Bowel perforation due to methotrexate therapeutic error: an insidious adverse reaction.

OBJECTIVE: Methotrexate (MTX) is widely used in the treatment of rheumatic and non-rheumatic disorders. Severe adverse effects are often associated with therapeutic errors, such as daily intake rather than weekly intake. Among them, the risk of bowel perforation is extremely rare (0.1%). We describe a case of bowel perforation, occurred following daily intake of MTX. CASE REPORT: A 68-year-old man was prescribed to take MTX 7,5 mg orally once a week, while waiting for switch to abatacept for a recent reactivation of rheumatoid arthritis. After 10 days he started having pharyngodynia, hematochezia and general malaise. At medical examination he presented oral and nasal mucositis; moreover, blood exams showed thrombocytopenia. The anamnesis revealed that he had been taken the prescribed dosage of MTX daily, instead of weekly. Therapy with Lederfolin 1000 mg (mg/m²/die) and urine alkalinization started. After 7 days of hospitalization, there was an abrupt worsening of clinical conditions and an emergency CT scan revealed millimetric gas bubbles indicating bowel perforation. The patient underwent an emergency exploratory laparotomy that resulted in peritoneal toilette and sigma resections. Anatomopathological findings were suggestive of MTX poisoning. CONCLUSIONS: The patient was discharged on the 17th day in good clinical condition.

A pharmacokinetic and pharmacodynamic investigation of Modufolin® compared to Isovorin® after single dose intravenous administration to patients with colon cancer: a randomized study.

PURPOSE: Leucovorin is commonly used as folate supplement in 5-fluorouracil-based chemotherapy, but needs to be converted to active 5,10-methylenetetrahydrofolate (methyleneTHF) intracellularly. This provides for interindividual differences. MethyleneTHF has recently been developed into the stable, distributable drug, Modufolin®. The aim was to compare the concentration of folate metabolites in tumor, mucosa, and plasma of patients with colon cancer after administration of Modufolin® or Isovorin® (levo-leucovorin). METHODS: Thirty-two patients scheduled for colon resection were randomized to receive Modufolin® or Isovorin® at dosage of 60 or 200 mg/m². The study drug was given as one i.v. bolus injection after anesthesia. Plasma was collected for pharmacokinetic (PK) analysis before, during, and after surgery. Tissue biopsies were collected at surgery. Folate metabolites were analyzed by LC-MS/MS. RESULTS: MethyleneTHF and THF concentrations were significantly higher in mucosa (p < 0.01, both dosages) and tumors (p < 0.01, 200 mg/m²) after Modufolin® as compared to Isovorin® administration. The results correlated with PK observations. The Modufolin® to Isovorin® C(max) ratio for methyleneTHF was 113 at 200 mg/m² and 52 at 60 mg/m²; the AUC(last) ratios were 17 and 9, respectively. The THF plasma concentrations were also higher after Modufolin® administration (C(max) ratio 23, AUC(last) ratio 13 at 200 mg/m²; C(max) ratio 15, AUC(last) ratio 11 at 60 mg/m²). CONCLUSION: Modufolin® administration resulted in significantly higher methyleneTHF levels than Isovorin® and may potentially increase the efficacy of 5-fluorouracil-based chemotherapy. The results encourage further evaluation of Modufolin® as a substitute to Isovorin® including the potential clinical benefits.

Local recurrence of gastric cancer after total gastrectomy: an unusual presentation.

A 71 years old Italian man had type 3 gastric cancer of the greater curvature. Total gastrectomy with splenectomy and D2 lymph node dissection were performed. After discharge chemotherapy ELF regimen was administered for 6 months. After 16 months from the operation a local recurrence was discovered by CT scan. Surgical en-bloc resection was performed removing pancreatic tail, splenic colic flexure and a portion of left diaphragm. Histological examination confirmed local recurrence of gastric adenocarcinoma infiltrating pancreas, colon and diaphragm with lymph node metastasis.

Levoleucovorin as replacement for leucovorin in cancer treatment.

OBJECTIVE: To comprehensively review the literature regarding the efficacy, safety, and costs associated with the use of levoleucovorin in cancer treatment and to assess whether levoleucovorin would be a reasonable alternative to the use of racemic leucovorin. DATA SOURCES: A MEDLINE search was conducted for English-language human studies published between January 1980 and April 2012 using the terms l-LV, levoleucovorin, d,l-LV, leucovorin, folinic acid, folinate, 5-formyltetrahydrofolate, folic acid, folates, methotrexate, 5-fluorouracil, and clinical trials. STUDY SELECTION AND DATA EXTRACTION: Articles pertinent to clinical trials (Phase 1, 2, 3) related to evaluating the efficacy, interchangeability, and safety of levoleucovorin were collected and their contents reviewed. DATA SYNTHESIS: From these pharmacokinetics and clinical studies, information on the use of levoleucovorin as a modulator of fluorouracil as well as when combined with other antitumor agents were scrutinized and extracted for comparison with leucovorin whenever possible. Two randomized Phase 3 clinical studies comparing the efficacy and adverse effect profiles of leucovorin and levoleucovorin demonstrated that levoleucovorin is as effective as leucovorin in terms of response, toxicity, and survival. Six randomized Phase 3 clinical studies demonstrated the safety and efficacy of levoleucovorin as a modulator of fluorouracil in combination with/without other antitumor agents in colorectal cancer patients. Levoleucovorin has been studied in other cancers. These clinical Phase 1/2/3 studies demonstrated efficacy and safety of levoleucovorin in combination chemotherapeutic regimens comprising fluorouracil and other antitumor agents. CONCLUSIONS: The results of the clinical studies suggest that levoleucovorin is efficacious and can be used safely in combination with fluorouracil and other antitumor agents. Levoleucovorin can be used interchangeably with leucovorin for modulating fluorouracil. The current shortage of the supply of leucovorin centered in North America renders levoleucovorin a reasonable alternative in terms of efficacy and toxicity profile, but from the perspective of cost, leucovorin remains the drug of choice.