Protocol of the EFFORT study: a prospective study of FOLFIRI plus aflibercept as second-line treatment after progression on FOLFOXIRI plus bevacizumab or during maintenance treatment in patients with unresectable/metastatic colorectal cancer.

BACKGROUND: FOLFOXIRI plus bevacizumab is used as a first-line therapy for patients with unresectable or metastatic colorectal cancer. However, there are no clear recommendations for second-line therapy after FOLFOXIRI plus bevacizumab combination. Here, we describe our planning for the EFFORT study to investigate whether FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for mCRC. METHODS: EFFORT is an open-label, multicenter, single arm phase II study to evaluate whether a FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for mCRC. Patients with unresectable or metastatic colorectal cancer who received FOLFOXIRI plus bevacizumab as a first-line therapy will receive aflibercept and FOLFIRI (aflibercept 4 mg/kg, irinotecan 150 mg/m2 IV over 90 min, with levofolinate 200 mg/m2 IV over 2 h, followed by fluorouracil 400 mg/m2 bolus and fluorouracil 2400 mg/m2 continuous infusion over 46 h) every 2 weeks on day 1 of each cycle. The primary endpoint is progression-free survival (PFS). To achieve 80% power to show a significant response benefit with a one-sided alpha level of 0.10, assuming a threshold progression-free survival of 3 months and an expected value of at least 5.4 months, we estimated that 32 patients are necessary. Secondary endpoints include overall survival, overall response rate, safety, and exploratory biomarker analysis for differentiating anti-VEGF drug in 2nd-line chemotherapy for unresectable or metastatic colorectal cancer. DISCUSSION: This is the first study to investigate whether FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for unresectable or metastatic colorectal cancer. Switching to a different type of anti-VEGF drug in second-line therapy after FOLFOXIRI plus bevacizumab appears to be an attractive treatment strategy when considering survival benefit. It is expected that this phase II study will prove the efficacy of this strategy and that a biomarker for drug selection will be discovered. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs071190003 . Registered April 18, 2019.

Successful Treatment with 5-fluorouracil and Levofolinate Calcium in Advanced Gastric Cancer Patient with Disseminated Intravascular Coagulation.

A 32-year-old woman was found to have a gastric adenocarcinoma with multiple bone metastases. Chemotherapy in the first, second and third-line was not effective. Blood examinations showed disseminated intravascular coagulation(DIC)at the end of the second-line chemotherapy. The fourth-line chemotherapy, infusional 5-fluorouracil and levofolinate calcium was performed. This resulted in a good response for DIC. This palliative therapy was effective and safety.

[A case of colorectal neuroendocrine carcinoma effectively treated with bevacizumab+levofolinate+5-FU chemotherapy].

A 76-year-old woman was admitted to our hospital with diarrhea and weight loss in February 2007. A CT scan revealed a tumor in the abdominal cavity, and although a thorough investigation was conducted, no diagnosis was made. Therefore, she underwent diagnostic surgery in April 2007. Intraoperatively, the tumor was determined to have originated in the transverse colon, with invasion to other organs. The patient underwent a transverse colectomy, partial ileal resection, and partial resection of the bladder and peritoneum were performed. The pathological diagnosis was colorectal neuroendocrine carcinoma. FOLFOX4 chemotherapy was initiated in May 2007. However, a CT scan in June 2007 revealed a recurrent tumor in the right pelvis. Although right hemicolectomy and right oophorectomy were performed in August, a CT scan in September 2007 revealed a recurrent tumor in the right pelvis. Following treatment with bevacizumab+levofolinate+5-FU, the tumor disappeared. The patient continued to receive this chemotherapy regimen until August 2010, and CT scans showed a complete response. Even though colorectal neuroendocrine carcinoma is known to have a poor prognosis, the present case was effectively treated with bevacizumab+levofolinate+5-FU chemotherapy. Herein we provide discussion and suggestions about treatment for colorectal neuroendocrine carcinoma.

Intermittent versus continuous chemotherapy in advanced colorectal cancer: a randomised 'GISCAD' trial.

BACKGROUND: In advanced colorectal cancer, chemotherapy is usually administered without pauses and until progression but patients can experience cumulative toxicity and cannot tolerate a heavy therapeutic charge. AIM: The aim of the present trial was to evaluate whether an intermittent chemotherapy with levo-leucovorin + 5-fluorouracil (5-FU) + irinotecan (CPT-11) was at least as effective as the same regimen given continuously, both administered until progression, in patients affected with advanced colorectal cancer and not previously exposed to chemotherapy for metastatic disease. PATIENTS, MATERIALS AND METHODS: A total of 337 patients from 27 institutions were randomised between levo-leucovorin, 100/mg/m(2) i.v. + 5-FU; 400 mg/m(2) i.v. bolus + 5-FU; 600 mg/m(2) 22-h continuous infusion, days 1 and 2 + CPT-11; 180 mg/m(2) day 1, administered every 2 weeks 2 months on and 2 months off (arm A) and the same regimen administered continuously (arm B), until progression in both arms. The main end point was overall survival (OS), the secondary progression-free survival (PFS) and toxicity. RESULTS: At a median follow-up of 41 months, OS was 18 months in arm A and 17 months in arm B [hazard ratio (HR), 0.88]. Also PFS was comparable in the two groups (6 months in both, with HR, 1.03), and even grades 3-4 toxicity (mainly myelosuppression, fever and diarrhoea) was similar. Second-line oxaliplatin-based treatment was administered in a similar percentage (66%) in the two arms. The median chemotherapy-free period (drug holiday) in arm A was 3.5 months. CONCLUSION: Reducing the charge of therapy in this population did not diminish the efficacy of treatment. Further studies with this strategy, including biologicals, are warranted.

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.

Evaluation of efficacy and safety of generic levofolinate in patients who received colorectal cancer chemotherapy.

The efficacy and safety of generic and brand name levofolinate injectable drugs were evaluated in 42 chemotherapy-naïve patients with colorectal cancer who received the combination chemotherapy of levofolinate, 5-fluorouracil, and oxaliplatin with or without bevacizumab. The tumor response rate was similar between generic drug group and brand drug group, in which the efficacy rate (complete response plus partial response) was 50% for generic drug group and 42% for brand name drug (odds ratio: 1.400, 95% confidence intervals: 0.409-4.788, P = 0.756). The rates of the decrease in plasma tumor markers such as carcinoembryonic antigen and carbohydrate antigen 19-9 were not different between the two groups. The incidence of adverse drug reactions was not significantly different between the two groups, although the incidence rates of adverse events associated predominantly with 5-fluorouracil such as hand-and-foot syndrome, diarrhea, and oral mucositis were rather higher, though not significantly, in generic drug group than in brand drug group (16 vs. 4% for hand-and-foot syndrome; 33 vs. 25% for diarrhea; 33 vs. 25% for oral mucositis). These findings suggest that both the effectiveness and safety profiles of the generic name levofolinate are comparable to those of the brand name drug, when used in combination with 5-fluorouracil and oxaliplatin in patients with colorectal cancer.