Initial Therapy with FOLFOXIRI and Bevacizumab for Metastatic Colorectal Cancer

Loupakis, Fotios; Cremolini, Chiara; Masi, Gianluca; Lonardi, Sara; Zagonel, Vittorina; Salvatore, Lisa; Cortesi, Enrico; Tomasello, Gianluca; Ronzoni, Monica; Spadi, Rosella; Zaniboni, Alberto; Tonini, Giuseppe; Buonadonna, Angela; Amoroso, Domenico; Chiara, Silvana; Carlomagno, Chiara; Boni, C.; Allegrini, Giacomo; Boni, Luca; Falcone, Alfredo

doi:10.1056/nejmoa1403108

Cited by 898 publications

(702 citation statements)

References 15 publications

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“…The Hardy-Weinberg equilibrium was evaluated using the χ 2 test [15]. AEs were dichotomized as either mild to moderate (grade 0-2) or severe (grade [3][4]. Association between chemotherapy-associated grade 3-4 AEs and selected genotypes was assessed using the Fisher exact test.…”

Section: Discussionmentioning

confidence: 99%

“…Initially, triplet chemotherapy with FOLFOXIRI plus bevacizumab gained popularity as conversion strategy in potentially resectable CRC liver metastases [17] or in selected, poor-prognosis patient populations, such as those with BRAF-mutated tumours [18]. However, this strategy of upfront treatment intensification was recently established as a palliative treatment option due to improvement of patients' survival [4]. We demonstrated that oral capecitabine can safely replace 5-FU as the fluoropyrimidine backbone for combination with oxaliplatin and irinotecan (COI regimen) with a manageable toxicity profile [19].…”

Section: Discussionmentioning

confidence: 99%

“…In particular, 36 (56%) patients received triplet chemotherapy with bevacizumab, while 28 (44%) received cetuximab. The median number of cycles was 8 (range [1][2][3][4][5][6][7][8]. A total of 23 (36%) patients developed grade 3-4 chemotherapy-related AEs.…”

Section: Patient Characteristicsmentioning

confidence: 99%

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DPD and UGT1A1 deficiency in colorectal cancer patients receiving triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan

Falvella

Cheli

Martinetti

et al. 2015

Brit J Clinical Pharma

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AIMSTriplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan is a standard therapy for metastatic colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) in DPYD and UGT1A1 influence fluoropyrimdines and irinotecan adverse events (AEs). Low frequency DPYD variants (c.1905 + 1G > A, c.1679 T > G, c.2846A > T) are validated but more frequent ones (c.496A > G, c.1129-5923C > G and c.1896 T > C) are not. rs895819 T > C polymorphism in hsa-mir-27a is associated with reduced DPD activity. In this study, we evaluated the clinical usefulness of a pharmacogenetic panel for patients receiving triplet combinations. METHODSGermline DNA was available from 64 CRC patients enrolled between 2008 and 2013 in two phase II trials of capecitabine, oxaliplatin and irinotecan plus bevacizumab or cetuximab. SNPs were determined by Real-Time PCR. We evaluated the functional variants in DPYD (rare: c.1905 + 1G > A, c.1679 T > G, c.2846A > T; most common: c.496A > G, c.1129-5923C > G, c.1896 T > C), hsa-mir-27a (rs895819) and UGT1A1 (*28) genes to assess their association with grade 3-4 AEs. RESULTSNone of the patients carried rare DPYD variants. We found DPYD c.496A > G, c.1129-5923C > G, c.1896 T > C in heterozygosity in 19%, 5% and 8%, WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Pharmacogenetic testing of DPYD and UGT1A1 is recommended in clinical practice prior to administration of fluoropyrimidines and irinotecan, respectively. respectively, homozygous rs895819 in hsa-mir-27a in 9% and homozygous UGT1A1*28 in 8%. Grade 3-4 AEs were observed in 36% patients and were associated with DPYD c.496A > G (odds ratio (OR) 4.93, 95% CI 1.29, 18.87; P = 0.021) and homozygous rs895819 in hsa-mir-27a (OR 11.11, 95% CI 1.21, 102.09; P = 0.020). Carriers of DPYD c.1896 T > C and homozygous UGT1A1*28 showed an OR of 8.42 (95% CI 0.88, 80.56; P = 0.052). Multivariate analysis confirmed an independent value for DPYD c

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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DPD and UGT1A1 deficiency in colorectal cancer patients receiving triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan

Falvella

Cheli

Martinetti

et al. 2015

Brit J Clinical Pharma

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“…In diese Studie wurden Patienten mit überwiegend günstigen Risikofaktoren eingeschlossen (1 -4 resektable Lebermetastasen, 52 % 1 Lebermetastase, 26 % 2 Lebermetastasen, 65 % metachrone Metastasierung). Bei primär resektabler Lebermetastasierung wurden eine perioperative Chemotherapie (6 Zyklen FOLFOX4 jeweils vor und nach der Operation) mit der alleinigen Operation [1084] [1110].…”

Section: Hintergrundunclassified

S3-Leitlinie – Kolorektales Karzinom

Schmiegel

Buchberger

Follmann³

et al. 2017

Z Gastroenterol

151

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“…As a result of recent advances in treatment, median overall survival (OS) can now be as long as 30 months in selected patient groups. [3][4][5][6] The first-line treatment will be the longest treatment phase and is thus of particular importance regarding the overall treatment strategy. The established standard for many years was continuation of the initial treatment until the occurrence of progression or unacceptable toxicity.…”

Section: Introductionmentioning

confidence: 99%

Effect of Application and Intensity of Bevacizumab-based Maintenance After Induction Chemotherapy With Bevacizumab for Metastatic Colorectal Cancer: A Meta-analysis

Stein

Schwenke²,

Folprecht

et al. 2016

Clinical Colorectal Cancer

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The role of bevacizumab-based maintenance after first-line bevacizumab-based induction treatment of metastatic colorectal cancer was evaluated in a meta-analysis of 3 randomized trials. Maintenance treatment with bevacizumab with or without fluoropyrimidines improved progression-free survival and showed a trend toward improved overall survival. Background: The administration and intensity of bevacizumab-based maintenance therapy after induction treatment with bevacizumab is still a matter of debate. Thus, the present meta-analysis and an indirect comparison were performed to clarify these issues. Patients and Methods: Trials evaluating a separately defined "maintenance phase," with randomization after the induction phase, were selected. Three trials of maintenance with bevacizumab with or without a fluoropyrimidine (CAIRO3, SAKK 41/06, and AIO KRK 0207) were analyzed regarding the effect on progression-free survival (PFS) and overall survival (OS) of any maintenance therapy compared with observation alone and different maintenance intensities (bevacizumab with or without fluoropyrimidine) compared with observation alone and between each other. Results: Maintenance with bevacizumab with or without fluoropyrimidine after bevacizumabbased induction treatment for 4 to 6 months significantly improved PFS (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.43-0.75; P ¼ .0004) and showed a trend toward prolonged OS (HR, 0.89; 95% CI, 0.78-1.02; P ¼ .09) compared with observation alone. The effect on PFS increased with the intensity of the maintenance regimen (HR, 0.72; 95% CI, 0.60-0.85 for single-agent bevacizumab vs. HR, 0.45; 95%, CI 0.39-0.51 for combination therapy, both compared to observation alone). In contrast, the HRs for OS remained in the same range. A similarly improved PFS (HR, 0.63; 95% CI, 0.50-0.79) was shown for the more intensive maintenance therapy (bevacizumab and fluoropyrimidine) compared with bevacizumab alone. Conclusion: Bevacizumab-based maintenance therapy after induction chemotherapy with bevacizumab significantly improves PFS and showed a trend toward prolonged OS and should thus be considered, in particular, in patients with a response to induction treatment.

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Initial Therapy with FOLFOXIRI and Bevacizumab for Metastatic Colorectal Cancer

Abstract: FOLFOXIRI plus bevacizumab, as compared with FOLFIRI plus bevacizumab, improved the outcome in patients with metastatic colorectal cancer and increased the incidence of some adverse events. (Funded by the Gruppo Oncologico Nord Ovest and others; ClinicalTrials.gov number, NCT00719797.).

Cited by 898 publications

References 15 publications

DPD and UGT1A1 deficiency in colorectal cancer patients receiving triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan

DPD and UGT1A1 deficiency in colorectal cancer patients receiving triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan

S3-Leitlinie – Kolorektales Karzinom

Effect of Application and Intensity of Bevacizumab-based Maintenance After Induction Chemotherapy With Bevacizumab for Metastatic Colorectal Cancer: A Meta-analysis

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