Administration Of Folinic Acid Research Articles

Intratumoral NKT cell accumulation promotes antitumor immunity in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDA) is a potentially lethal disease lacking effective treatments. Its immunosuppressive tumor microenvironment (TME) allows it to evade host immunosurveillance and limits response to immunotherapy. Here, using the mouse KRT19-deficient (sgKRT19-edited) PDA model, we find that intratumoral accumulation of natural killer T (NKT) cells is required to establish an immunologically active TME. Mechanistically, intratumoral NKT cells facilitate type I interferon (IFN) production to initiate an antitumor adaptive immune response, and orchestrate the intratumoral infiltration of T cells, dendritic cells, natural killer cells, and myeloid-derived suppressor cells. At the molecular level, NKT cells promote the production of type I IFN through the interaction of their CD40L with CD40 on myeloid cells. To evaluate the therapeutic potential of these observations, we find that administration of folinic acid to mice bearing PDA increases NKT cells in the TME and improves their response to anti-PD-1 antibody treatment. In conclusion, NKT cells have an essential role in the immune response to mouse PDA and are potential targets for immunotherapy.

Navigating methotrexate toxicity: Examining the therapeutic roles of folinic acid and glucarpidase.

Methotrexate (MTX) toxicity varies depending on factors such as dosing frequency (acute or repeated), dosage (low or high) and the administration route (oral, parenteral or intrathecal). Renal impairment can trigger or exacerbate MTX toxicity. Acute oral low-dose MTX (LDMTX) overdoses seldom lead to toxicity due to the saturable maximal bioavailable dose, but toxicity risks increase with repeated low doses (>3 days), high-dose MTX (HDMTX) or intrathecal poisoning. Folinic acid shares MTX transporters in the gut and cells and bypasses the MTX-induced dihydrofolate reductase inhibition. The required folinic acid dosage differs for low-dose and high-dose MTX toxicities. Acute LDMTX poisoning rarely requires folinic acid, while chronic LDMTX poisoning needs low-dose folinic acid until cellular function is restored. In HDMTX toxicities, early intravenous folinic acid administration is recommended, with dose and duration being guided by MTX concentrations and clinical improvement. In intrathecal MTX poisoning, folinic acid should be administered intravenously. Glucarpidase, a recombinant bacterial enzyme, has a high affinity for MTX and folate analogues in the intravascular or intrathecal systems. It decreases serum MTX concentrations by 90%-95% within 15 min. Its primary indication is for intrathecal MTX poisoning. It is rarely indicated in HDMTX toxicity unless patients have renal injury. However, there is no literature evidence supporting its use in HDMTX poisoning. Its use is limited by its significant cost and lack of availability. Haemodialysis can be potentially useful for MTX removal in cases where glucarpidase is not available. Additionally, fluid hydration, renal support and urine alkalinization are important adjunctive therapies for managing MTX toxicities.

Treatment of patients with carcinomas in advanced stages with 5-fluorouracil, folinic acid and pyridoxine in tandem

The effect of high-dose pyridoxine (PN) on activity of 5-fluorouracil (FUra) and folinic acid (FA)-containing regimens was studied in 50 patients including 14 with digestive tract, and 36 with breast carcinomas (BC) in advanced stages with poor prognostic characteristics. Patients with colorectal, and pancreas adenocarcinoma received oxaliplatin, irinotecan, FUra, FA (Folfirinox), and patients with squamous cell carcinoma of the esophagus had paclitaxel, carboplatin, FUra, FA (TCbF). Patients with BC received AVCF (doxorubicin, vinorelbine, cyclophosphamide, FUra, FA) followed by TCbF or TCbF only, and patients who overexpressed HER2 received TCbF plus trastuzumab and pertuzumab. PN (1000–3000 mg/day iv) preceded each administration of FUra and FA. 47 patients (94%) responded, including 16 (32%) with CR. Median tumor reduction was 93%. Median event-free survival (EFS) was 37.7 months. The 25 patients with tumor shrinkage ≥ 91% had EFS of 52% from 42 months onwards. Unexpected toxicity did not occur. PN enhances potency of chemotherapy regimens comprising FUra and FA.

High-Dose Methotrexate (Hd-Mtx) : Therapeutic Drug Monitoring Of Patients Followed At The Toxicology Department Of The University Hospital Of Setif, Algeria

Therapeutic drug monitoring (TDM) of methotrexate is widely recommended during high-dose administration (> 1 g/m2) in various chemotherapy protocols. This study aims to analyze the blood concentration methotrexate profile to detect delayed elimination in patients monitored at the toxicology department of the University Hospital of Sétif for MTX blood testing. A retrospective descriptive monocentric study was conducted, including all adult patients over 15 years old treated for malignant hematologic disorders with HD-MTX (> 1 g/m2) during their initial therapy. The results revealed that out of 189 monitored patients, only 79 underwent MTX level assessment at 48 hours and 72 hours. Among them, 77.2% exhibited elimination delays at 48 hours and 52% at 72 hours. The analysis of risk factors associated with elimination delay (age, gender, and dosage) did not show any statistically significant correlation. Considering the risk associated with elimination delay in potentiating the toxic effect of MTX, pharmacological therapeutic monitoring remains essential to adjust rescue measures through folinic acid administration and/or intensification of alkaline hydration. This approach aims to enhance the safety and efficacy of HD-MTX-based treatments.

Severe methotrexate toxicity in elderly patients under diuretics

ObjectivesTo explore the toxicity of low-dose methotrexate (MTX), an uncommon, but life-threatening event.MethodsWe analysed the presentation, course and risk factors of all patients admitted to the rheumatology ward with severe...

The effects of folinic acid and l-methylfolate supplementation on serum total homocysteine levels in healthy adults

Hyperhomocysteinemia is recognized as a risk factor for several diseases and conditions. The aim of this study was to investigate and compare the efficacy of two total homocysteine (tHcy)-lowering treatments including folinic acid or l-methylfolate in healthy Greek adults. Two hundred and seventy-two healthy Greek adults (143 men, 129 women; mean age±SD: 43.0±15.3 years), with serum tHcy levels ≥10μmol/L received randomized folinic acid ("Folinic acid Group") or l-methylfolate ("l-methylfolate Group") orally for three months. All subjects with serum cobalamin (Cbl) levels <300pg/mL additionally received 1mg hydroxycobalamine intramuscularly twice a week for the first month only. Serum folate, Cbl and tHcy levels were determined using immunoassays methods at the beginning and the end of the study period. The MTHFR C677T and MTHFR A1298C gene polymorphisms were genotyped using polymerase chain reaction and reverse hybridization. At the end of the 3-month intervention period, the levels of serum folate and Cbl increased significantly, whereas the levels of serum tHcy decreased significantly in the two groups. The individuals with MTHFR 677TT genotype had a significantly higher reduction in serum tHcy levels than the individuals with the MTHFR 677CC or MTHFR 677CT genotypes. Although the "Folinic acid Group" had a considerably higher increase in their serum folate levels (but not Cbl) than the "l-methylfolate Group", the reduction of serum tHcy levels between the two groups was not substantially different. The individuals with MTHFR 677CT genotype had a statistically significant higher reduction in serum tHcy levels when supplemented with folinic acid rather than l-methylfolate. The administration of folinic acid compared to l-methylfolate caused a higher increase of serum folate levels but no difference in the reduction of serum tHcy levels. The reduction of serum tHcy levels was influenced by the existence of MTHFR C677T and not MTHFR A1298C gene polymorphisms. The individuals with MTHFR 677CT genotype appear to benefit more by folinic acid than l-methylfolate supplementation.

Hypersensitivity reactions to folinic acid: mechanisms involved based on two case reports and a literature review

BackgroundHypersensitivity reactions (HSR) to antineoplastic agents are an increasing problem, especially when they lead to treatment discontinuation, sometimes without any equivalent therapeutic option. HSR to folinic acid (FA), used particularly for the treatment of digestive carcinoma along with oxaliplatin and 5-fluorouracil, are rare. Only seven publications report HSR to FA, mainly confirmed by the disappearance of symptoms after the withdrawal of FA from chemotherapy. Only two papers describe allergy testing. Due to the difficult diagnosis, patients usually receive several further cycles of chemotherapy with progressively more intense symptoms before the withdrawal of FA.Case presentationHere we document two cases of HSR to FA, initially misattributed to oxaliplatin. The first patient described successive cycles with first back muscle pain, then chills and facial oedema and finally diffuse erythema with labial edema despite premedication. The allergy assessment highlighted high acute tryptase levels and intradermal tests positive for FA, pointing to an immunoglobulin E (IgE)-mediated mechanism. The second patient also had lower back muscle pain and chills in addition to tachycardia and desaturation during the administration of FA. Skin tests were negative and tryptase levels normal. After withdrawing FA, the symptoms did not recur, thus allowing the patient to continue chemotherapy. The mechanism of FA hypersensitivity is still unclear. The chronology of symptoms suggests an IgE-mediated mechanism that was not documented in the allergy assessment. A non-IgE-mediated mast cell/basophil activation could be involved, through complement activation or through Mas-related G protein-coupled receptors X2 (MRGPRX2) particularly.ConclusionsThese two cases of anaphylaxis to FA document the clinical manifestations associated with two different mechanisms of HSR. This paper provided the opportunity to review the limited literature on HSR to FA. Through these cases, we hope to draw the practitioner’s attention to FA as a potential agent of severe hypersensitivity, especially if symptoms remain after withdrawing the most suspected chemotherapeutic agents. We want also to stress the importance of allergy testing.

76 A Report on 83 Patients with Suspected Methanol Poisoning from Philippine Coconut Wine (Lambanog) Seen at East Avenue Medical Center: A Case Series

Lambanog or Philippine Coconut wine is locally made distilled alcohol made from coconut sap and is well known for its strong alcohol content (40-45%). Severe methanol intoxication from Lambanog wine is rare but frequently lethal. Poor prognosis criteria include coma and seizure and severe metabolic acidosis. We present epidemiological and clinical data from a recent toxicologic mass casual incident involving suspected methanol poisoning. The management of methanol poisoning includes standard supportive care, correction of metabolic acidosis, administration of folinic acid, provision of an antidote to inhibit the metabolism of methanol to formate, and selective hemodialysis to correct severe metabolic abnormalities and enhance methanol and formate elimination.

The Prevention of Ischemia-Reperfusion Injury in Elderly Rats after Lower Limb Tourniquet Use.

Background: Lower limb ischemia-reperfusion injury (IRI-LL) is a common major complication of orthopedic surgery, especially in elderly patients. It has previously been demonstrated that folinic acid (FA) reduced IRI-LL damage in 3–4-month-old rats. This current work analyses the effect of FA in the prevention of IRI-LL in elderly animals. Methods: Forty-two 18-month-old male WAG/RijHsd rats were subjected to 3 h of ischemia. Eighteen animals received FA (2.5 mg/kg, ip) 20 min before the end of the ischemia period, while the other half received the same volume of saline solution. The animals were sacrificed after 3 h, 24 h, and 14 days of reperfusion for biochemical (tissue damage markers and electrolytes), histopathological studies of the gastrocnemius muscle and the daily assessment of the limb function by the Rota Rod test, respectively. Results: The administration of FA prior to the end of the ischemia period reduced the increase in LDH and CK observed in non-treated animals by 30–40% (p < 0.0001). When the histological sections were analyzed, FA was found to have reduced the number of damaged muscle fibers per field by 20% (60 ± 17.1 vs. 80.7 ± 16.4, p < 0.0001). The functional test revealed that FA also led to an improvement in the muscle function, assessed by the length of time that the animals kept running on the rod, compared to untreated animals. Conclusions: The administration of FA, prior to the end of the ischemic period, decreases the damage induced by IRI-LL, also achieving a faster recovery of mobility.

Effects of Folinic Acid Administration on Lower Limb Ischemia/Reperfusion Injury in Rats.

Surgery under ischemic conditions, lasting up to 3 h, is routinely performed in orthopedic surgery, causing undesirable injury due to ischemia-reperfusion syndrome, with short and medium-term functional repercussions. To date, there is no established prophylactic treatment. In this work we evaluated folinic acid (FA) in a rodent model of lower limb ischemia-reperfusion (IRI-LL). 36 male WAG rats underwent 3 h of lower limb ischemia. In the saline group, rats received intraperitoneal administration of saline (used as vehicle for treatment). In the experimental group, rats were pretreated with FA (2.5 mg/kg) before the end of ischemia. After ischemia, animals were sacrificed at 3 h, 24 h or 14 days (for biochemical determination (Na+, K+, Cl-, urea, creatinine, CK, LDH, ALP, ALT, and AST), pathological assessment, or functional study using the rotarod test; respectively). Another six animals were used to establish the reference values. The prophylactic administration of FA significantly reduced the elevation of biochemical markers, especially those that most directly indicate muscle damage (CK and LDH). In addition, it also improved direct tissue damage, both in terms of edema, weight, PMN infiltrate and percentage of damaged fibers. Finally, the administration of FA allowed the animals to equal baseline values in the rotarod test; what did not occur in the saline group, where pre-ischemia levels were not recovered. Following 3 h of lower limb ischemia, FA minimizes the increase of CK and LDH, as well as local edema and leukocyte infiltration, allowing a faster recovery of limb functionality. Therefore, it could be considered as a prophylactic treatment when tourniquet is used in clinics.

Pharmacologic modulation of 5-fluorouracil by folinic acid and high-dose pyridoxine for treatment of patients with digestive tract carcinomas

Supplementation of cancer cells exposed to 5-fluorouracil (FUra) and folinic acid (FA) with high concentration pyridoxal 5′-phosphate, the cofactor of vitamin B6, potentiates the cytotoxicity of FUra in a synergistic interaction mode. We report a pilot study in 13 patients with previously untreated advanced carcinoma of the digestive tract to assess the impact of high-dose pyridoxine (PN) on the antitumor activity of regimens comprising FUra and FA. Five patients had colorectal adenocarcinoma (CRC); 5 had pancreas adenocarcinoma (PC); and 3 had squamous cell carcinoma of the esophagus (EC). Patients with CRC and with PC received oxaliplatin, irinotecan, FUra and FA, and patients with EC had paclitaxel, carboplatin, FUra and FA. PN iv from 1000 to 3000 mg/day preceded each administration of FA and FUra. Eleven patients responded. Two patients with CRC attained CRs and 3 had PRs with reduction rates ≥ 78%. Two patients with PC attained CRs, and 2 had PRs with reduction rates ≥ 79%. Responders experienced disappearance of most metastases. Of 3 patients with EC, 2 attained CRs. Median time to attain a response was 3 months. Unexpected toxicity did not occur. Results suggest that high-dose vitamin B6 enhances antitumor potency of regimens comprising FUra and FA.

Role of folinic acid in methotrexate-based prophylaxis of graft-versus-host disease following hematopoietic stem cell transplantation

ABSTRACT Methotrexate (MTX) is one of the main therapeutic agents currently used for the prophylaxis of graft-versus-host disease (GvHD) following hematopoietic stem cell transplantation. However, it is associated with significant toxicity and considerable side effects in many patients, which lead to either early withdrawal or dose reductions that may expose patients to the risk of GvHD and graft failure. Folinic acid (FA) can bypass the inhibitory effects of MTX on folate availability and control MTX toxicity. However, concerns that FA might inhibit the anti-GvHD effect of MTX and limited reports on its clinical usefulness have led to reluctance in its inclusion in standard GvHD prophylaxis regimens. Additionally, universal dosing and timing guidelines are lacking. I discuss the available literature and evaluate the evidence for the effect of FA on MTX toxicity and its safety regarding GvHD development and graft rejection in both adult and pediatric patients. Although FA administration appears to be safe, its efficacy for routine use in all types of transplants in adult patients is unproven and further research is required to confirm its MTX toxicity-lowering effect, identify the individual parameters that influence its usefulness in clinical practice, and evaluate its potential when developing a personalized prophylaxis regimen.

The Effect of Folinic Acid (FA) Rescue Following MTX Gvhd Prophylaxis on Regimen Related Toxicity and Transplantation Outcome: A Double Blind Randomized Controlled Study

<h3>Background</h3> The use of MTX for GVHD prophylaxis is associated with increased rates of oral mucositis (OM), delayed engraftment, hepatotoxicity and nephrotoxicity. Based on limited data, the EBMT and ELN working group recommend the use of FA-rescue to reduce MTX toxicity after alloHCT. We aimed to determine whether FA-rescue reduces the rate of MTX-induced toxicity in patients who receive post-transplant MTX for GVHD prophylaxis. <h3>Methods</h3> This is a double blind RCT conducted in 3 centers. We enrolled patients undergoing alloHCT from MSD or MUDs with a MAC regimen and PBSC grafts, and GVHD prophylaxis consisting CSA/MTX, plus ATG for MUDs. Patients were randomized to oral FA or placebo, stratified by center and conditioning intensity (standard <i>vs.</i> reduced toxicity MAC). FA administration started 24h after each MTX dose: 15 mg TID after MTX administration on day +1 and QID after MTX administration on days +3 and +6. The primary endpoint was the rate of grade 3-4 OM according to the WHO scale. A sample size of 58 subjects in each group was estimated to detect a difference in grade 3-4 OM of 50% <i>vs.</i> 25%. <h3>Results</h3> From 2/2016 through 7/2019, 52 patients with acute leukemia in CR (n = 45), MDS (n=6) or NHL in CR (n=1) were randomized to FA (n=28) or placebo (n=24). Patient characteristics were similar between groups (table). After enrolment of 52 patients, interim analysis revealed that the rate (46.6% <i>vs.</i> 45.8%, P=0.97) and duration (4 <i>vs.</i> 4 days) of grade 3-4 OM and the rate of OM of any severity (83.3% <i>vs.</i> 77.8%, P=0.65) were similar in both groups. Also, time to neutrophil and platelet engraftment, rates of febrile neutropenia and blood stream infections, VOD, need for opiates or TPN and time from HCT to discharge were not significantly different between groups. With a median follow-up of 9 months we did not observe any difference in rates of acute or chronic GVHD, DFS and OS. <h3>Conclusions</h3> The interim results, showing similar rates of grade 3-4 OM and secondary outcomes, do not support continuation of the study. FA-rescue following MTX GVHD prophylaxis does not seem to decrease regimen related toxicity and affect transplant outcomes.

Klinička farmakokinetika metotreksata u terapiji akutne limfoblastne leukemije i ne-Hodkinovog limfoma u pedijatrijskoj populaciji pacijenata

High dose methotrexate (MTX) is used in therapy of acute lymphoblastic leukemia and non-Hodgkin lymphoma in pediatric patients. It acts as competitive inhibitor of dihydrofolate reductase and consequently inhibits synthesis of deoxyribonucleic acid. The bioavailability is dependent upon dose and route of administration. The drug is moderately bound to plasma proteins and distributes in body tissues and cells. After the administration in high doses, MTX partially undergoes hepatic and intracellular metabolism, but renal excretion of parent compound is the main route of elimination. Numerous factors may influence pharmacokinetics and concentration of drug, but primarily the effect of renal function on elimination is described. Delayed elimination might also be the consequence of drug interaction in renal tubules. Toxicity can arise with high MTX doses, especially in patients with delayed MTX elimination. Therapeutic drug monitoring is indicated due to safety reasons, in order to optimize leucovorin (folinic acid) administration as it reduces MTX toxicity. Considering the variability and the toxicity of high dose MTX therapy, special caution is required in pediatric patients.

Successful Treatment of Hereditary Folate Malabsorption With Intramuscular Folinic Acid

BackgroundHereditary folate malabsorption is a multisystem disease owing to biallelic variants in the gene encoding the proton-coupled folate transporter. Hereditary folate malabsorption is treated with folinic acid, aimed to restore blood and cerebrospinal fluid folate levels. Little is known as to whether oral or intramuscular supplementation of folinic acid is most effective. MethodsHere we describe a one-year-old boy with hereditary folate malabsorption presenting with the typical features including failure to thrive, aphthous stomatitis, macrocytic anemia along with severe developmental impairment and epilepsy, as well as a magnetic resonance imaging of the brain showing bilateral occipital, cortical calcifications characteristic of hereditary folate malabsorption. We compared the effect of treatment with oral folinic acid versus intramuscular folinic acid supplementation by measuring plasma and cerebrospinal fluid folate levels. ResultsCompared with oral administration, intramuscular treatment resulted in higher folate levels in blood and, most importantly, normalization of folate levels in cerebrospinal fluid. Clinically, nearly all systemic and neurological symptoms resolved. ConclusionNormal cerebrospinal fluid folate levels can be achieved in individuals with hereditary folate malabsorption with intramuscular (but not with oral) administration of folinic acid.

Paroxyzmální noční hemoglobinurie

Paroxysmal nocturnal hemoglobinuria (PNH) results from a deficiency in inhibitors of activated complement. This lack leads to complement mediated intravascular hemolysis, to activation of coagulation system with increased risk of thrombotic complications and to various degree of bone marrow failure. A molecular basis of PNH is a somatic mutation of PIGA gene causing a lack of glycosyl phosphatidyl inositol which binds many important antigens to cell surface membrane including inhibitors of activated complement CD59 and CD55 antigens. Presence of CD59 and CD55 deficient cells in peripheral blood detected by flow cytometry is essential for diagnosis of PNH. Standard treatment of PNH includes transfusions of leukocyte depleted red blood cells, anticoagulation prophylaxis and administration of folinic acid. PNH patients with predominant signs of bone marrow failure and profound cytopenia may by candidates for stem cell transplantation or combination immunosuppression. Patients with severe hemo-lysis and/or thrombotic complications are indicated for administration of eculizumab - a monoclonal antibody against C5 part of complement. Key words: diagnosis - eculizumab - immunosuppression - paroxysmal nocturnal hemoglobinuria - pathogenesis - transplantation - treatment.

Effects of leucovorin (folinic acid) in the methotrexate-treated rat brain.

Folinic acid (FA) is generally administered to patients with CNS tumors in order to treat severe neurological disorders caused by methotrexate (MTX); therefore, we herein examined the effects of the co-administration of FA on MTX concentrations in the rat brain and cerebrospinal fluid (CSF) as well as the pharmacokinetics of MTX. MTX was intravenously or intrathecally administered to rats with or without FA. MTX concentrations were assessed by HPLC. No significant differences were observed in pharmacokinetic parameters, including kel, Vd, AUC, Cltot and t1/2, between the FA-treated and non-treated groups. MTX concentrations were not significantly different in the brain or CSF 6 hr after the intrathecal administration of MTX. However, compare to intravenous administration of MTX, intravenous administration of both FA and MTX significantly decreased MTX concentrations in the brains and CSF. These results suggest that FA inhibits the influx of MTX into the brain and CSF, possibly by competing with folate carriers, but has no effect on its efflux from these regions. Therefore, FA may be administered to CNS tumor patients receiving intrathecal MTX therapy in order to treat the adverse effects of MTX without affecting its concentrations in the brain and CSF.

Management of folinic acid administration in patients with metastatic colo-rectal cancer

Management of folinic acid administration in patients with metastatic colo-rectal cancer

Is FOLFOXIRI alone or combined with targeted therapy administered as first-line treatment a reasonable choice for most patients with mCRC? Systematic review and network meta-analysis.

e15018 Background: Controversy surrounds the question of whether the prognosis of most patients with metastatic colorectal cancer (mCRC) is improved using intensive administration of folinic acid, 5-fluorouracil, oxaliplatin and irinotecan (FOLFOXIRI) alone or combined with target therapy as first-line treatment. Methods: We queried PubMed, the Cochrane Collaboration Central Register of Controlled Clinical Trials, Cochrane Systematic Reviews, ClinicalTrials.gov, the databases of the European Society for Medical Oncology and the American Society of Clinical Oncology to identify abstracts of randomized controlled trials evaluating the efficacies and toxicities of intensive therapies used for first-line treatment of patients with mCRC. The search included articles dated from the inception of these resources until December 31, 2016. We estimated hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and relative risks (RRs) for the objective response rate (ORR), the R0 resection rate, and toxicities. Results: Nine RCTs comprising 2,256 patients were included in this network meta-analysis. The PFS of patients administered FOLFOXIRI plus target therapy experienced prolonged PFS and OS and improved ORRs compared with FOLFOX or FOLFIRI plus target therapy (PFS: HR 0.65, 95% CI 0.46–0.91; OS: HR 0.80, 95% CI 0.65–0.98; ORR: HR 1.70, 95% CI 1.16–2.49; R0 resection rate: HR 2.66, 95% CI 1.86–3.82). There were no significant differences between PFS, OS, ORRs, or R0 resection rates and toxicities of patients administered FOLFOXIRI and FOLFOX or FOLFIRI plus target therapy. Further, FOLFOXIRI plus target therapy did not increase toxicities compared with FOLFOX or FOLFIRI plus target therapy, except for neutropenia. Conclusions: FOLFOXIRI plus target therapy when administered as first-line treatment of patients with mCRC is the best choice and did not significantly increase toxicities. FOLFOXIRI is as effective as FOLFOX or FOLFIRI plus target therapy.

Is FOLFOXIRI alone or combined with targeted therapy administered as first-line treatment a reasonable choice for most patients with mCRC? Systematic review and network meta-analysis.

Whether the intensive administration of folinic acid, 5-fluorouracil, oxaliplatin and irinotecan (FOLFOXIRI) alone or combined with target therapy as first-line treatment could improve the prognosis of metastatic colorectal cancer (mCRC) patients is controversial. PubMed, the Cochrane Collaboration Central Register of Controlled Clinical Trials, Cochrane Systematic Reviews, ClinicalTrials.gov, the databases of conferences were queried to identify RCTs evaluating the efficacies and toxicities of intensive therapies used for first-line treatment of mCRC patients. The search included articles dated from the inception of these resources until March 31, 2017. We estimated HRs for OS and PFS and RRs for ORR, the R0 resection rate, and toxicities. Ten RCTs comprising 2,506 patients were included in this network meta-analysis. The PFS of patients administered FOLFOXIRI plus target therapy experienced prolonged PFS and OS and improved ORRs compared with FOLFOX/FOLFIRI plus target therapy (PFS: HR 0.71, 95% CI 0.59–0.86; OS: HR 0.81, 95% CI 0.69–0.94; ORR: RR 1.66, 95% CI 0.96–2.88; R0 resection rate: RR 2.66, 95% CI 1.86–3.82). There were no significant differences between PFS, OS, ORRs, or R0 resection rates and toxicities of patients administered FOLFOXIRI and FOLFOX/FOLFIRI plus target therapy. Further, FOLFOXIRI plus target therapy did not increase toxicities compared with FOLFOX/FOLFIRI plus target therapy. FOLFOXIRI plus target therapy when administered as first-line treatment of patients with mCRC is the best choice and did not increase toxicities. The patients with RAS/BRAF mutations could benefit from FOLFOXIRI plus Bev. FOLFOXIRI is as effective as FOLFOX/FOLFIRI plus target therapy.