Dataset Information

Treatments after progression to first-line FOLFOXIRI and bevacizumab in metastatic colorectal cancer: a pooled analysis of TRIBE and TRIBE2 studies by GONO.

ABSTRACT:

Background

FOLFOXIRI/bevacizumab (bev) is a first-line regimen of proven activity and efficacy in metastatic colorectal cancer. The upfront exposure to three cytotoxics raises concerns about the efficacy of treatments after progression.

Methods

We performed a pooled analysis of treatments after progression to upfront FOLFOXIRI/bev in patients enrolled in two randomised Phase 3 studies (TRIBE and TRIBE2) that compared FOLFOXIRI/bev to doublets (FOLFOX or FOLFIRI)/bev. Response rate, progression-free survival (2nd PFS) and overall survival (2nd OS) during treatments after progression were assessed. The RECIST response in first line and the oxaliplatin and irinotecan-free interval (OIFI) were investigated as potential predictors of benefit from FOLFOXIRI ± bev reintroduction.

Results

Longer 2nd PFS was reported in patients receiving FOLFOXIRI ± bev reintroduction compared to doublets ± bev or other treatments (6.1 versus 4.4 and 3.9 months, respectively, P = 0.013), and seems limited to patients achieving a response during first line (6.9 versus 4.2 and 4.7 months, respectively, P = 0.005) and an OIFI ≥ 4 months (7.2 versus 6.5 and 4.6 months, respectively, P = 0.045).

Conclusions

First-line FOLFOXIRI/bev does not impair the administration of effective second-line therapies. First-line response and longer OIFI seem associated with improved response and 2nd PFS from FOLFOXIRI ± bev reintroduction, without impacting 2nd OS.

SUBMITTER: Rossini D

PROVIDER: S-EPMC7782547 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Treatments after progression to first-line FOLFOXIRI and bevacizumab in metastatic colorectal cancer: a pooled analysis of TRIBE and TRIBE2 studies by GONO.

Rossini Daniele D Lonardi Sara S Antoniotti Carlotta C Santini Daniele D Tomasello Gianluca G Ermacora Paola P Germani Marco Maria MM Bergamo Francesca F Ricci Vincenzo V Caponnetto Salvatore S Moretto Roberto R Zaniboni Alberto A Pietrantonio Filippo F Buonadonna Angela A Ritorto Giuliana G Masi Gianluca G Latiano Tiziana Pia TP Rapisardi Stefania S Falcone Alfredo A Cremolini Chiara C

British journal of cancer 20201007 1

<h4>Background</h4>FOLFOXIRI/bevacizumab (bev) is a first-line regimen of proven activity and efficacy in metastatic colorectal cancer. The upfront exposure to three cytotoxics raises concerns about the efficacy of treatments after progression.<h4>Methods</h4>We performed a pooled analysis of treatments after progression to upfront FOLFOXIRI/bev in patients enrolled in two randomised Phase 3 studies (TRIBE and TRIBE2) that compared FOLFOXIRI/bev to doublets (FOLFOX or FOLFIRI)/bev. Response rate ...[more]

PMID: 33024268

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Project description:Background TRIBE and TRIBE-2 studies demonstrated higher benefit from FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan)/bevacizumab compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) or FOLFOX/bevacizumab as an upfront option for metastatic colorectal cancer patients, with more toxicities. We focused on the incidence and longitudinal dynamics of neutropenia and febrile neutropenia (FN) in the two studies, to evaluate their clinical relevance, the magnitude of impact of FOLFOXIRI/bevacizumab, and the role of risk factors in predicting their occurrence. Methods The overall incidence of grade 3-4 (G3-4) neutropenia and FN, the time to their onset, the use of granulocyte colony-stimulating factor, and the association with risk factors were evaluated in the overall population and according to treatment arm. FN episodes were assessed by Multinational Association for Supportive Care in Cancer (MASCC) score. Results Among 1155 patients, 568 (49%) received FOLFOXIRI/bevacizumab. Overall, 410 (35%) experienced G3-4 neutropenia and 70 (6%) FN, 21 (2%) at high risk. FOLFOXIRI/bevacizumab was associated with higher incidence of neutropenia (51% versus 21%, P < 0.001), FN (8% versus 4%, P = 0.02), and high-risk FN [18 (3%) versus 3 (1%), P = 0.015]. No related deaths were observed. The first episode of G3-4 neutropenia and FN occurred mainly in the first 2 months in both arms. Longitudinal analysis showed different patterns of evolution over cycles between the arms (P < 0.001) G3-4 neutropenia being more frequent in the first cycles with FOLFOXIRI/bevacizumab. Older patients (P = 0.01) and females (P < 0.001) had a significantly higher risk of G3-4 neutropenia. No significant interaction effect between arm and analysed risk factors in terms of risk of G3-4 neutropenia or FN was observed. The incidence of FN among older females receiving FOLFOXIRI/bevacizumab was 12%. Neither G3-4 neutropenia nor FN impaired efficacy in terms of overall response rate, progression-free survival, and overall survival. Conclusions FOLFOXIRI/bevacizumab has a higher risk of G3-4 neutropenia and FN than doublets/bevacizumab. FN occurred in <10% of patients, mostly as low-risk episodes. A closer monitoring during the first 2 months is recommended; prophylactic use of granulocyte colony-stimulating factor may be considered for older females. Highlights • FOLFOXIRI/bevacizumab is associated with a higher incidence of G3-4 neutropenia and FN than doublets/bevacizumab.• FN occurred in <10% of patients receiving FOLFOXIRI/bevacizumab and mostly as low-risk episodes.• Older patients and females show a significantly higher risk of G3-4 neutropenia.• Longitudinal analysis of neutropenia showed different patterns of evolution with doublets versus triplet.• Neither G3-4 neutropenia nor FN impaired treatment efficacy.

Project description:ImportanceThe combination of fluorouracil, oxaliplatin, and irinotecan plus bevacizumab (FOLFOXIRI-Bev) is an established and effective first-line chemotherapy regimen for metastatic colorectal cancer. However, resection rates of metastases and overall survival with this schedule have never been systematically evaluated in published studies including, but not limited to, the TRIBE (TRIplet plus BEvacizumab) trial.ObjectiveTo assess the clinical efficacy of FOLFOXIRI-Bev, including outcomes and rates of surgical conversions.Data sourcesA systematic review was conducted in October 2016 in concordance with the PRISMA guidelines of PubMed, the Cochrane Central Register of Controlled Trials, SCOPUS, Web of Science, Google Scholar, CINAHL, Ovid, and EMBASE using the terms FOLFOXIRI and bevacizumab and (colorectal cancer).Study selectionClinical trials, retrospective case series, and prospective case series that used FOLFOXIRI-Bev for the treatment of initially unresectable metastatic colorectal cancer in humans were included. Individual case reports and retrospective case series with fewer than 10 patients were excluded.Data extraction and synthesisData were extracted independently by 2 reviewers on a predesigned, standardized form. Ultimately, data were aggregated to obtain the pooled effect size of efficacy, according to the random-effects model and weighted for the number of patients included in each trial.Main outcomes and measuresMedian overall survival and progression-free survival, overall response rates, and rates of R0 surgical conversions and overall surgical conversions.ResultsEleven FOLFOXIRI-Bev studies published between 2010 and 2016 met the inclusion criteria and were pooled for analysis. The studies included 889 patients, with 877 patients clinically evaluable for overall response rates. The objective response rate to FOLFOXIRI-Bev was 69% (95% CI, 65%-72%; I2 = 25%). The rate of overall surgical conversions was 39.1% (95% CI, 26.9%-52.8%), and the rate of R0 surgical conversions was 28.1% (95% CI, 18.1%-40.8%). Median pooled overall survival was 30.2 months (95% CI, 26.5-33.7 months) in 6 trials with data available, and progression-free survival was 12.4 months (95% CI, 10.0-14.3 months) in 9 trials with data available. In meta-regression analysis, variables significantly associated with conversion surgery were disease limited to the liver and a higher median number of cycles (close to 12).Conclusions and relevanceFor patients with surgically unresectable metastatic colorectal cancer, FOLFOXIRI-Bev is associated with a significant overall response rate. Such an effective regimen leads to a probability of surgical conversion of distant metastases approaching 40%, with more than one-fourth of patients having an R0 resection.

Project description:BackgroundNo biomarkers exist to predict benefit from antiangiogenic therapy in metastatic colorectal cancer patients. ACVRL1 (activin receptor like-protein 1) encodes for ALK1, a member of the transforming growth factor-β receptor family, which directs pathologic angiogenesis. We examined the intratumoral expression of ACVRL1 and other angiogenesis pathway-related genes to identify molecular markers in the TRIBE study.Materials and methodsOf 503 randomized patients, 228 had sufficient tissue for analysis. Formalin-fixed paraffin-embedded specimens were examined for expression of VEGF-A, VEGF-B, VEGF-C, VEGFR1, VEGFR2, ACVRL1, EphB4, and EGFL7 using reverse transcription polymerase chain reaction. A maximal χ2 approach was used to determine the messenger RNA levels associated with progression-free survival (PFS), overall survival (OS), response rate, early tumor shrinkage, and depth of response. Recursive partitioning trees were constructed to identify composite prognostic biomarker profiles. External validation was conducted in silico using the Oncomine database.ResultsHigh ACVRL1 expression was associated with superior OS in both treatment arms (FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan]-bevacizumab, 32.7 vs. 13.5 months, hazard ratio [HR], 0.38, P = .023; FOLFIRI [5-fluorouracil, leucovorin, irinotecan]-bevacizumab, 35.1 vs. 22.0 months, HR, 0.36, P = .006) and prolonged PFS (11.7 vs. 5.9 months, multivariate HR, 0.17; P = .001) for patients receiving FOLFOXIRI-bevacizumab on univariate and multivariate analyses. In recursive partitioning analysis, ACVRL1 was the strongest discriminator of the response rate, PFS, and OS in patients receiving FOLFOXIRI-bevacizumab and of OS in patients receiving FOLFIRI-bevacizumab. In silico validation revealed significant associations between ACVRL1 expression, disease recurrence, and 1-year survival (P < .05) among all colorectal cancer stages.ConclusionACVRL1 expression could serve as a prognostic biomarker in metastatic colorectal cancer patients receiving chemotherapy and bevacizumab and warrants further evaluation in prospective studies.

Project description:BackgroundChemotherapy plus bevacizumab is a standard first-line treatment for unresectable metastatic colorectal cancer patients. Different chemotherapy backbones may be chosen, including one to three drugs, based on patients' general conditions and comorbidities, treatments' objectives, and disease characteristics. TRIBE trial demonstrated a significant advantage in terms of progression-free survival and overall survival for FOLFOXIRI plus bevacizumab as compared with FOLFIRI plus bevacizumab. Based on recent evidence, the de-intensification of the upfront regimen after 4-6 months of treatment is nowadays regarded as a valuable option. Moreover, the prolonged inhibition of angiogenesis, and in particular the continuation of bevacizumab beyond the evidence of disease progression, is an efficacious strategy in the treatment of metastatic colorectal cancer patients.Methods/designTRIBE-2 is a prospective, open-label, multicentric phase III randomized trial in which unresectable and previously untreated metastatic colorectal cancer patients are randomized to receive first-line FOLFOX plus bevacizumab followed by FOLFIRI plus bevacizumab after disease progression or FOLFOXIRI plus bevacizumab followed by the re-introduction of the same regimen after disease progression. The primary endpoint is to compare the efficacy of the two proposed treatment strategies in terms of Progression Free Survival 2.DiscussionThe TRIBE-2 study aims at answering the question whether the upfront use of FOLFOXIRI improves the clinical outcome of metastatic colorectal cancer patients, when compared with the pre-planned, sequential use of oxaliplatin-based and irinotecan-based doublets. Both proposed treatment strategies are designed to exploit the effectiveness of the prolonged inhibition of angiogenesis, alternating short (up to 4 months) induction periods and less intensive maintenance phases.Trial registrationTRIBE2 is registered at Clinicaltrials.gov: NCT02339116 . January 12, 2015. TRIBE-2 is registered at EUDRACT 2014-004436-19, October 10, 2014.

Project description:BackgroundColorectal cancer (CRC) is one of the most common cancers; ∼20% of patients have metastases at diagnosis, and 50%-60% subsequently develop metachronous metastases. Bone involvement, despite being rare, is usually associated with higher disease burden, worse prognosis, impaired quality of life, and significant health-related cost. In the last few years, following the positive results of the TRIBE and TRIBE2 trials, the association of FOLFOXIRI plus bevacizumab has become the new standard of care for metastatic CRC. Despite being highly efficacious in all subgroups, little is known about the activity of this regimen in patients with bone metastases.Patients and methodsWe carried out a pooled analysis of TRIBE and TRIBE2 studies focusing on patients with skeletal deposits.ResultsOur analyses on the whole population showed that patients with baseline bone involvement reported shorter overall survival [OS; 14.0 versus 26.2 months; hazard ratio (HR) 2.04, 95% confidence interval (CI) 1.46-2.87; P < 0.001] and progression-free survival (PFS; 6.2 versus 11.1 months; HR 1.96, 95% CI 1.42-2.69; P < 0.001) compared with those without bone metastases; no significant interaction with the treatment was reported for PFS (P = 0.094) and OS (P = 0.38). Bone metastases had a negative prognostic implication in the multivariate analysis (HR 2.24, 95% CI 1.54-3.26; P < 0.001). Furthermore, patients with bone lesions at first radiological progression (including those with baseline bone metastases) had a shorter OS compared with those who progressed in other sites (10.4 versus 13.2 months; HR 1.48, 95% CI 1.15-1.91; P = 0.002). A trend toward inferior OS (7.5 versus 11 months, HR 1.50, 95% CI 0.92-2.45; P = 0.10) appeared in patients with basal skeletal deposits compared with those with bone involvement at first radiological progression.ConclusionsOur study confirmed the negative prognostic impact of bone metastases in CRC. Furthermore, we demonstrated for the first time that the survival advantage of triplet chemotherapy plus bevacizumab is maintained even in this prognostically unfavorable subgroup.

Dataset Information

Treatments after progression to first-line FOLFOXIRI and bevacizumab in metastatic colorectal cancer: a pooled analysis of TRIBE and TRIBE2 studies by GONO.

Background

Methods

Results

Conclusions

Publications

Treatments after progression to first-line FOLFOXIRI and bevacizumab in metastatic colorectal cancer: a pooled analysis of TRIBE and TRIBE2 studies by GONO.

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