatment, while frequencies of grade 3/4 alopecia (RR=0.36, 95% CI: 0.26-0.50, P<0.00001) and stomatitis/mucositis (RR=0.14, 95% CI: 0.07-0.31, P<0.00001) were increased in the 5-fluorouracil group.. Raltitrexed-based chemotherapy regimen leads to an equivalent overall survival and response rates with acceptable toxicities compared to traditional 5-fluorouracil-based regimen in patients with advanced colorectal cancer. Raltitrexed can be a treatment option for these patients when 5-fluorouracil-based regimens are not tolerated or inappropriate.

Topics: Alopecia; Anemia; Antineoplastic Combined Chemotherapy Protocols; Asthenia; Chemical and Drug Induced Liver Injury; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Mucositis; Nausea; Organoplatinum Compounds; Oxaliplatin; Quinazolines; Randomized Controlled Trials as Topic; Stomatitis; Thiophenes; Vomiting

The aim of this study was to evaluate systematically the efficacy and safety of oral uracil-tegafur (UFT) plus leucovorin (LV) compared with infusional fluorouracil (5-FU) plus LV for advanced colorectal cancer.. Eligible studies were identified from Medline, Embase and the Cochrane Library. The end-points included overall survival and overall tumour response rate, and toxicity including leucopenia, febrile neutropenia, stomatitis/mucositis and diarrhoea.. Five randomized controlled trials were identified. Pooled data demonstrated no difference in overall survival between the oral UFT plus LV regimen and the 5-FU bolus plus LV regimen [hazard ratio 1.013; 95% confidence interval (CI) 0.911-1.127].The fixed-effect pooled estimate for overall tumour response rate showed no significant difference between the two regimens (relative risk 0.893; 0.672-1.187). Grade 3-4 leucopenia [odds ratio (OR) 0.126; 955 CI 0.048-0.326], grade 1-4 leucopenia (OR 0.089; 95% CI 0.067-0.119) and grade1-4 febrile neutropenia (OR 0.020; 95% CI 0.004-0.102) were significantly less prominent in the oral UFT regimens. For nonhaematological toxicities, grade 3-4 stomatitis/mucositis (OR 0.075; 95% CI 0.039-0.146), grade 3-4 infection (OR 0.484; 95% CI 0.310-0.758), grade 1-4 infection (OR 0.672; 95% CI 0.547-0.826, P < 0.001), grade 1-4 diarrhoea (OR 0.743; 95% CI 0.626-0.881) were also less likely to happen in patients in the oral UFT plus LV regimen, while there was no significant difference between the two treatment regimens with respect to grade 1-4 stomatitis/mucositis (OR 0.278; 95% CI 0.053-1.456) and grade 3-4 (OR 1.174; 95% CI 0.983-1.403) diarrhoea.. Oral UFT or 5-FU bolus combined with LV results in similar overall survival and tumour response rates for advanced colorectal cancer. The former treatment regimen is greatly superior in terms of toxicity, especially haematological toxicity.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Diarrhea; Fluorouracil; Humans; Infections; Leucovorin; Leukopenia; Mucositis; Neutropenia; Odds Ratio; Randomized Controlled Trials as Topic; Stomatitis; Survival Analysis; Tegafur; Uracil

Leucovorin (folinic acid) is a commonly used antidote for severe toxicity with low-dose methotrexate, but its optimum dose is unclear, varying from 15 to 25 mg every 6-h.. Open-label RCT included patients with severe low-dose (≤ 50 mg/week) methotrexate toxicity defined as WBC ≤ 2 × 10^9/L or platelet ≤ 50 × 10^9/L and randomized them to receive either usual (15 mg) or high-dose (25 mg) intravenous leucovorin given every 6-h. Primary outcome was mortality at 30-days and secondary outcomes were hematological recovery and mucositis recovery.. CTRI/2019/09/021152.. Thirty-eight patients were included, most with underlying RA who had inadvertently overdosed MTX (taken daily instead of weekly). At randomization, the median white blood and platelet count were 0.8 × 10^9/L and 23.5 × 10^9/L. 19 patients each were randomized to receive either usual or high-dose leucovorin. Number (%) of deaths over 30-days was 8 (42) and 9 (47) in usual and high-dose leucovorin groups (Odds ratio 1.2, 95% CI 0.3 to 4.5, p = 0.74). On Kaplan-Meier, there was no significant difference in survival between the groups (hazard ratio 1.1, 95% CI 0.4 to 2.9, p = 0.84). On multivariable cox-regression, serum albumin was the only predictor of survival (hazard ratio 0.3, 95% CI 0.1 to 0.9, p = 0.02). There was no significant difference in hematological or mucositis recovery between the two groups.. There was no significant difference in survival or time-to hematological recovery between the two doses of leucovorin. Severe low-dose methotrexate toxicity carried a significant mortality.

Topics: Blood Platelets; Humans; Leucovorin; Methotrexate; Mucositis

This phase I study investigated the safety, dose-limiting toxicity, and efficacy in three cohorts all treated with the mTOR inhibitor everolimus that was delivered (1) in combination with 5-fluorouracil with leucovorin (5-FU/LV), (2) with mFOLFOX6 (5-FU/LV + oxaliplatin), and (3) with mFOLFOX6 + panitumumab in patients with refractory solid tumors.. Patients were accrued using a 3-patient cohort design consisting of two sub-trials in which the maximum tolerated combination (MTC) and dose-limiting toxicity (DLT) of everolimus and 5-FU/LV was established in Sub-trial A and of everolimus in combination with mFOLFOX6 and mFOLFOX6 plus panitumumab in Sub-trial B.. Thirty-six patients were evaluable for toxicity, 21 on Sub-trial A and 15 on Sub-trial B. In Sub-trial A, DLT was observed in 1/6 patients enrolled on dose level 1A and 2/3 patients in level 6A. In Sub-trial B, 2/3 patients experienced DLT on level 1B and subsequent patients were enrolled on level 1B-1 without DLT. Three of six patients in cohort 2B-1 experienced grade 3 mucositis, and further study of the combination of everolimus, mFOLFOX6 and panitumumab was aborted. Among the 24 patients enrolled with refractory metastatic colorectal cancer, the median time on treatment was 2.7 months with 45 % of patients remaining on treatment with stable disease for at least 3 months.. While a regimen of everolimus in addition to 5-FU/LV and mFOLFOX6 appears safe and tolerable, the further addition of panitumumab resulted in an unacceptable level of toxicity that cannot be recommended for further study. Further investigation is warranted to better elucidate the role which mTOR inhibitors play in patients with refractory solid tumors, with a specific focus on mCRC as a potential for the combination of this targeted and cytotoxic therapy in future studies.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Monitoring; Early Termination of Clinical Trials; Everolimus; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mucositis; Neoplasm Metastasis; Neoplasms; Organoplatinum Compounds; Oxaliplatin; Panitumumab; Protein Kinase Inhibitors; Severity of Illness Index; Sirolimus; TOR Serine-Threonine Kinases

Since the 1990s, fluorouracil-based adjuvant chemotherapy has significantly reduced the risk of tumour recurrence in patients with stage III colon cancer. We aimed to assess whether the addition of cetuximab to standard adjuvant oxaliplatin, fluorouracil, and leucovorin chemotherapy (FOLFOX4) in patients with stage III colon cancer improved disease-free survival (DFS).. For this open-label, randomised phase 3 study done in nine European countries, we enrolled patients through an interactive voice response system to the central randomisation centre, with a central stratified permuted block randomisation procedure. We randomly assigned patients with resected (R0) stage III disease (1:1) to receive 12 cycles of FOLFOX4 twice a week with or without cetuximab. Patients were stratified by N-status (N1 vs N2), T-status (T1-3 vs T4), and obstruction or perforation status (no obstruction and no perforation vs obstruction or perforation or both). A protocol amendment (applied in June, 2008, after 2096 patients had been randomly assigned to treatment-restricted enrolment to patients with tumours wild-type at codons 12 and 13 in exon 2 of the KRAS gene (KRAS exon 2 wild-type). The primary endpoint was DFS. Analysis was intention to treat in all patients with KRAS exon 2 wild-type tumours. The study is registered at EudraCT, number 2005-003463-23.. Between Dec 22, 2005, and Nov 5, 2009, 2559 patients from 340 sites in Europe were randomly assigned. Of these patients, 1602 had KRAS exon 2 wild-type tumours (intention-to-treat population), 791 in the FOLFOX4 plus cetuximab group and 811 in the FOLFOX4 group. Median follow-up was 3·3 years (IQR 3·2-3·4). In the experimental and control groups, DFS was similar in the intention-to-treat population (hazard ratio [HR] 1·05; 95% CI 0·85-1·29; p=0·66), and in patients with KRAS exon 2/BRAF wild-type (n=984, HR 0·99; 95% CI 0·76-1·28) or KRAS exon 2-mutated tumours (n=742, HR 1·06; 95% CI 0·82-1·37). We noted heterogeneous responses to the addition of cetuximab in preplanned subgroup analyses. Grade 3 or 4 acne-like rash (in 209 of 785 patients [27%] vs four of 805 [<1%]), diarrhoea (113 [14%] vs 70 [9%]), mucositis (63 [8%] vs 10 [1%]), and infusion-related reactions (55 [7%] vs 30 [4%]) were more frequent in patients treated with FOLFOX4 plus cetuximab than in those patients who received FOLFOX4 alone.. The addition of cetuximab to FOLFOX4 did not improve DFS compared with FOLFOX4 alone in patients with KRAS exon 2 wild-type resected stage III colon cancer. This trial cannot conclude on the benefit of cetuximab in the studied population, but the heterogeneity of response suggests that further investigation of the role of FOLFOX4 plus cetuximab in specific patient subgroups is warranted.. Fédération Francophone de Cancérologie Digestive (FFCD), Merck KGaA, and Sanofi-Aventis.

Topics: Adenocarcinoma; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Chemotherapy, Adjuvant; Colonic Neoplasms; Diarrhea; Disease-Free Survival; Drug Eruptions; Exons; Female; Fluorouracil; Humans; Infusions, Intravenous; Intention to Treat Analysis; Leucovorin; Male; Middle Aged; Mucositis; Neoplasm Staging; Organoplatinum Compounds; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins

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

To assess the predictive value of polymorphisms in dihydropyrimidine dehydrogenase (DPYD ), thymidylate synthase (TYMS ), and methylene tetrahydrofolate reductase (MTHFR ) and of nongenetic factors for severe leukopenia, diarrhea, and mucositis related to fluorouracil (FU) treatment.. A multicenter prospective clinical trial included 683 patients with cancer treated with FU monotherapy. Toxicity was documented according to World Health Organization grades. DPYD, TYMS, and MTHFR genotypes were determined, and DPYD was resequenced in patients with severe toxicity.. Grade 3 to 4 toxicity occurred in 16.1% of patients. The sensitivity of DPYD*2A genotyping for overall toxicity was 5.5% (95%CI, 0.02 to 0.11), with a positive predictive value of 0.46 (95% CI, 0.19 to 0.75; P = .01). Inclusion of additional DPYD variants improved prediction only marginally. Analysis according to toxicity type revealed significant association of DPYD with mucositis and leukopenia, whereas TYMS was associated with diarrhea. Genotype, female sex, mode of FU administration, and modulation by folinic acid were identified as independent risk factors by multivariable analysis. A previously unrecognized significant interaction was found between sex and DPYD, which resulted in an odds ratio for toxicity of 41.8 for male patients (95% CI, 9.2 to 190; P < .0001) but only 1.33 (95% CI, 0.34 to 5.2) in female patients. Homozygosity for the TYMS enhancer region double repeat allele increased risk for toxicity 1.6-fold (95% CI, 1.08 to 2.22; P = .02).. DPYD, TYMS, and MTHFR play a limited role for FU related toxicity but a pronounced DPYD gene/sex-interaction increases prediction rate for male patients. Toxicity risk assessment should include sex, mode of administration, and folinic acid as additional predictive factors.

Topics: Antimetabolites, Antineoplastic; Diarrhea; Dihydrouracil Dehydrogenase (NADP); DNA Methylation; Female; Fluorouracil; Gene Frequency; Genetic Predisposition to Disease; Genetic Testing; Germany; Homozygote; Humans; Leucovorin; Leukopenia; Logistic Models; Male; Methylenetetrahydrofolate Reductase (NADPH2); Mucositis; Odds Ratio; Patient Selection; Polymorphism, Genetic; Predictive Value of Tests; Promoter Regions, Genetic; Prospective Studies; Risk Assessment; Risk Factors; Severity of Illness Index; Thymidylate Synthase; Vitamin B Complex

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

Systemic chemotherapy may damage gastrointestinal epithelium. Mucositis is associated with increased intestinal permeability (IP). It is known that IP test with chromium 51-ethylene diaminetetra-acetate (51Cr-EDTA) is a useful tool to assess the mucositis. Oral glutamine supplements (OGS) may have a role in the prevention of chemotherapy-induced mucositis/stomatitis. The aim of this study was to characterize the relationship between the urinary excretion of 51Cr-EDTA and the severity of mucositis, and the effect of OGS on 5-fluorouracil/leucovorin (FU/LV)-induced mucositis/stomatitis.. Fifty-one patients with advanced or metastatic cancer received FU/LV chemotherapy. The control group included 18 healthy volunteers. IP was assessed via the measurement of 51Cr-EDTA urinary excretion after oral challenge, on days 7 after the discontinuation of chemotherapy. Of the 51 patients, 22 patients received OGS (30 g/day) and 29 received only best supportive care (BSC). Glutamine supplementation continued for 15 days. It was initiated at least 3 days before the beginning of chemotherapy. Mucositis/stomatitis was graded according to version 3.0 of the Common Terminology Criteria for Adverse Events.. In the chemotherapy group, the median (25 percentile, 75 percentile) IP test score was significantly higher than those of the control group [6.78% (4.63, 10.66) vs. 2.17% (1.38, 2.40), P<0.001]. The severity of stomatitis was significantly correlated with IP test scores (r=0.898, P<0.001). In the OGS group, the median IP test score was significantly lower than that of the BSC group [4.69% (3.10, 6.48) vs. 8.54% (6.48, 15.31), P<0.001]. A mucositis/stomatitis of grade 2-4 was observed in two patients of the OGS group (9%), and in 11 patients (38%) in the BSC group (P<0.001).. The IP test may be a useful tool in the evaluation of mucositis/stomatitis. OGS may exert a protective effect on FU/LV-induced mucositis/stomatitis. Further studies, however, will be necessary to define the role of glutamine supplementation in FU/LV-induced mucositis/stomatitis.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chromium Radioisotopes; Edetic Acid; Female; Fluorouracil; Glutamine; Humans; Intestinal Absorption; Leucovorin; Male; Middle Aged; Mucositis; Neoplasms; Permeability; Severity of Illness Index; Stomatitis; Treatment Outcome

The aim of this study was to evaluate the efficacy and toxicity of concurrent chemoradiotherapy using cisplatin (CDDP), 5-fluorouracil (5-FU), methotrexate (MTX) and leucovorin (LV) (PFML) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).. Seventy-seven patients with previously untreated stages III-IV SCCHN were included in this trial. Patients received two cycles of chemotherapy repeated every 4 weeks. The chemotherapy regimen consisted CDDP (60 mg/m2, day 4), 5-FU (600 mg/m2 given over 24 h for 5 days, days 1-5), MTX (30 mg/m2, day 1) and LV (20 mg/m2, days 1-5). Radiation was targeted to begin on the starting day of chemotherapy, day 1. The total radiation dose to the primary site and neck lymph nodes was 70.0 Gy. When grade>or=3 toxicities were observed frequently, radiotherapy and/or chemotherapy were delayed or reduced.. The main toxicities were mucositis (grade>or=3, 39%), leukocytopenia (grade>or=3, 34%) and neutropenia (grade>or=3, 30%). The overall clinical response rate and the pathological complete response (CR) were 94% (72/77) and 71% (55/77). The primary site CR and neck lymph node CR were 79% (61/77) and 85% (44/52), and 3-year survival rate was 73%.. This concurrent chemoradiotherapy with PFML was safe and well tolerated. The high CR rate justifies further evaluation of this chemoradiotherapy modality in locally advanced SCCHN patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Drug Administration Schedule; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Leukopenia; Male; Methotrexate; Middle Aged; Mucositis; Neutropenia; Radiotherapy Dosage

Chemotherapy-induced diarrhea occurs secondary to mucosal inflammation and may be cyclooxygenase-2 mediated. Cyclooxygenase-2 inhibitors may ameliorate chemotherapy-induced mucosal toxicity and enhance its antitumor effect. We investigated this hypothesis in the Ward colorectal cancer rat model and in a phase I clinical study.. In the Ward rat model, irinotecan was given daily x 3 or weekly x 4 with or without celecoxib. In the phase I clinical study, we planned to escalate the dose of irinotecan in the FOLFIRI regimen (irinotecan, 5-fluorouracil, and leucovorin) with a fixed dose of celecoxib. Irinotecan was escalated in four dose levels: 180, 200, 220, and 260 mg/m2. Celecoxib was administered as 400 mg, twice daily starting on day 2 of cycle 1. Pharmacokinetics of irinotecan, SN-38, and SN-38G were obtained on days 1 and 14. A standard 3+3 dose escalation scheme was used. Plasma concentrations of irinotecan, SN-38, and SN-38G were measured using high-pressure liquid chromatography.. Celecoxib ameliorated diarrhea, weight loss, and lethality and resulted in synergistic antitumor effect in the rat model. Twelve patients with advanced cancers were enrolled and evaluable for dose-limiting toxicity (DLT). Diarrhea was the cause for discontinuation in one. Grade 2 and 3 diarrhea occurred in three and two patients, respectively. One patient had DLT at dose level 2 (grade 3 diarrhea). Two had a DLT at DL3 (G3 emesis and myocardial infarct). Celecoxib had limited influence on the pharmacokinetics of irinotecan in this data set.. Maximum tolerated dose of irinotecan in FOLFIRI schedule with celecoxib is 200 mg/m2.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Celecoxib; Colorectal Neoplasms; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fluorouracil; Glucuronates; Humans; Intestinal Mucosa; Irinotecan; Leucovorin; Male; Maximum Tolerated Dose; Mucositis; Neoplasm Transplantation; Neoplasms, Experimental; Pyrazoles; Rats; Rats, Inbred F344; Sulfonamides

Several clinical trials have demonstrated that oxaliplatin is a useful agent in combination with 5-fluorouracil (5-FU) and folinic acid (FA) for the treatment of patients with colorectal carcinoma. The aims of this pilot study were to evaluate non-hematological toxicity and patient characteristics in gastrointestinal cancer patients treated with chronomodulated chemotherapy consisting of oxaliplatin, 5-FU and sodium folinate.. Patients with metastatic gastrointestinal cancer received a chronomodulated regimen with oxaliplatin (25 mg/m2), 5-FU (750 mg/m2) and sodium folinate (150 mg/m2). Non-hematological toxicities were evaluated and analyzed in relation to patient characteristics, i.e. age, sex, body weight, body mass index (BMI), body surface area and smoking status. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria.. The severity of non-hematological toxicity was generally moderate. Grade 4 toxicity was only found in 2 patients with diarrhea (12.5%). The most frequent common adverse events were nausea, Grades 1 - 2 in 13 patients (81.3%), followed by motor neuropathy, Grades 1 - 3 in 11 patients (68.9%). The analyses showed that patient characteristics such as BMI and smoking status were associated with mucositis/stomatitis, vomiting or mood alteration. Furthermore, there was a relationship between smoking status and the overall non-hematological toxicity. Smokers had significantly higher overall toxicity than non-smokers and body mass index correlated significant with overall toxicity.. The results of this pilot investigation suggest that a chronomodulated regimen with oxaliplatin, 5-FU and sodium folinate has a manageable non-hematological toxicity profile and that toxicity of the chronomodulated schedule studied depends on the patient characteristics. In further investigations, risk factors determining chemotherapeutic toxicity should be considered. Because of the small number of patients in this pilot investigation, the findings need to be confirmed in a larger clinical study.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Body Mass Index; Chronotherapy; Diarrhea; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Middle Aged; Motor Neurons; Mucositis; Nausea; Organoplatinum Compounds; Oxaliplatin; Patient Selection; Pilot Projects; Risk Factors; Severity of Illness Index; Stomatitis; Vomiting

As no standard chemotherapy regimen has been established for advanced gastric cancer, this study sought to evaluate the efficacy and safety of combination chemotherapy that included paclitaxel and leucovorin (LV)-modulated infusional 5-fluorouracil (5-FU) in metastatic gastric cancer. Patients received a three-hour infusion of 175 mg/m2 of paclitaxel on day 1. A bolus of 20 mg/m2 of LV was then administered, followed by a 24-h infusion of 1,000 mg/m2 of 5-FU on days 1 through 3. The treatment cycle was re-peated every 3 weeks until disease progression. Response evaluation was performed according to the RECIST criteria, with toxicity determined by NCI-CTC (version 2.0). A total of 66 patients, including 21 (31.8%) with a history of prior chemotherapy, were enrolled. Fifteen (71.4%) of the 21 patients with prior chemotherapy received prolonged infusional 5-FU. In the 56 evaluable patients (37 in the chemotherapy-naïve group and 19 in the prior chemotherapy group), tumor responses according to prior exposure to chemotherapy were as follows: 17 (45.9%) partial response (PR), 6 (16.2%) stable disease (SD) and 14 (37.8%) progressive disease (PD) in the chemotherapy-naïve group; 1 (7.1%) complete response, 3 (15.8%) PRs, 8 (42.1%) SDs and 7 (36.8%) PDs in the prior chemotherapy group. The overall median response duration was 20 weeks (range, 8-61 weeks), with a median progression-free survival of 20 weeks [95% confidence interval (CI), 13.4-26.6 weeks] and 12 weeks (95% CI, 5.7-18.3 weeks) in the chemotherapy-naïve and prior chemotherapy groups, respectively. The median overall survival was 48 weeks (95% CI, 38-58 weeks) in the chemotherapy-naïve group and 28 weeks (95% CI, 22-34 weeks) in the prior chemotherapy group. The most frequent grade III/IV toxicity was neutro-penia. Non-hematological toxicity of grade III/IV was rare. Paclitaxel in combination with 5-FU/LV is clinically beneficial for patients with advanced gastric cancer and is a feasible salvage regimen for 5-FU-refractory gastric cancer patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Diarrhea; Disease Progression; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Mucositis; Multivariate Analysis; Neutropenia; Paclitaxel; Prognosis; Stomach Neoplasms; Survival Analysis; Treatment Outcome

Given the biological differences between females and males, sex-specific evaluations should be carried out to obtain better cancer prevention, diagnosis, and treatment strategies. To this purpose, our aim was to evaluate sex differences for toxicity in a cohort of colorectal cancer (CRC) patients undergoing chemotherapy.. We performed a retrospective study in 329 CRC patients. Differences between males and females were tested performing the Mann-Whitney U test or the Fisher exact test. Multivariate logistic regression models were computed to evaluate the association between sex and risk of chemotherapy agent-related toxicity.. According association sex toxicity, significant differences were observed in the median number of episodes of nausea (p = 0.044), vomit (p = 0.007), heartburn (p = 0.022), thrombocytopenia (p = 0.005), mucositis (p = 0.024). Moreover, statistically significant differences between males and females were observed in the distribution of the highest toxicity grades of nausea (p = 0.024), heartburn (p = 0.016), and thrombocytopenia (p = 0.034). Females have an increased risk of vomit (p = 0.002), alopecia (p = 0.035), heartburn (p = 0.005), mucositis (p = 0.003), and lower risk for thrombocytopenia (p = 0.005).. According to the association of sex chemotherapy agent-related toxicities, females resulted on average at a significant increased risk of more common adverse events (constipation, dysgeusia, alopecia, heartburn, vomit, asthenia, nausea, pain events, and mucositis). Sex-tailored CRC chemotherapy treatment is necessary to obtain efficacy avoiding toxicity, based on patients' biological and genetic characteristics, a vision that would change CRC setting, a stable disease but still orphan of a real tailored approach.

Topics: Alopecia; Anemia; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug-Related Side Effects and Adverse Reactions; Female; Fluorouracil; Heartburn; Humans; Leucovorin; Male; Mucositis; Nausea; Retrospective Studies; Thrombocytopenia; Vomiting

Gastrointestinal mucositis is a complication of anticancer treatment, with few validated in vitro systems suitable to study the complex mechanisms of mucosal injury. Therefore, we aimed to develop and characterize a chemotherapeutic-induced model of mucositis using 3D intestinal organoids. Organoids derived from mouse ileum were grown for 7 days and incubated with different concentrations of the chemotherapeutic agent methotrexate (MTX). Metabolic activity, citrulline levels and cytokine/chemokine production were measured to determine the optimal dosage and incubation time. The protective effects of folinic acid on the toxicity of MTX were investigated by pre-treating organoids with (0.0005-50 µg/mL) folinic acid. The impact of microbial-derived short-chain fatty acids was evaluated by supplementation with butyrate in the organoid model. MTX caused a dose-dependent reduction in cell metabolic activity and citrulline production that was salvaged by folinic acid treatment. Overall, MTX causes significant organoid damage, which can be reversed upon removal of MTX. The protective effect of folinic acid suggest that the organoids respond in a clinical relevant manner. By using the model for intervention, it was found that prophylactic treatment with butyrate might be a valuable strategy for prophylactic mucositis prevention.

Topics: Animals; Antimetabolites, Antineoplastic; Butyrates; Citrulline; Cytokines; Female; Ileum; Intestinal Mucosa; Leucovorin; Methotrexate; Mice, Inbred C57BL; Mucositis; Organoids; Tissue Culture Techniques

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System; Cerebrospinal Fluid; Chemical and Drug Induced Liver Injury; Cyclophosphamide; Cytarabine; Dexamethasone; Doxorubicin; Female; Humans; Kaplan-Meier Estimate; Kidney Diseases; Leucovorin; Lymphoma, Large B-Cell, Diffuse; Male; Methotrexate; Middle Aged; Mucositis; Neoplasm Invasiveness; Prednisone; Proportional Hazards Models; Prospective Studies; Recurrence; Rituximab; Vincristine

Topics: Bone Marrow; Humans; Leucovorin; Methotrexate; Mucositis; Retrospective Studies

Peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) are rare, heterogeneous non-Hodgkin lymphomas with poor prognoses. Pralatrexate has demonstrated efficacy in T-cell lymphomas; however, mucositis has been reported as the most common dose-modifying adverse event. Leucovorin has been shown to minimize mucositis incidence, without sacrificing pralatrexate efficacy. We retrospectively studied 34 patients (7-PTCL/27-CTCL) treated with pralatrexate alone or pralatrexate and leucovorin. Leucovorin was administered preemptively prior to any mucositis occurrence. Pralatrexate dosing ranged from 10-30 mg/m

Topics: Adult; Aged; Aged, 80 and over; Aminopterin; Female; Humans; Leucovorin; Lymphoma, T-Cell, Cutaneous; Lymphoma, T-Cell, Peripheral; Male; Middle Aged; Mucositis; Neoplasm Staging; Premedication; Retrospective Studies; Skin Diseases; Treatment Outcome

The authors present a case of an 18-year-old man with metastasized osteosarcoma, admitted for methotrexate (MTX) treatment combined with cisplatin and doxorubicin. During the first cycle, severe MTX toxicity was observed with increased MTX serum levels and delayed MTX clearance requiring rescue treatment with intensified leucovorin. In the following cycles, cisplatin and doxorubicin were discontinued, and MTX dose was reduced. The elimination half-life slowly improved over the following cycles suggesting a reversible cause responsible for reduced MTX clearance and toxicity during the first cycle. Cisplatin is well-known for its nephrotoxic effects and can induce reversible tubular injury. Previous treatment with cisplatin may well have been responsible for decreased MTX clearance, and combination treatment should be used with adequate monitoring of MTX levels. Other factors that may have contributed, such as urine alkalization, gene polymorphisms, and other drug-drug interactions are discussed.

Topics: Adolescent; Anti-Bacterial Agents; Antineoplastic Agents; Cisplatin; Doxorubicin; Drug Interactions; Female; Humans; Kidney Diseases; Leucovorin; Methotrexate; Morphine; Mucositis; Osteosarcoma

Acute methotrexate overdose rarely causes systemic toxicity due to saturable absorption and rapid renal elimination. We present a case of methotrexate toxicity following acute overdose.. A 56-year-old female presented soon after an overdose of 1250 mg of methotrexate, zopiclone and tramadol. The methotrexate was initially under-reported (500 mg) and folinic acid was not provided. Despite normal renal function, the patient developed toxicity. She represented 5 days following the overdose with mucositis, bone marrow suppression and prolonged febrile neutropenia. Treatment included folinic acid, broad-spectrum antibiotics, filgrastim, red cell and platelet transfusion. Her bone marrow began to recover 12 days following the overdose. She was discharged home on Day 17.. Severe toxicity following an acute ingestion of a large amount of methotrexate is rarely reported. The development of toxicity was unexpected in this case given methotrexate's pharmacokinetics and the patient's normal renal function. The serum methotrexate concentrations were below the treatment threshold of the folinic acid rescue therapy nomogram suggesting that the nomogram should not be relied on in acute ingestions. Large acute oral methotrexate poisoning can result in systemic toxicity and folinic acid therapy should be provided in ingestions >1000 mg.

Topics: Anti-Bacterial Agents; Antirheumatic Agents; Azabicyclo Compounds; Blood Transfusion; Bone Marrow Diseases; Drug Overdose; Febrile Neutropenia; Female; Filgrastim; Gastrointestinal Diseases; Humans; Leucovorin; Methotrexate; Middle Aged; Mucositis; Piperazines; Suicide, Attempted; Tramadol

Stereotactic body radiation therapy (SBRT) is an emerging treatment option for unresectable pancreatic cancer, and is postulated to be more effective and less toxic than conventionally fractionated intensity modulated radiation therapy (IMRT).. We retrospectively reviewed unresectable stage I-III pancreatic adenocarcinoma treated from 2008 to 2016 at our institution with SBRT (five fractions, 30-33 Gy) or IMRT (25-28 fractions, 45-56 Gy with concurrent chemotherapy). Groups were compared with respect to overall survival (OS), local and distant failure, and toxicity. Log-rank test and Cox proportional hazards regression model, and competing risks methods were used for univariate and multivariate analysis.. SBRT patients (n = 44) were older than IMRT (n = 226) patients; otherwise there was no significant difference in baseline characteristics. There was no significant difference in OS or local or distant failure. There was no significant difference in rates of subsequent resection (IMRT =17%, SBRT =7%, p = .11). IMRT was associated with more acute grade 2+ gastrointestinal toxicity, grade 2+ fatigue, and grade 3+ hematologic toxicity (p = .008, p < .0001, p = .001, respectively).. In this analysis, SBRT achieves similar disease control outcomes as IMRT, with less acute toxicity. This suggests SBRT is an attractive technique for pancreatic radiotherapy because of improved convenience and tolerability with equivalent efficacy. However, the lack of observed advantages in disease control with this moderate-dose SBRT regimen may suggest a role for increasing SBRT dose, if this can be accomplished without significant increase in toxicity.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Chemoradiotherapy; Deoxycytidine; Diarrhea; Fatigue; Female; Fluorouracil; Gemcitabine; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Mucositis; Multivariate Analysis; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Proportional Hazards Models; Radiation Injuries; Radiosurgery; Radiotherapy, Intensity-Modulated; Retrospective Studies; Survival Rate; Thrombocytopenia

The purpose of this study was to evaluate the feasibility and safety of ambulatory high-dose methotrexate (HDMTX) administration with oral hydration, alkalinization, and leucovorin rescue. HDMTX (12 g/m) was given intravenously over 4 hours after urine alkalinization. Families and patients were instructed to continue ambulatory oral hydration and alkalinization to monitor urine pH and to adjust bicarbonate according to our institution's treatment algorithm. Clinical status and MTX levels were controlled every 24 hours, and oral leucovorin dose was adjusted accordingly.. From April 2007 to December 2010, 150 of 447 courses of HDMTX (31.4%) were given on an outpatient basis, and 91.2% were successfully completed. The main causes of failure were poor oral tolerance (n=6) and fever (n=4). Most patients (81%) had MTX levels of <10 μmol/L 24 hours post-HDMTX; only in 1 course the levels were >50 μmol/L (50.96 μmol/L). Neutropenia grade III/IV was observed in 18.3% of the courses, grade III/IV leukopenia in 2.7%, and grade III/IV thrombocytopenia and anemia in 4.7%. Around 39% were associated with grade III/IV hepatic toxicity (asymptomatic hypertransaminasemia), grade III-IV gastrointestinal toxicity (vomiting and diarrhea) (5%), grade III-IV mucositis (4%), and none of the patients developed renal toxicity.. Ambulatory HDMTX administration is feasible and safe in a population with poor resources in a developing country.

Topics: Adolescent; Algorithms; Ambulatory Care; Anemia; Antacids; Argentina; Chemical and Drug Induced Liver Injury; Child; Diarrhea; Female; Humans; Hydrogen-Ion Concentration; Leucovorin; Leukopenia; Male; Methotrexate; Mucositis; Neutropenia; Osteosarcoma; Retrospective Studies; Thrombocytopenia; Vomiting

5-Fluorouracil (5-FU) is commonly administered as a therapeutic agent for the treatment of various aggressive cancers. Severe toxic reactions to 5-FU have been associated with decreased levels of dihydropyrimidine dehydrogenase (DPD) enzyme activity. Manifestations of 5-FU toxicity typically include cytopenia, diarrhea, stomatitis, mucositis, neurotoxicity, and, in extreme cases, death. A variety of genetic variations in DPYD, the gene encoding DPD, are known to result in decreased DPD enzyme activity and to contribute to 5-FU toxic effects. Recently, it was reported that healthy African American individuals carrying the Y186C DPYD variant (rs115232898) had significantly reduced DPD enzyme activity compared with noncarriers of Y186C. Herein, we describe for the first time, to our knowledge, an African American patient with cancer with the Y186C variant who had severe toxic effects after administration of the standard dose of 5-FU chemotherapy. The patient lacked any additional toxic effect-associated variations in the DPYD gene or the thymidylate synthase (TYMS) promoter. This case suggests that Y186C may have contributed to 5-FU toxicity in this patient and supports the use of Y186C as a predictive marker for 5-FU toxic effects in individuals of African ancestry.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Black or African American; Colonic Neoplasms; Diarrhea; Dihydrouracil Dehydrogenase (NADP); Fatal Outcome; Female; Fluorouracil; Genetic Markers; Heat-Shock Proteins; Humans; Leucovorin; Middle Aged; Mucositis; Neoplasm Staging; Organoplatinum Compounds; Peptide Fragments; Polymorphism, Genetic; Precision Medicine; Stomatitis

Topics: Aged; Anti-Infective Agents; Crohn Disease; Diarrhea; Drug Interactions; Female; Humans; Immunosuppressive Agents; Leucovorin; Methotrexate; Mucositis; Pneumonia, Pneumocystis; Prednisone; Stomatitis; Trimethoprim, Sulfamethoxazole Drug Combination

The present study aimed to determine the effect of oral β-glucan on mucositis and leukopenia in 62 consecutive patients with colorectal cancer treated with an adjuvant FOLFOX-4 regimen. The patients were retrospectively evaluated in 2 groups: one group received β-glucan and the other did not (control group). Leucocytes, neutrophils, and platelets were evaluated before and 1 week after chemotherapy and oral mucositis and diarrhea were noted. Leucocyte and neutrophil counts after chemotherapy in the β-glucan group were 7,300/mm3 and 3,800/mm3, respectively, and the reductions, as compared to baseline, were not significant (p=0.673 and 0.784). The median platelet count was 264,000/mm3 after chemotherapy in the β-glucan group and the reduction, as compared to baseline, was borderline significant (p=0.048). In the control group, reduction in leucocyte, neutrophil, and platelet counts was statistically significant. Oral mucositis and diarrhea were less common in the β-glucan group. We conclude that β-glucan can be used to reduce the adverse effects of chemotherapy.

Topics: Adenocarcinoma; Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; beta-Glucans; Chemotherapy, Adjuvant; Cohort Studies; Colorectal Neoplasms; Diarrhea; Female; Fluorouracil; Humans; Leucovorin; Leukocyte Count; Leukopenia; Male; Middle Aged; Mucositis; Organoplatinum Compounds; Platelet Count; Retrospective Studies; Stomatitis; Treatment Outcome

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

Amifostine has been shown to be capable of minimizing radiotherapy-induced oral mucositis, but whether it protects small intestinal mucosae from high-dose methotrexate-induced damage is presently unknown.. We aimed to evaluate the protective effect of amifostine against high-dose methotrexate-induced small intestinal mucositis and its mechanism.. Ninety Kunming mice were randomly divided into five experimental groups: saline control; high-dose methotrexate (HDMTX) group: treated with a single high dose of methotrexate; calcium folinate (CF) group: treated with high-dose methotrexate followed with CF; Amifostine group: treated with amifostine, followed with high-dose methotrexate; and amifostine-CF group: treated with amifostine pre-high-dose methotrexate and followed by CF post-high-dose methotrexate. Mouse weight, villus height and crypt depth, stool consistency, white blood cell count, death and survival were recorded. Bax and Bcl-2 mRNA expression were quantified by semi-quantitative PCR.. Compared to the mice treated with HDMTX, CF, and amifostine, mice treated with Amifostine-CF group were heavier and had greater villus height, crypt depth, and normal white blood cell count and lower diarrhea rate and mortality than the HDMTX, CF and amifostine groups. There was a significant decrease in enterocyte apoptosis in amifostine-CF mice compared with the HDMTX and CF groups.. The effect of amifostine plus CF was greater than amifostine or CF alone in preventing high-dose methotrexate-induced intestinal mucositis and improving intestinal recovery in mice.

Topics: Amifostine; Animals; Body Weight; Female; Immunosuppressive Agents; Intestine, Small; Leucovorin; Male; Methotrexate; Mice; Mucositis; Radiation-Protective Agents; Random Allocation; Specific Pathogen-Free Organisms

Cyclosporine (CsA) and MTX are commonly used for GVHD prophylaxis in pediatric allo-SCT. Mucositis and hepatic toxicity frequently restrict the delivery of the fourth dose of MTX. Folinic acid (FA) may ameliorate MTX toxicity. We conducted a retrospective chart review of all pediatric patients who received CsA and MTX for GVHD prophylaxis from January 2000 to July 2010. Patients treated before July 2007 (N=29) did not receive FA and those treated from July 2007 onward did receive FA (N=18). Patients who received FA were significantly more likely to receive day +11 MTX (odds ratio (OR) 10.42, 95% confidence interval (CI): 1.21-262.27) but there was no significant difference in Grade III-IV GVHD between the two groups (OR 1.15, 95% CI: 0.08-18.14). FA did not impact relapse-free survival (RFS) (P=0.82). Increased likelihood of receiving day +11 MTX suggests that FA ameliorates MTX toxicity, such as severe mucositis. FA administration for MTX GVHD prophylaxis should be studied in a prospective, randomized fashion.

Topics: Adolescent; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Cyclosporine; Drug Monitoring; Drug Therapy, Combination; Female; Folic Acid Antagonists; Graft vs Host Disease; Humans; Immunosuppressive Agents; Infant; Leucovorin; Male; Methotrexate; Mucositis; Retrospective Studies; Severity of Illness Index; Stem Cell Transplantation; Survival Analysis; Transplantation, Homologous; Vitamin B Complex

Intensification of systemic chemotherapy with inclusion of high dose methotrexate (HDMTX) has helped omit cranial irradiation from standard risk acute lymphoblastic leukemia (ALL) protocols, thereby eliminating the adverse side effects associated with its use. Administration of HDMTX needs meticulous monitoring. Limitations in the availability of trained staff and adequate infrastructure often pose problems in the developing world. The aim of this study was (1) to treat childhood ALL with a protocol that would have reduced use of cranial irradiation and containing infusions of high-dose methotrexate HDMTX (5 g/m(2)) without compromising on survival, and (2) evaluate the experience with HDMTX in a tertiary care cancer centre in a developing country.. A retrospective chart review was done of 41 consecutive children with a confirmed diagnosis of ALL who had received at least one cycle of HDMTX as part of their consolidation treatment with regard to the patient demographic profile, details of HDMTX infusion and leucovorin rescue, toxicity, additional hospitalization, delay in next cycle of chemotherapy and survival.. The clinically most significant toxicities observed were mucositis 39% (58/149) and fever 28% (42/149) together leading to additional hospital stay in 7% (11/149) cycles and neutropenia grade 3 or more in 24.8% (34/137) contributing to delay in next cycle of chemotherapy in 15% (23/149) cycles.. With this strategy, it was possible to omit or reduce the dose of cranial irradiation while maintaining survival outcomes. The administration of HDMTX therapy was found to be feasible and safe with the precautions described.

Topics: Antimetabolites, Antineoplastic; Cancer Care Facilities; Child; Child, Preschool; Female; Humans; Infant; Injections, Spinal; Leucovorin; Male; Methotrexate; Mucositis; Neutropenia; Patient Readmission; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies

To investigate the relationship between serum concentration of fluorouracil and therapeutic efficacy as well as adverse reactions in patients with unresectable locally advanced or measurable metastatic colorectal cancer, and to analyze its role in further improving therapeutic efficacy and reducing adverse reactions of fluorouracil-based chemotherapy.. Eighty-six patients were randomly assigned into three groups according to the average plasma concentration of fluorouracil after three cycles of chemotherapy with the initial regimen of two weeks FOLFOX-4 (oxaliplatin + leucovorin + fluorouracil) or FOLFIRI (irinotecan + leucovorin + fluorouracil): group 1 (plasma concentration of fluorouracil < 25 ng/ml), group 2 (25 - 35 ng/ml) and group 3 (> 35 ng/ml). The blood samples were taken at 12 h after continuous infusion of fluorouracil in each cycle and the plasma concentration of fluorouracil was detected by high performance liquid chromatography (HPLC) (about 5 am ± 1 h). The relationship between the drug plasma concentration, therapeutic efficacy and adverse reactions in different fluorouracil plasma concentration arms was analyzed retrospectively.. The average plasma concentrations of fluorouracil of the three groups were (23.48 ± 1.95) ng/ml, (31.47 ± 2.33) ng/ml and (39.89 ± 3.87) ng/ml, respectively (P < 0.01). As for therapeutic efficacy, the median OS of the groups 2 and 3 were 18.0 and 17.5 months, significantly higher than that in the group 1 (13.0 months, P < 0.01). The PFS were 4.5, 7.5 and 8.0 months, respectively (P < 0.01). In terms of adverse reactions, the incidences of bone marrow suppression, mucositis and diarrhea in the group 3 were significantly higher than that in the first two groups (P = 0.02, P = 0.04 and P = 0.02).. The patients with local advanced and metastatic colorectal cancer, receiving fluorouracil-based chemotherapy, and with an average plasma concentration of fluorouracil between 25 - 35 mg/L have a better prognosis, and lower incidence of adverse reactions such as bone marrow suppression, mucositis and diarrhea.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Colonic Neoplasms; Diarrhea; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mucositis; Neoplasm Staging; Organoplatinum Compounds; Random Allocation; Rectal Neoplasms; Remission Induction; Survival Rate

In addition to the well-known signs of methotrexate toxicity, rare cutaneous side effects have been described. These cutaneous signs may provide a diagnostic clue into the diagnosis of toxicity as well as facilitate early and aggressive therapy. We describe the case of a 37-year-old male, with a diagnosis of psoriasis, who developed characteristic signs and symptoms of acute methotrexate toxicity after receiving an unknown amount of intravenous methotrexate. The patient experienced a distinct change in the morphology of his existing psoriatic plaques, which became ulcerated and necrotic in the week following the methotrexate injection. Shortly after the development of cutaneous erosions, the patient developed pancytopenia, which ultimately led to his death. Ulceration and necrosis of cutaneous psoriasis plaques may serve as a herald for the impending development of life-threatening pancytopenia in patients with acute methotrexate toxicity.

Topics: Acute Kidney Injury; Adult; Azithromycin; Biopsy; Fatal Outcome; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Immunosuppressive Agents; Leucovorin; Male; Methotrexate; Mucositis; Necrosis; Pancytopenia; Plasma; Psoriasis; Recombinant Proteins; Self Medication; Skin Ulcer; Trimethoprim, Sulfamethoxazole Drug Combination

We retrospectively analyzed comparative toxicities and efficacies of chemotherapy regimens in advanced gastric cancer (AGC) patients who achieved complete response (CR) after chemotherapy.. We reviewed the medical records of 1,203 patients, who were pathologically diagnosed as AGC in a single center between January 2001 and October 2007. On the basis of the Response Evaluation Criteria in Solid Tumors, CR was evaluated with abdominal computed tomography. Toxicities were evaluated using the National Cancer Institute's common toxicity criteria before each chemotherapy cycle.. Among the 1,203 AGC patients enrolled in this study, 568 received chemotherapy and 635 received best supportive care. The major chemotherapy regimens were 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX), docetaxel, cisplatin and 5-fluorouracil (DCF) and 5-fluorouracil, leucovorin and irinotecan (FOLFIRI). Among the 568 patients, 51 (9.0%) achieved CR (49 [8.6%] with FOLFOX [n=12], DCF [n=26], or FOLFIRI [n=11] and 2 [0.3%] with etoposide, leucovorin and 5-fluorouracil). For patients administered FOLFOX, DCF, and FOLFIRI, the median time to disease progression was 4 months (range, 1.8-59.5), 15 months (range, 2.9-31.2) and 10 months (range, 2.0-39.5), and the median survival times were 48 months (range, 5.9-74.0), 37 months (range, 14.0-86.0), and 30 months (range, 6.0-50.0), respectively. Grades 3-4 mucositis occurred mostly in patients administered DCF (n=8, 30.8%). Grades 3-4 leucopenia were observed in 1 (8.3%), 11 (42.3%), and 4 (36.4%) patients administered FOLFOX, DCF and FOLFIRI, respectively. No statistically significant differences were observed in the 3 regimens.. All 3 regimens (FOLFOX, DCF and FOLFIRI) were active and tolerable. Their efficacies and toxicities were not significantly different.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cisplatin; Docetaxel; Drug Therapy, Combination; Female; Fluorouracil; Humans; Leucovorin; Leukopenia; Male; Middle Aged; Mucositis; Nausea; Neoplasm Staging; Organoplatinum Compounds; Retrospective Studies; Stomach Neoplasms; Survival Rate; Taxoids; Tomography, X-Ray Computed; Vomiting

Chemotherapy-associated mucositis often prevents completion of an entire chemotherapy cycle. The underlying pathophysiology of chemotherapy-associated mucositis has not been well established. The individual immunologic predisposition of patients seems to play an important role.. One hundred fifty-six patients with locally advanced or metastatic esophageal adenocarcinoma received neoadjuvant chemotherapy with cisplatin, 5-fluorouracil, and leucovorin followed by resection. Before the neoadjuvant therapy, monocytes were isolated from blood samples and were stimulated with lipopolysaccharide and interferon. An enzyme-linked immunosorbent assay was used to measure interleukin (IL)-10 and -12 levels and correlated with patients' clinical course.. Twenty-two patients (14,1%) developed grade III to IV mucositis (according to the NCI-Common toxicity criteria scales) within the neoadjuvant chemotherapy. Pretherapeutic low IL-10 (<24.1 pg/ml) and high IL-12 (>5500 pg/ml) levels were significantly associated with mucositis causing a therapy interruption or even cessation. Patients with high IL-10 (>43.6 pg/ml) and low IL-12 (<4408.5 pg/ml) levels had an uneventful neoadjuvant chemotherapy.. Pretherapeutic individual monocyte function is correlated with the development and the grade of chemotherapy induced mucositis. This knowledge might help us in predicting the grade of mucositis and in understanding the genesis regarding the association to pro- and anti-inflammatory effects of monocyte cytokines.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cisplatin; Enzyme-Linked Immunosorbent Assay; Esophageal Neoplasms; Female; Fluorouracil; Humans; Interleukin-10; Interleukin-12; Leucovorin; Male; Middle Aged; Mucositis; Neoadjuvant Therapy; Neoplasm Staging; Prognosis; Prospective Studies; Survival Rate

The use of MTX for GVHD prophylaxis may be associated with significant toxicity, including hepatotoxicity, graft failure and mucositis. Folinic acid may be involved in the amelioration of MTX toxicity. There is, however, no consensus regarding its use. A survey was conducted in Australian and New Zealand transplant centres (n=22) regarding the use of folinic acid following MTX in the transplant setting. Of 18 participating transplant centres, 12 (66%) used folinic acid following MTX--8 (44%) routinely and 4 (22%) only in the presence of significant mucositis. Those centres that did not use routine dosing of folinic acid post transplant chose not to do so on the grounds that they believed that it was not efficacious or may increase the risk of GVHD. Grading of mucositis was inconsistently done. There is wide variation in the use of folinic acid following HSCT. Folinic acid is infrequently used in the adult transplant setting or is used after mucositis is already apparent, practices that appear to run counter to available clinical evidence and to pharmacological data. Further research is required to conclusively determine whether folinic acid has any benefit in the post-BMT setting.

Topics: Australia; Data Collection; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leucovorin; Male; Methotrexate; Mucositis; New Zealand; Transplantation, Homologous; Vitamin B Complex

Topics: Antimetabolites, Antineoplastic; Diarrhea; Dihydrouracil Dehydrogenase (NADP); Fluorouracil; Genetic Predisposition to Disease; Genetic Testing; Humans; Leucovorin; Leukopenia; Logistic Models; Methylenetetrahydrofolate Reductase (NADPH2); Mucositis; Odds Ratio; Patient Selection; Polymorphism, Genetic; Predictive Value of Tests; Risk Assessment; Risk Factors; Severity of Illness Index; Thymidylate Synthase; Vitamin B Complex

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Fibroblast Growth Factor 7; Fluorouracil; Humans; Leucovorin; Mouth Mucosa; Mucositis; Treatment Outcome

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

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Budesonide; Camptothecin; Dehydration; Diarrhea; Fluorouracil; Gastric Mucosa; Gastrointestinal Tract; Humans; Infusions, Intravenous; Intestinal Absorption; Intestinal Mucosa; Irinotecan; Leucovorin; Loperamide; Mice; Mucositis; Organoplatinum Compounds; Rats

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

Toxicities and their severities vary among advanced gastric cancer patients when they receive the same regimen containing continuous infusion of 5-fluorouracil (5-FU). Dihydropyrimidine dehydrogenase (DPD) is the key rate-limiting enzymes which is closely related to toxicities of 5-FU in chemotherapy. This study was to explore the relationship between activity of DPD and concentration of 5-FU, and their correlation to adverse events among advanced gastric cancer patients treated with the same regimen containing 5-FU continuous infusion.. Patients received the same regimen (intravenous injection of paclitaxel 75 mg/m(2), leucovorin 200 mg/m(2) and 5-FU 375 mg/m(2), continuous infusion of 5-FU 2.5 g/m2 for 46 hours every two weeks). The peripheral blood was collected from 36 patients with advanced gastric cancer before and after chemotherapy to detect the activity of DPD and concentration of 5-FU by high-performance liquid chromatography (HPLC). Adverse events were assessed every cycle.. Serum activity of DPD revealed a unimodel distribution, which globally fits to a guassian distribution (range 1.56-6.01). Mean and median DPD activity values were 2.38 and 2.13, respectively. No total DPD deficiency was found in the patients. The concentration of 5-FU varied from 179.2 microg/L to 1 589.2 microg/L, which demonstrated normality distribution after a logarithmic transformation was applied. The DPD activity was inversely correlated with 5-FU concentration (r=-0.376, P=0.024). The patients with low activity of DPD were more frequently suffering from severe diarrhea, mucositis, and myelosuppression. And high level of 5-FU concentration led to the increase of adverse events.. Pre-chemotherapy DPD activity and 5-FU concentration during chemotherapy vary among gastric cancer patients, which may help to prevent severe toxicities during the treatment.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Diarrhea; Dihydrouracil Dehydrogenase (NADP); Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mucositis; Neoplasm Staging; Paclitaxel; Stomach Neoplasms; Young Adult

Toxicities and response are different when patients with advanced colorectal cancer were treated with standard FOLFOX6 regimen. Serum level of dihydropyrimidine dehydrogenase (DPD) relates to efficacy and toxicities of chemotherapy containing 5-fluorouracil (5-FU). This study was to explore relationship of DPD to serum concentration of 5-FU in colorectal cancer patients treated with FOLFOX6 regimen, and their correlation to treatment response and adverse events.. Serum level of DPD in 72 patients with colorectal cancer was detected by high-performance liquid chromatography (HPLC) before chemotherapy. Serum concentration of 5-FU at steady state was detected by HPLC after patients received FOLFOX6 regimen. Treatment response and adverse events in the patients were assessed.. Serum levels of DPD were normally distributed in 72 patients (ranged 1.55-5.94), while serum concentrations of 5-FU at steady state were not (ranged 141.1-1 741.9 microg/L). Serum level of DPD was negatively correlated with serum concentration of 5-FU (r=-0.460, P < 0.01). Occurrence of adverse events was lower when 5-FU concentration was less than 600 microg/L than when 5-FU concentration was more than 600 microg/L (P < 0.05). The mean serum concentration of 5-FU was significantly higher in patients with complete response and partial response than in patients with steady disease, and progressive disease (513.9 microg/L vs. 409.8 microg/L, and 259.3 microg/L, P < 0.05). Serum level of DPD was lower in patients suffered oral mucositis and diarrhea of grade II-IV than in patients suffered oral mucositis and diarrhea of grade 0-I (P=0.016, P=0.047). Serum level of DPD had no relation with treatment response of the patients (r=0.312, P=0.078).. DPD level and serum 5-FU concentration vary a lot among patients with colorectal cancer. DPD level negatively correlates with serum 5-FU concentration. Serum concentration of 5-FU correlates with treatment effect and toxicities.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Diarrhea; Dihydrouracil Dehydrogenase (NADP); Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mucositis; Nausea; Organoplatinum Compounds; Rectal Neoplasms