Randomized Phase III Study of Capecitabine Plus Oxaliplatin Compared With Fluorouracil/Folinic Acid Plus Oxaliplatin As First-Line Therapy for Metastatic Colorectal Cancer

PurposeTo evaluate whether capecitabine plus oxaliplatin (XELOX) is noninferior to fluorouracil. folinic acid, and oxaliplatin (FOLFOX-4) as first-line therapy in metastatic colorectal cancer (MCRC).Patients and MethodsThe initial design of this trial was a randomized, two-arm, noninferiority, phase III comparison of XELOX versus FOLFOX-4. After patient accrual had begun, the trial design was amended in 2003 after bevacizumab phase III data became available. The resulting 2 × 2 factorial design randomly assigned patients to XELOX versus FOLFOX-4, and then to also receive either bevacizumab or placebo. We report here the results of the analysis of the XELOX versus FOLFOX-4 arms. The analysis of bevacizumab versus placebo with oxaliplatin-based chemotherapy is reported separately. The prespecified primary end point for the noninferiority analysis was progression-free survival.ResultsThe intent-to-treat population comprised 634 patients from the original two-arm portion of the study, plus an additional 1,400 patients after the start of the amended 2 × 2 design, for a total of 2,034 patients. The median PFS was 8.0 months in the pooled XELOX-containing arms versus 8.5 months in the FOLFOX-4–containing arms (hazard ratio [HR], 1.04; 97.5% CI, 0.93 to 1.16). The median overall survival was 19.8 months with XELOX versus 19.6 months with FOLFOX-4 (HR, 0.99; 97.5% CI, 0.88 to 1.12). FOLFOX-4 was associated with more grade 3/4 neutropenia/granulocytopenia and febrile neutropenia than XELOX, and XELOX with more grade 3 diarrhea and grade 3 hand-foot syndrome than FOLFOX-4.ConclusionXELOX is noninferior to FOLFOX-4 as a first-line treatment for MCRC, and may be considered as a routine treatment option for appropriate patients.

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FOLFIRI Followed by FOLFOX6 or the Reverse Sequence in Advanced Colorectal Cancer: A Randomized GERCOR Study

Journal of Clinical Oncology ◽

10.1200/jco.2004.05.113 ◽

2004 ◽

Vol 22 (2) ◽

pp. 229-237 ◽

Cited By ~ 2048

Author(s):

Christophe Tournigand ◽

Thierry André ◽

Emmanuel Achille ◽

Gérard Lledo ◽

Michel Flesh ◽

...

Keyword(s):

Colorectal Cancer ◽

Folinic Acid ◽

Progression Free Survival ◽

Similar Efficacy ◽

Phase Iii ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Phase Iii Study ◽

Grade 3

Purpose In metastatic colorectal cancer, phase III studies have demonstrated the superiority of fluorouracil (FU) with leucovorin (LV) in combination with irinotecan or oxaliplatin over FU + LV alone. This phase III study investigated two sequences: folinic acid, FU, and irinotecan (FOLFIRI) followed by folinic acid, FU, and oxaliplatin (FOLFOX6; arm A), and FOLFOX6 followed by FOLFIRI (arm B). Patients and Methods Previously untreated patients with assessable disease were randomly assigned to receive a 2-hour infusion of l-LV 200 mg/m2 or dl-LV 400 mg/m2 followed by a FU bolus 400 mg/m2 and 46-hour infusion 2,400 to 3,000 mg/m2 every 46 hours every 2 weeks, either with irinotecan 180 mg/m2 or with oxaliplatin 100 mg/m2 as a 2-hour infusion on day 1. At progression, irinotecan was replaced by oxaliplatin (arm A), or oxaliplatin by irinotecan (arm B). Results Median survival was 21.5 months in 109 patients allocated to FOLFIRI then FOLFOX6 versus 20.6 months in 111 patients allocated to FOLFOX6 then FOLFIRI (P = .99). Median second progression-free survival (PFS) was 14.2 months in arm A versus 10.9 in arm B (P = .64). In first-line therapy, FOLFIRI achieved 56% response rate (RR) and 8.5 months median PFS, versus FOLFOX6 which achieved 54% RR and 8.0 months median PFS (P = .26). Second-line FOLFIRI achieved 4% RR and 2.5 months median PFS, versus FOLFOX6 which achieved 15% RR and 4.2 months PFS. In first-line therapy, National Cancer Institute Common Toxicity Criteria grade 3/4 mucositis, nausea/vomiting, and grade 2 alopecia were more frequent with FOLFIRI, and grade 3/4 neutropenia and neurosensory toxicity were more frequent with FOLFOX6. Conclusion Both sequences achieved a prolonged survival and similar efficacy. The toxicity profiles were different.

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FOLFOXIRI plus bevacizumab versus FOLFOX plus bevacizumab for patients with metastatic colorectal cancer and ≥3 circulating tumour cells: the randomised phase III VISNÚ-1 trial

ESMO Open ◽

10.1136/esmoopen-2020-000944 ◽

2020 ◽

Vol 5 (6) ◽

pp. e000944 ◽

Cited By ~ 1

Author(s):

Enrique Aranda ◽

Jose Maria Viéitez ◽

Auxiliadora Gómez-España ◽

Silvia Gil Calle ◽

Antonieta Salud-Salvia ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Predictive Biomarkers ◽

Progression Free Survival ◽

Phase Iii ◽

First Line ◽

Open Label ◽

Intention To Treat ◽

First Line Therapy ◽

Line Therapy

Purpose5-Fluorouracil/leucovorin, oxaliplatin, irinotecan (FOLFOXIRI) plus bevacizumab is more effective than doublets plus bevacizumab as first-line therapy for metastatic colorectal cancer, but is not widely used because of concerns about toxicity and lack of predictive biomarkers. This study was designed to explore the role of circulating tumour cell (CTC) count as a biomarker to select patients for therapy with FOLFOXIRI-bevacizumab.Patients and methodsVISNÚ-1 was a multicentre, open-label, randomised, phase III study in patients with previously untreated, unresectable, metastatic colorectal carcinoma and ≥3 CTC/7.5 mL blood. Patients received bevacizumab 5 mg/kg plus FOLFOXIRI (irinotecan 165 mg/m2, oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 and 5-fluorouracil 3200 mg/m2) or FOLFOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil 400 mg/m2 then 2400 mg/m2) by intravenous administration every 2 weeks. The primary outcome was progression-free survival (PFS).ResultsThe intention-to-treat population comprised 349 patients (FOLFOXIRI-bevacizumab, n=172; FOLFOX-bevacizumab, n=177). Median PFS was 12.4 months (95% CI 11.2 to 14.0) with FOLFOXIRI bevacizumab and 9.3 months (95% CI 8.5 to 10.7) with FOLFOX-bevacizumab (stratified HR, 0.64; 95% CI 0.49 to 0.82; p=0.0006). Grade≥3 adverse events were more common with FOLFOXIRI-bevacizumab 85.3% vs 75.1% with FOLFOX-bevacizumab (p=0.0178). Treatment-related deaths occurred in 8 (4.7%) and 6 (3.4%) patients, respectively.ConclusionsFirst-line FOLFOXIRI-bevacizumab significantly improved PFS compared with FOLFOX-bevacizumab in patients with metastatic colorectal cancer and ≥3 CTCs at baseline, which indicate a poor prognosis. CTC count may be a useful non-invasive biomarker to assist with the selection of patients for intensive first-line therapy.

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A phase II study of oxaliplatin (OX), capecitabine (CAP), and bevacizumab (BV) in the treatment of metastatic colorectal cancer

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.3541 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 3541-3541 ◽

Cited By ~ 1

Author(s):

J. C. Bendell ◽

N. Fernando ◽

M. Morse ◽

G. Blobe ◽

D. Yu ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Infusion Pump ◽

Progression Free Survival ◽

First Line ◽

Intention To Treat ◽

First Line Therapy ◽

Hand Foot Syndrome ◽

Grade 3 ◽

Endothelial Growth Factor

3541 Background: BV, a monoclonal antibody against vascular endothelial growth factor, provides a survival advantage when added to first line therapy for metastatic colorectal cancer. CAP allows for fluoropyrimide treatment without the inconvenience of an infusion pump. We aimed to investigate the combination of OX, CAP, and BV (XeloxA) as a more convenient and active regimen. Methods: Pts with untreated metastatic colorectal cancer received OX 85 mg/m2 d1, CAP 1000 mg/m2 BID d1–5 and 8–12, and BV 10 mg/kg d1. Cycles were repeated every two weeks. The starting dose of CAP was changed to 850 mg/m2 BID due to toxicity in the first 28 patients. Data were analyzed under an intention to treat method. Results: 50 pts received therapy (28M, 22F), median age 55 (range 24–81). Data were available on 49 pts. The most common toxicity was diarrhea, with 12/49 (24%) having grade 3 diarrhea, and 22% with grade 2. After the dose reduction of CAP, 3/21 (14%) pts had grade 3 diarrhea and 2/21 (10%) with grade 2 as compared to 32% grade 3 and 32% grade 2 at the higher dose. At the higher dose of CAP 4% of pts had grade 3 hand-foot syndrome (HFS) and 39% had grade 2. At the lower dose, 10% had grade 3 and 5% had grade 2. Other grade 3 toxicities were minimal, including neurotoxicity (8%), vomiting (6%), and neutropenia (4%). There were 23 responses, 1 CR and 22 PR (RR=47%; 95% CI: 33%-62%). 21 pts had stable disease (43%). Median progression free survival (PFS) was 10.7 months (95% CI: 8.6–13.6). Conclusions: XeloxA is a well tolerated, active regimen in the first line treatment of metastatic colorectal cancer. RR and PFS data approximate that of infusional 5-FU regimens in combination with BV without the necessity of an infusion pump. [Table: see text]

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Protocol of the EFFORT study: a prospective study of FOLFIRI plus aflibercept as second-line treatment after progression on FOLFOXIRI plus bevacizumab or during maintenance treatment in patients with unresectable/metastatic colorectal cancer

BMC Cancer ◽

10.1186/s12885-020-07576-9 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Hironaga Satake ◽

Koji Ando ◽

Eiji Oki ◽

Mototsugu Shimokawa ◽

Akitaka Makiyama ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Phase Ii Study ◽

Progression Free Survival ◽

Second Line ◽

First Line ◽

Second Line Therapy ◽

Free Survival ◽

First Line Therapy ◽

Line Therapy

Abstract Background FOLFOXIRI plus bevacizumab is used as a first-line therapy for patients with unresectable or metastatic colorectal cancer. However, there are no clear recommendations for second-line therapy after FOLFOXIRI plus bevacizumab combination. Here, we describe our planning for the EFFORT study to investigate whether FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for mCRC. Methods EFFORT is an open-label, multicenter, single arm phase II study to evaluate whether a FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for mCRC. Patients with unresectable or metastatic colorectal cancer who received FOLFOXIRI plus bevacizumab as a first-line therapy will receive aflibercept and FOLFIRI (aflibercept 4 mg/kg, irinotecan 150 mg/m2 IV over 90 min, with levofolinate 200 mg/m2 IV over 2 h, followed by fluorouracil 400 mg/m2 bolus and fluorouracil 2400 mg/m2 continuous infusion over 46 h) every 2 weeks on day 1 of each cycle. The primary endpoint is progression-free survival (PFS). To achieve 80% power to show a significant response benefit with a one-sided alpha level of 0.10, assuming a threshold progression-free survival of 3 months and an expected value of at least 5.4 months, we estimated that 32 patients are necessary. Secondary endpoints include overall survival, overall response rate, safety, and exploratory biomarker analysis for differentiating anti-VEGF drug in 2nd-line chemotherapy for unresectable or metastatic colorectal cancer. Discussion This is the first study to investigate whether FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for unresectable or metastatic colorectal cancer. Switching to a different type of anti-VEGF drug in second-line therapy after FOLFOXIRI plus bevacizumab appears to be an attractive treatment strategy when considering survival benefit. It is expected that this phase II study will prove the efficacy of this strategy and that a biomarker for drug selection will be discovered. Trial registration Japan Registry of Clinical Trials jRCTs071190003. Registered April 18, 2019.

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Response-Independent Survival Benefit in Metastatic Colorectal Cancer: A Comparative Analysis of N9741 and AVF2107

Journal of Clinical Oncology ◽

10.1200/jco.2007.13.8099 ◽

2008 ◽

Vol 26 (2) ◽

pp. 183-189 ◽

Cited By ~ 124

Author(s):

Axel Grothey ◽

Eric E. Hedrick ◽

Robert D. Mass ◽

Somnath Sarkar ◽

Sam Suzuki ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Survival Benefit ◽

Tumor Response ◽

Objective Response ◽

Progression Free Survival ◽

Phase Iii ◽

First Line ◽

First Line Therapy ◽

Phase Iii Study

PurposeIn the phase III study AVF2107g, bevacizumab (BV) demonstrated a survival benefit when added to irinotecan, fluorouracil, and leucovorin (IFL) in first-line metastatic colorectal cancer (mCRC). In a parallel phase III study, Intergroup N9741, oxaliplatin plus fluorouracil and leucovorin (FOLFOX) also demonstrated a survival benefit compared with IFL. As these two superior therapies have differing mechanisms of action, we explored whether the improved survival associated with the superior therapy was dependent on tumor response.Patients and MethodsFor these retrospective, exploratory analyses, patients were defined as responders or nonresponders by whether complete or partial response was achieved with first-line therapy.ResultsCompared with IFL alone, BV plus IFL and FOLFOX each demonstrated statistically significant improvements in progression-free survival (PFS) and overall survival (OS) regardless of objective tumor response. BV-treated nonresponders had a hazard ratio (HR) of 0.63 (P = .0001) for PFS and 0.76 (P = .0188) for OS compared with IFL-treated nonresponders. FOLFOX-treated nonresponders had an HR of 0.75 (P = .0029) for PFS and 0.74 (P = .0030) for OS compared with IFL-treated nonresponders.ConclusionIn both AVF2107g and N9741, objective response did not predict the magnitude of PFS or OS benefit from the superior therapy; nonresponders, despite a poorer prognosis than responders, achieved extended PFS and OS from BV plus IFL or FOLFOX compared with IFL. On the basis of these data, tumor response in metastatic colorectal cancer is not a necessary factor for a therapy to provide benefit to an individual patient.

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Genome Wide Association Study for Predictors of Progression Free Survival in Patients on Capecitabine, Oxaliplatin, Bevacizumab and Cetuximab in First-Line Therapy of Metastatic Colorectal Cancer

PLoS ONE ◽

10.1371/journal.pone.0131091 ◽

2015 ◽

Vol 10 (7) ◽

pp. e0131091 ◽

Cited By ~ 6

Author(s):

Jan Pander ◽

Lieke van Huis-Tanja ◽

Stefan Böhringer ◽

Tahar van der Straaten ◽

Hans Gelderblom ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Genome Wide Association Study ◽

Progression Free Survival ◽

Genome Wide Association ◽

First Line ◽

Free Survival ◽

First Line Therapy ◽

Line Therapy ◽

Genome Wide

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Comparison between the three oxaliplatin-based regimens with bevacizumab in patients with metastatic colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.687 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 687-687

Author(s):

Yoshihito Ohhara ◽

Mitsukuni Suenaga ◽

Satoshi Matsusaka ◽

Eiji Shinozaki ◽

Nobuyuki Mizunuma ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Progression Free Survival ◽

Line Treatment ◽

First Line ◽

Kaplan Meier ◽

Hand Foot Syndrome ◽

Chemotherapeutic Treatment ◽

Grade 3 ◽

First Line Treatment

687 Background: XELOX (capecitabine/L-OHP) therapy that includes orally administered ﬂuoropyrimidine instead of infusional fluorouracil (5-FU) was approved for metastatic colorectal cancer (mCRC) in Sep 2009 in Japan. A pivotal trial (NO16966 study) demonstrated the non-inferiority of XELOX to FOLFOX (5-FU/L-OHP/LV) and the superiority of those L-OHP-based regimens plus bevacizumab (BV) to those without in the first-line treatment of mCRC. We evaluated the safety and efficacy of XELO+BV compared with FOLFOX4 or mFOLFOX6 plus BV in the first-line treatment for mCRC patients at a single institute. Methods: Between Jun 2007 and Nov 2008, 85 patients received FOLFOX4+BV (FF4 arm), between Dec 2008 and Sep 2009, 40 patients received mFOLFOX6+BV (FF6 arm), and between Oct 2009 and Sep 2010, 60 patients received XELOX+BV (XELOX arm). The best overall responses were evaluated using RECIST 1.0 during chemotherapeutic treatment, and adverse events were graded according to CTCAE ver.3.0. Progression-free survival (PFS) was estimated by Kaplan-Meier methods. Results: Characteristics of patients of FF4 arm, FF6 arm, and XELOX arm were below: median age, 60 yr vs. 62 yr vs. 60.5 yr; gender (male), 48.2 % vs. 62.5 % vs. 58.3%. The overall response rates (CR+PR) were 61.1 %, 72.5 %, and 75 % (95% CI; 50.6-71.8%, 58.0-87.0%, and 63.7-86.3%). Median PFS were 17.0 months, 15.5 months, and 14.4 months, respectively (cut-off: Aug 31, 2011). There were no statistical significances not only between FF4 arm and FF6 arm (log-rank; p=0.641), but also between XELOX arm and FF4+FF6 (FOLFOX) arm (log-rank; p=0.138). FOLFOX arm was associated with higher incidence of grade 3/4 neutropenia than XELOX arm. Grade3 diarrhea and hand-foot syndrome (HFS) were more frequent in XELOX arm. Conclusions: This study suggests that XELOX arm was equal to FOLFOX arm, regardless of regimen, in tumor response and PFS. Further follow-up is necessary to confirm the benefit on survival.

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