Cetuximab plus FOLFOX6 or FOLFIRI in metastatic colorectal cancer: CECOG trial

Ocvirk, Janja; Brodowicz, Thomas; Wrba, Fritz; Ciuleanu, Tudor-Eliade; Kurteva, G.; Beslija, S.; Koza, I; Pápai, Zsuzsanna; Messinger, Diethelm; Yılmaz, Uğur; Faluhelyi, Zsolt; Yalçın, Şuayib; Papamichael, Demetris; Wenczl, M.; Mrsic-Krmpotic, Zrinka; Shacham‐Shmueli, Einat; Vrbanec, Damir; Esser, Regina; Scheithauer, Werner; Zielinski, Christoph

doi:10.3748/wjg.v16.i25.3133

Cited by 94 publications

(66 citation statements)

References 33 publications

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“…Our findings may be explained by divergent results obtained for different fluoropyrimidine backbones. Among the available trials, 4 used infusional 5-FU regimens (77)(78)(79)(80), whereas other 3 used either capecitabine or bolus 5-FU as their chemotherapy backbone (81)(82)(83). An interaction between anti-EGFR agents and the mode of fluoropyrimidine application (oral vs. infusional) is currently discussed (84).…”

Section: Discussionmentioning

confidence: 99%

Progression-Free Survival as a Surrogate Endpoint for Median Overall Survival in Metastatic Colorectal Cancer: Literature-Based Analysis from 50 Randomized First-Line Trials

Gießen

Laubender

Ankerst

et al. 2013

Clinical Cancer Research

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Purpose: To evaluate progression-free survival (PFS) as a potential surrogate endpoint (SEP) for overall survival (OS) in metastatic colorectal cancer (mCRC) with a focus on applicability to trials containing targeted therapy with anti-VEGF-or anti-EGF receptor (EGFR)-directed monoclonal antibodies.Experimental Design: A systematic literature search of randomized trials of first-line chemotherapy for mCRC reported from January 2000 to January 2012 was conducted. Adjusted weighted linear regression was used to calculate correlations within PFS and OS (endpoints; R EP ) and between treatment effects on PFS and on OS (treatment effects; R TE ).Results: Fifty trials reflecting 22,736 patients met the inclusion criteria. Correlation between treatment effects on PFS and OS and between the endpoints PFS and OS was high across all studies (R TE ¼ 0.87, R EP ¼ 0.86). This was also observed in chemotherapy-only trials (R TE ¼ 0.93, R EP ¼ 0.81) but less so for trials containing monoclonal antibodies (R TE ¼ 0.47; R EP ¼ 0.52). Limiting the analysis to bevacizumab-based studies (11 trials, 3,310 patients) again yielded high correlations between treatment effects on PFS and on OS (R TE ¼ 0.84), whereas correlation within PFS and OS was low (R EP ¼ 0.45). In 7 trials (1,335 patients) investigating cetuximab-or panitumumab-based studies, contrasting correlations with very wide confidence intervals were observed (R TE ¼ 0.28; R EP ¼ 0.96).Conclusions: PFS showed consistently high correlation with OS of an order that would justify its use as an SEP in chemotherapy regimens. For validation of surrogacy in anti-VEGF and anti-EGFR-directed therapies, further research and a larger set of trials is needed.

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Section: Discussionmentioning

confidence: 99%

Progression-Free Survival as a Surrogate Endpoint for Median Overall Survival in Metastatic Colorectal Cancer: Literature-Based Analysis from 50 Randomized First-Line Trials

Gießen

Laubender

Ankerst

et al. 2013

Clinical Cancer Research

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“…Cetuximab and panitumumab, two monoclonal antibodies, which neutralize the extracellular domain of EGFR, have demonstrated effectiveness in terms of both response and survival when used as first, second or thirdline chemotherapy. Although anti-EGFR agents are routinely used in clinical practice, their use is limited to 60% of patients who have KRAS wild-type tumors (2) because randomized-controlled studies have shown activating mutations of this oncogene were predictive of resistance to these agents (3)(4)(5)(6)(7)(8)(9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Hsa-miR-31-3p Expression Is Linked to Progression-free Survival in Patients with KRAS Wild-type Metastatic Colorectal Cancer Treated with Anti-EGFR Therapy

Manceau

Imbeaud

Thiébaut

et al. 2014

Clinical Cancer Research

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Purpose: To identify microRNAs (miRNA) that predict response to anti-EGFR antibodies in patients with wild-type KRAS metastatic colorectal cancer (mCRC).Experimental Design: miRNA profiling was performed in a training set of 87 patients with mCRC refractory to chemotherapy treated with anti-EGFR antibodies. This included 33 fresh-frozen (FF) and 35 formalin-fixed paraffin-embedded (FFPE) samples retrospectively collected and 19 prospectively collected FF samples. An independent validation cohort consisting of 19 FF and 26 FFPE prospectively collected samples from patients with mCRC treated with anti-EGFR antibodies was used to confirm our findings.Results: After screening the expression of 1,145 miRNAs in FF samples from the training set, we identified that hsa-miR-31-3p expression level was significantly associated with progression-free survival (PFS). Statistical models based on miRNA expression discriminated between high and low risk of progression for both FF and FFPE samples. These models were confirmed in the validation cohort for both FF [HR, 4.1; 95% confidence interval (CI), 1.1-15.3; P < 0.04] and FFPE samples (HR, 2.44; 95% CI, 1.1-5.4; P ¼ 0.028). The percentage of variation of RECIST criteria in the validation series was significantly associated with the expression level of hsa-miR-31-3p (r 2 ¼ 0.49; P ¼ 0.0035) and risk status determined by hsa-miR-31-3p expression level (P ¼ 0.02, Kruskal-Wallis rank test). Nomograms were built and validated to predict PFSdepending on hsa-miR-31-3p expression level. Following in vitro studies, we identified 47 genes regulated by hsa-miR-31-3p. Conclusion: Hsa-miR-31-3p seems to be a new mCRC biomarker whose expression level allows for the identification of patients with wild-type KRAS mCRC who are more likely to respond to anti-EGFR therapy.

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“…Despite recent advances in the development of various diagnostic tools, in many patients, colorectal cancer is still diagnosed at an advanced stage, and recurrent tumors are often detected even after curative surgery. On the other hand, new chemotherapeutic regimens such as FOLFOX, FOLFIRI, and XELOX have been developed to exert a more potent activity 3, 4, 5, 6. More recently, molecular targeted therapies such as tyrosine kinase inhibitors and monoclonal antibodies have been shown to enhance tumor regression in combination with chemotherapy 7, 8…”

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confidence: 99%

Combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of KRAS status

Kato

Futamura

Kanematsu

et al. 2015

Intl Journal of Cancer

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Targeted molecular therapy is an effective anticancer strategy. Anti‐EGFR monoclonal antibodies such as cetuximab (CTX) have been approved for the treatment of various malignancies, including colorectal cancer (CRC) with wild‐type KRAS. However, their efficacy in patients with KRAS mutations has not been established. Therefore, we investigated whether CTX treatment was effective as a single agent or in combination with zoledronic acid (ZOL) in human CRC cell lines with different KRAS status. CRC cell lines SW48 (wild‐type KRAS) and LS174T (mutant KRAS) were treated with ZOL, CTX and a combination of both drugs. Cytotoxicity was measured using the MTT assay. Changes in the levels of intracellular signaling proteins were evaluated using western blot analysis. Finally, we evaluated the efficacy of the combination treatment in an in vivo xenograft model. We observed that ZOL apparently inhibited growth in both cell lines, whereas CTX showed little effect. ZOL also increased the levels of unprenylated RAS. Combined ZOL and CTX treatment was synergistic in both cell lines and was associated with inhibition of the RAS‐MAPK and AKT‐mTOR signaling pathways. Furthermore, the combination treatment was more effective in suppressing the growth of xenografts derived from both SW48 and LS174T cells; this effect was associated with increased apoptosis. These results demonstrate that ZOL inhibits the growth of colon cancer cells regardless of KRAS status, and combination therapy using ZOL and CTX enhances this growth suppression. These findings suggest a novel strategy for the treatment of CRC independent of KRAS mutational status.

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Cetuximab plus FOLFOX6 or FOLFIRI in metastatic colorectal cancer: CECOG trial

Abstract: This study confirms that combinations of cetuximab with FOLFOX6 or FOLFIRI are effective and significantly improve clinical outcome in KRAS wild-type compared with KRAS mutated mCRC.

Cited by 94 publications

References 33 publications

Progression-Free Survival as a Surrogate Endpoint for Median Overall Survival in Metastatic Colorectal Cancer: Literature-Based Analysis from 50 Randomized First-Line Trials

Progression-Free Survival as a Surrogate Endpoint for Median Overall Survival in Metastatic Colorectal Cancer: Literature-Based Analysis from 50 Randomized First-Line Trials

Hsa-miR-31-3p Expression Is Linked to Progression-free Survival in Patients with KRAS Wild-type Metastatic Colorectal Cancer Treated with Anti-EGFR Therapy

Combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of KRAS status

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