FOLFOXIRI or FOLFOXIRI plus bevacizumab as first-line treatment of metastatic colorectal cancer: a propensity score-adjusted analysis from two randomized clinical trials

Cremolini, Chiara; Loupakis, Fotios; Masi, Gianluca; Lonardi, Sara; Granetto, Cristina; Mancini, Maria; Chiara, S.; Moretto, Roberto; Rossini, Daniele; Vitello, S.; Allegrini, Giacomo; Tonini, Giuseppe; Bergamo, Francesca; Tomasello, Gianluca; Ronzoni, Monica; Buonadonna, Angela; Bustreo, Sara; Barbara, C.; Boni, Luca; Falcone, Alfredo

doi:10.1093/annonc/mdw052

Cited by 50 publications

(37 citation statements)

References 22 publications

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“…The use of multiple anticancer agents with distinct mechanisms of action may help prevent the development of resistant clones and provide longer disease control [20]. Our findings suggest that cFOLFOXIRI-BEV and sFOLFOXIRI-BEV are active and well tolerated in patients with mCRC, consistent with prior data from TRIBE and OLIVIA, as well as several recent metaanalyses [21,22]. cFOLFOXIRI-BEV conferred either statistically significant or strong trends for improvements in both ORR and PFS compared with FOLFOX-BEV, benefits that appeared largely independent of the molecular characteristics or sidedness of the tumor.…”

Section: Discussionsupporting

confidence: 87%

Phase II Randomized Trial of Sequential or Concurrent FOLFOXIRI-Bevacizumab Versus FOLFOX-Bevacizumab for Metastatic Colorectal Cancer (STEAM)

et al. 2018

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Background First‐line treatment for metastatic colorectal cancer (mCRC) typically entails a biologic such as bevacizumab (BEV) with 5‐fluorouracil/leucovorin/oxaliplatin (FOLFOX) or 5‐fluorouracil/leucovorin/irinotecan (FOLFIRI). STEAM (NCT01765582) assessed the efficacy of BEV plus FOLFOX/FOLFIRI (FOLFOXIRI), administered concurrently (cFOLFOXIRI‐BEV) or sequentially (sFOLFOXIRI‐BEV, FOLFOX‐BEV alternating with FOLFIRI‐BEV), versus FOLFOX‐BEV for mCRC. Patients and Methods Patients with previously untreated mCRC (n = 280) were randomized 1:1:1 to cFOLFOXIRI‐BEV, sFOLFOXIRI‐BEV, or FOLFOX‐BEV and treated with 4–6‐month induction followed by maintenance. Coprimary objectives were overall response rate (ORR; first‐line cFOLFOXIRI‐BEV vs. FOLFOX‐BEV) and progression‐free survival (PFS; pooled first‐line cFOLFOXIRI‐BEV and sFOLFOXIRI‐BEV vs. FOLFOX‐BEV). Secondary/exploratory objectives included overall survival (OS), liver resection rates, biomarker analyses, and safety. Results ORR was 72.0%, 72.8%, and 62.1% and median PFS was 11.9, 11.4, and 9.5 months with cFOLFOXIRI‐BEV, sFOLFOXIRI‐BEV, and FOLFOX‐BEV, respectively. OS was similar between arms. ORR between cFOLFOXIRI‐BEV and FOLFOX‐BEV did not significantly differ (p = .132); thus, the primary ORR endpoint was not met. cFOLFOXIRI‐BEV and sFOLFOXIRI‐BEV numerically improved ORR and PFS, regardless of RAS status. Median PFS was higher with pooled concurrent and sequential FOLFOXIRI‐BEV versus FOLFOX‐BEV (11.7 vs. 9.5 months; hazard ratio, 0.7; 90% confidence interval, 0.5–0.9; p < .01). Liver resection rates were 17.2% (cFOLFOXIRI‐BEV), 9.8% (sFOLFOXIRI‐BEV), and 8.4% (FOLFOX‐BEV). Grade ≥ 3 treatment‐emergent adverse events (TEAEs) were observed in 91.2% (cFOLFOXIRI‐BEV), 86.7% (sFOLFOXIRI‐BEV), and 85.6% (FOLFOX‐BEV) of patients, with no increase in serious chemotherapy‐associated TEAEs. Conclusion cFOLFOXIRI‐BEV and sFOLFOXIRI‐BEV were well tolerated with numerically improved ORR, PFS, and liver resection rates versus FOLFOX‐BEV, supporting triplet chemotherapy plus BEV as a first‐line treatment option for mCRC. Implications for Practice The combination of first‐line FOLFIRI with FOLFOX and bevacizumab (concurrent FOLFOXIRI‐BEV) improves clinical outcomes in patients with metastatic colorectal cancer (mCRC) relative to FOLFIRI‐BEV or FOLFOX‐BEV, but it is thought to be associated with increased toxicity. Alternating treatment of FOLFOX and FOLFIRI (sequential FOLFOXIRI‐BEV) could improve tolerability. In the phase II STEAM trial, which is the largest study of FOLFOXIRI‐BEV in patients in the U.S., it was found that both concurrent and sequential FOLFOXIRI‐BEV are active and well tolerated in patients with previously untreated mCRC, supporting the use of these regimens as potential first‐line treatment options for this population.

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Section: Discussionsupporting

confidence: 87%

Phase II Randomized Trial of Sequential or Concurrent FOLFOXIRI-Bevacizumab Versus FOLFOX-Bevacizumab for Metastatic Colorectal Cancer (STEAM)

et al. 2018

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“…Propensityscore matching is a well-established statistical approach and has been used to compare therapeutic outcomes indirectly in numerous clinical fields, including T2D, allowing better comparison of different study populations by minimizing confounding factors. [10][11][12][13][14] Aside from the obvious advantage of fixed-ratio combinations in terms of the ease and simplicity of a single injection, the aim of this exploratory indirect analysis was to provide preliminary evidence for any further efficacy or safety benefits in favour of the titratable fixed-ratio combination iGlarLixi vs the separate sequential administration of iGlar and Lixi.…”

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confidence: 99%

Propensity‐score‐matched comparative analyses of simultaneously administered fixed‐ratio insulin glargine 100 U and lixisenatide (iGlarLixi) vs sequential administration of insulin glargine and lixisenatide in uncontrolled type 2 diabetes

Rosenstock

Handelsman

Vidal

et al. 2018

Diabetes Obesity Metabolism

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AimTo conduct two exploratory analyses to compare indirectly the efficacy and safety of simultaneous administration of insulin glargine 100 U (iGlar) and the glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) lixisenatide (Lixi) as a single‐pen, titratable, fixed‐ratio combination (iGlarLixi [LixiLan trials]) vs sequential administration of iGlar + Lixi (GetGoal Duo trials) in people with type 2 diabetes (T2D).Materials and MethodsPropensity‐score matching based on baseline covariates was used to compare simultaneous iGlarLixi vs sequential combination of iGlar + Lixi with the addition of Lixi in patients who did not reach the glycated haemoglobin (HbA1c) goal of <53 mmol/mol (<7%) after short‐term use of iGlar alone (LixiLan‐O vs GetGoal Duo‐1 comparison) and vs sequential addition of Lixi in uncontrolled patients after long‐term use of iGlar alone (LixiLan‐L vs GetGoal Duo‐2 comparison).ResultsIn both analyses, compared with sequential iGlar + Lixi, iGlarLixi led to significantly greater HbA1c reductions with associated weight loss and significantly more patients reaching target HbA1c <53 mmol/mol despite lower insulin doses. Symptomatic hypoglycaemia rates were similar, despite greater HbA1c reductions with iGlarLixi. Lower rates of gastrointestinal adverse events were observed with iGlarLixi, probably as a result of the more gradual titration of Lixi with iGlarLixi.ConclusionsIndirect propensity‐score‐matched exploratory comparisons suggest that early treatment with a simultaneous, titratable, fixed‐ratio combination of basal insulin and a GLP‐1RA (iGlarLixi) may be more effective and possess better gastrointestinal tolerability than a sequential approach of adding a GLP‐1RA in patients with uncontrolled T2D initiating or intensifying basal insulin therapy.

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“…The classical procedures are portal vein ligation or embolization, while ALPPS (Associating Liver Partition and Portal vein ligation for Stage hepatectomy) and its modified versions have shown to improve even further the potential for liver regeneration (see Resection for colorectal metastases: to ALPPS or not to ALPPS? In this issue) (20,21); (II) The combination of chemotherapeutic agents including biological compounds show a tumor response rate >60% (22)(23)(24), and the improved conversion rate toward resection of initially unresectable metastases (25,26). If R0 resection is still the goal to achieve, limited observations suggest that R1 resection leads to similar postoperative overall survival pending that metastases responded to the neo-adjuvant chemotherapy (27,28); (III) Multiple repeated liver resections yield improved survival once the metastases have recurred (29), strengthening the concept of liver parenchyma sparing (30); (IV) Loco-regional treatments, mostly thermal ablation, allow for the destruction of deeply located metastases and limited parenchymal sacrifice during surgery in case of multiple metastases (31).…”

Section: Crlmmentioning

confidence: 99%

Transplantation for colorectal metastases: on the edge of a revolution

Andrès

Oldani

Berney

et al. 2018

Transl. Gastroenterol. Hepatol

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Liver transplantation (LT) has become the standard of care for selected primary and secondary malignancies. Considered a contra-indication to transplantation until recently, unresectable colorectal liver metastases (CRLM) have gained interest since the publication of the SECA trial by the University of Oslo. It showed a 5-year overall survival of 60%, comparable to the one of standard transplant indication. This report generated multiple questions about the place of LT for CRLM and gave raise to several trials aiming at answering them. The present review is exploring this topic, defining the current state of the field, and extrapolating the future milestones.

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FOLFOXIRI or FOLFOXIRI plus bevacizumab as first-line treatment of metastatic colorectal cancer: a propensity score-adjusted analysis from two randomized clinical trials

Cited by 50 publications

References 22 publications

Phase II Randomized Trial of Sequential or Concurrent FOLFOXIRI-Bevacizumab Versus FOLFOX-Bevacizumab for Metastatic Colorectal Cancer (STEAM)

Phase II Randomized Trial of Sequential or Concurrent FOLFOXIRI-Bevacizumab Versus FOLFOX-Bevacizumab for Metastatic Colorectal Cancer (STEAM)

Propensity‐score‐matched comparative analyses of simultaneously administered fixed‐ratio insulin glargine 100 U and lixisenatide (iGlarLixi) vs sequential administration of insulin glargine and lixisenatide in uncontrolled type 2 diabetes

Transplantation for colorectal metastases: on the edge of a revolution

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