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Drug-Drug Interactions of Irinotecan, 5-Fluorouracil, Folinic Acid and Oxaliplatin and Its Activity in Colorectal Carcinoma Treatment.

ABSTRACT: The combination of folinic acid, 5-fluorouracil, oxaliplatin and/or irinotecan (FOLFOXIRI) is the standard of care for metastatic colorectal cancer (CRC). This strategy inhibits tumor growth but provokes drug resistance and serious side effects. We aimed to improve FOLFOXIRI by optimization of the dosing and the sequence of drug administration. We employed an orthogonal array composite design and linear regression analysis to obtain cell line-specific drug combinations for four CRC cell lines (DLD1, SW620, HCT116, LS174T). Our results confirmed the synergy between folinic acid and 5-fluorouracil and additivity, or even antagonism, between the other drugs of the combination. The drug combination administered at clinical doses resulted in significantly higher antagonistic interactions compared to the low-dose optimized drug combination (ODC). We found that the concomitant administration of the optimized drug combination (ODC) was comparatively active to sequential administration. However, the administration of oxaliplatin or the active metabolite of irinotecan seemed to sensitize the cells to the combination of folinic acid and 5-fluorouracil. ODCs were similarly active in non-cancerous cells as compared to the clinically used doses, indicating a lack of reduction of side effects. Interestingly, ODCs were inactive in CRC cells chronically pretreated with FOLFOXIRI, suggesting the occurrence of resistance. We were unable to improve FOLFOXIRI in terms of efficacy or specificity. Improvement of CRC treatment should come from the optimization of targeted drugs and immunotherapy strategies.

SUBMITTER: Zoetemelk M

PROVIDER: S-EPMC7321123 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Drug-Drug Interactions of Irinotecan, 5-Fluorouracil, Folinic Acid and Oxaliplatin and Its Activity in Colorectal Carcinoma Treatment.

Zoetemelk Marloes M Ramzy George M GM Rausch Magdalena M Nowak-Sliwinska Patrycja P

Molecules (Basel, Switzerland) 20200604 11

The combination of folinic acid, 5-fluorouracil, oxaliplatin and/or irinotecan (FOLFOXIRI) is the standard of care for metastatic colorectal cancer (CRC). This strategy inhibits tumor growth but provokes drug resistance and serious side effects. We aimed to improve FOLFOXIRI by optimization of the dosing and the sequence of drug administration. We employed an orthogonal array composite design and linear regression analysis to obtain cell line-specific drug combinations for four CRC cell lines (D ...[more]

PMID: 32512790

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Project description:The care of metastatic colorectal cancers is based on combination chemotherapies including 5-fluorouracil, oxaliplatin, irinotecan, and monoclonal antibodies targeting the epidermal growth factor receptor or vascular endothelial growth factor. The regimen is determined based on the patient's molecular biology and general condition. Irinotecan bifractionation showed efficacy in chemorefractory patients in a previous study, FOLFIRI-3, but a desynchronized triplet has never been tested. The aim of bFOLFIRINOX-3 is to determine the safety, tolerance, and efficacy of a new regimen (FOLFIRINOX-3 bevacizumab) in chemorefractory patients. The aim of this study was to evaluate the safety and efficacy of FOLFIRINOX-3 bevacizumab in chemorefractory metastatic colorectal cancer (mCRC). A standard phase I, "3 + 3" design study was performed. The standard protocol comprised simplified FOLFOX 4 (folinic acid 400 mg/m2), 5-fluorouracil (a 400 mg/m2 bolus followed by 2400 mg/m2 for 46 h), oxaliplatin (85 mg/m2) and irinotecan (administered before and after 5-fluorouracil infusion), plus bevacizumab (5 mg/kg). In a "3 + 3" design, three different doses of irinotecan were tested: 60, 70 and 90 mg/m2. The primary endpoint was the maximum tolerable dose (MTD) of irinotecan. The secondary endpoints included the objective response (at 8 and 16 weeks) according to the RECIST 1.1 criteria and progression free survival. Thirteen patients were enrolled, and twelve patients were finally evaluated for dose-limiting toxicity (DLT). The dose level defined was 70 mg/m2 irinotecan. A total of three DLTs were observed (grade 3 diarrhea): two DLTs at the 90 mg/m2 dose level and one at the 70 mg/m2 dose level. The most frequently described adverse events were asthenia (93%), diarrhea (77%), nausea (62%) and peripheral sensory neuropathy (46%). The most frequent biological event was thrombopenia (54%). Regarding efficacy, among the 11 evaluable patients, no progression was observed at 8 weeks, and the partial response rate was 18.2%. At 16 weeks, a partial response rate of 27.3% was observed, and five patients had a stable disease. The new regimen of bFOLFIRINOX-3 with irinotecan at 70 mg/m2 was well tolerated. In chemorefractory patients, this protocol shows a high response rate.

Project description:BackgroundPolymorphisms of genes encoding the Fcy receptors (Fc fragment of IgG receptor 2A (FCGR2A) and 3A (FCGR3A)), which influence their affinity for the Fc fragment, have been linked to the pharmacodynamics of monoclonal antibodies. Most studies have been limited by small samples sizes and have reported inconsistent associations between the FCGR2A and the FCGR3A polymorphisms and clinical outcome in metastatic colorectal cancer (mCRC) patients treated with cetuximab. We investigated the association of these polymorphisms and clinical outcome in a large cohort of mCRC patients treated with first-line 5-fluorouracil/folinic acid and oxaliplatin (Nordic FLOX) +/- cetuximab in the NORDIC-VII study (NCT00145314).Methods504 and 497 mCRC patients were evaluable for the FCGR2A and FCGR3A genotyping, respectively. Genotyping was performed on TaqMan ABI HT 7900 (Applied Biosystems, Foster City, CA, USA) with pre-designed SNP genotyping assays for FCGR2A (rs1801274) and FCGR3A (rs396991).ResultsThe response rate for patients with the FCGR2A R/R genotype was significantly increased when cetuximab was added to Nordic FLOX (31% versus 53%, interaction P = 0.03), but was not significantly different compared to the response rate of patients with the FCGR2A H/H or H/R genotypes given the same treatment. A larger increase in response rate with the addition of cetuximab to Nordic FLOX in patients with KRAS mutated tumors and the FCGR2A R/R genotype was observed (19% versus 50%, interaction P = 0.04). None of the FCGR3A polymorphisms were associated with altered response when cetuximab was added to Nordic FLOX (interaction P = 0.63). Neither of the FCGR polymorphisms showed any significant associations with progression-free survival or overall survival.ConclusionPatients with KRAS mutated tumors and the FCGR2A R/R polymorphism responded poorly when treated with chemotherapy only, and experienced the most benefit of the addition of cetuximab in terms of response rate.

Project description:The FOLFOXIRI regimen (irinotecan, oxaliplatin, fluorouracil [5-FU] and folinic acid [FA]) increased the response rate and overall survival compared to FOLFIRI in patients with metastatic colorectal cancer (mCRC). Adding cetuximab to FOLFOX or FOLFIRI increased efficacy in patients with k-ras wild type mCRC. We explored the dose limiting toxicity and feasibility of the combination cetuximab, irinotecan, oxaliplatin, 5-FU and FA in mCRC patients.In a dose-escalation study patients with previously untreated mCRC and a WHO performance status 0-1 received cetuximab (500 mg/m2, 2 h), followed by irinotecan (95, 125, and 165 mg/m2 in the dose levels [DL] 1, 2, and 3 respectively), followed by oxaliplatin (85 mg/m2, 2 h) which was given parallel to FA (400 mg/m2, 2 h) and followed by 5-FU (3200 mg/m2, 46 h) in an outpatient setting every two weeks. The primary endpoints were the maximum tolerable dose and the safety. The trial was approved by the local ethics committee.From 2007 to 2008, twenty patients were treated in this trial. In the first dose level (irinotecan 95 mg/m2) one patient developed neutropenia grade 4. One patient experienced diarrhoea grade 3 as DLT in dose level 2 (irinotecan 125 mg/m2). In dose level 3 (irinotecan 165 mg/m2), three patients experienced a DLT (diarrhoea grade 3 and two patients with neutropenia grade 4). Thus, the recommended dose for a phase II trial is 125 mg/m2 irinotecan in combination with oxaliplatin, 5-FU/FA and cetuximab. Most common grade ?3 toxicities were neutropenia (40%), diarrhoea (25%) and acne-like rash (15%). No therapy associated death occurred.The confirmed overall response rate in all cohorts was 75% (95%-CI 51-91%). The best response was reached after a median of 3.0 (95%-CI 2.2 to 3.7) months. Median progression free survival (PFS) is 16 (95%-CI 12.6-19.4) months, overall survival (OS) 33 (95%-CI 26.2-39.8) months.The combination of cetuximab and FOLFOXIRIis feasible and has an acceptable toxicity profile in patients with a good performance status. The observed clinical activity with a confirmed response rate of 75% is promising and further evaluated in the ongoing CELIM2.http://www.clinicaltrials.gov: NCT00422773.

Project description:BackgroundFOLFIRI [irinotecan, folinic acid (CF), and fluorouracil] is considered a standard second-line chemotherapy regimen for patients with metastatic colorectal cancer (mCRC) who failed first-line XELOX/FOLFOX regimens. However, it remains unknown whether fluorouracil is still necessary in this case. This trial was designed to test the superiority of FOLFIRI over single-agent irinotecan as a second-line treatment for patients with mCRC.MethodsThis randomized clinical trial was conducted in five hospitals in China. From 4 November 2016 to 17 January 2020, patients aged 18 years or older with histologically confirmed unresectable mCRC and who had failed first-line XELOX/FOLFOX regimens were screened and enrolled. Patients were randomized to receive either FOLFIRI or irinotecan. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and toxicity. Data were analyzed on an intention-to-treat basis.ResultsA total of 172 patients with mCRC were randomly treated with FOLFIRI (n = 88) or irinotecan (n = 84). The median PFS was 104 and 112 days (3.5 and 3.7 months) in the FOLFIRI and irinotecan groups, respectively [hazard ratio (HR) = 1.084, 95% confidence interval (CI) = 0.7911-1.485; p = 0.6094], and there was also no significant difference in OS and ORR between the two groups. The incidence of the following adverse events (AEs) was significantly higher in the FOLFIRI group than in the irinotecan group: any grade AEs including leucopenia (73.9% versus 55.4%), neutropenia (72.7% versus 56.6%), thrombocytopenia (31.8% versus 18.1%), jaundice (18.2% versus 7.2%), mucositis (40.9% versus 14.5%), vomiting (37.5% versus 21.7%), and fever (19.3% versus 7.2%) and grade 3-4 neutropenia (47.7% versus 21.7%).ConclusionThis is the first head-to-head trial showing that single-agent irinotecan yielded PFS, OS, and ORR similar to FOLFIRI, with a more favorable toxicity profile; therefore, it might be a more favorable standard chemotherapy regimen for mCRC patients who failed first-line XELOX/FOLFOX regimens.Trial registrationThis study is registered with ClinicalTrials.gov, number NCT02935764, registered 17 October 2016, https://clinicaltrials.gov/ct2/show/NCT02935764.

Project description:BackgroundThe RAISE phase III clinical trial demonstrated that ramucirumab + FOLFIRI improved overall survival (OS) [hazard ratio (HR) = 0.844, P = 0.0219] and progression-free survival (PFS) (HR = 0.793, P < 0.0005) compared with placebo + FOLFIRI for second-line metastatic colorectal carcinoma (mCRC) patients previously treated with first-line bevacizumab, oxaliplatin, and a fluoropyrimidine. Since some patient or disease characteristics could be associated with differential efficacy or safety, prespecified subgroup analyses were undertaken. This report focuses on three of the most relevant ones: KRAS status (wild-type versus mutant), age (<65 versus ≥65 years), and time to progression (TTP) on first-line therapy (<6 versus ≥6 months).Patients and methodsOS and PFS were evaluated by the Kaplan-Meier analysis, with HR determined by the Cox proportional hazards model. Treatment-by-subgroup interaction was tested to determine whether treatment effect was consistent between subgroup pairs.ResultsPatients with both wild-type and mutant KRAS benefited from ramucirumab + FOLFIRI treatment over placebo + FOLFIRI (interaction P = 0.526); although numerically, wild-type KRAS patients benefited more (wild-type KRAS: median OS = 14.4 versus 11.9 months, HR = 0.82, P = 0.049; mutant KRAS: median OS = 12.7 versus 11.3 months, HR = 0.89, P = 0.263). Patients with both longer and shorter first-line TTP benefited from ramucirumab (interaction P = 0.9434), although TTP <6 months was associated with poorer OS (TTP ≥6 months: median OS = 14.3 versus 12.5 months, HR = 0.86, P = 0.061; TTP <6 months: median OS = 10.4 versus 8.0 months, HR = 0.86, P = 0.276). The subgroups of patients ≥65 versus <65 years also derived a similar ramucirumab survival benefit (interaction P = 0.9521) (≥65 years: median OS = 13.8 versus 11.7 months, HR = 0.85, P = 0.156; <65 years: median OS = 13.1 versus 11.9 months, HR = 0.86, P = 0.098). The safety profile of ramucirumab + FOLFIRI was similar across subgroups.ConclusionsThese analyses revealed similar efficacy and safety among patient subgroups with differing KRAS mutation status, longer or shorter first-line TTP, and age. Ramucirumab is a beneficial addition to second-line FOLFIRI treatment for a wide range of patients with mCRC.Trial registrationClinicalTrials.gov, NCT01183780.

Dataset Information

Drug-Drug Interactions of Irinotecan, 5-Fluorouracil, Folinic Acid and Oxaliplatin and Its Activity in Colorectal Carcinoma Treatment.

Publications

Drug-Drug Interactions of Irinotecan, 5-Fluorouracil, Folinic Acid and Oxaliplatin and Its Activity in Colorectal Carcinoma Treatment.

Similar Datasets

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