Impact of primary tumour location and RAS/BRAF mutational status in metastatic colorectal cancer treated with first-line regimens containing oxaliplatin and bevacizumab: Prognostic factors from the AIO KRK0207 first-line and maintenance therapy trial

Hegewisch‐Becker, Susanna; Nöpel-Dünnebacke, Stefanie; Hinke, Axel; Graeven, Ullrich; Reinacher‐Schick, Anke; Hertel, Jan; Lerchenmüller, Christian; Killing, B.; Depenbusch, Reinhard; Al‐Batran, Salah‐Eddin; Lange, Thoralf; Dietrich, Georg; Tannapfel, Andrea; Arnold, Dirk

doi:10.1016/j.ejca.2018.06.015

Cited by 21 publications

(15 citation statements)

References 23 publications

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“…The impact of primary tumor location on bevacizumab plus adjuvant chemotherapy in mCRC patients remains controversial (16, 18). In this study, we found that left-sided mCRC patients could benefit more from bevacizumab plus FOLFIRI compared with its counterpart.…”

Section: Discussionmentioning

confidence: 99%

Primary Tumor Sidedness Predicts Bevacizumab Benefit in Metastatic Colorectal Cancer Patients

et al. 2019

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The emerging debate between primary tumor location and clinical outcome of bevacizumab treated metastatic colorectal cancer (mCRC) continues. The aim of the present study is to investigate the association between the primary tumor location and clinical outcome of 115 mCRC patients receiving bevacizumab based treatment. A meta-analysis including 21 studies was carried out to confirm the conclusion. In our prospective study, we found that right-sided mCRC commonly occurred in older cases ( p = 0.03) with multiple-site metastasis ( p = 0.03). Progression-free survival (PFS) of the left-sided patients undergoing bevacizumab plus a FOLFIRI regimen was superior to the right-sided cases ( p = 0.03, crude HR = 0.31, 95%CI = 0.11–0.87; adjusted HR = 0.21, 95%CI = 0.06–0.66). The meta-analysis confirmed that efficacy of bevacizumab-based treatment in left-sided mCRC patients was better than the right-sided cases in the overall population ( P h = 0.24, combined OR = 1.36, 95%CI = 1.07–1.72), RAS / BRAF wild-type ( P h = 0.19, combined OR = 1.66, 95%CI = 1.17–2.34), clinical trial ( P h = 0.23, combined OR = 1.42, 95%CI = 1.07–1.88), Caucasian population ( P h = 0.18, combined OR = 1.37, 95%CI = 1.02–1.85) and first-line ( P h = 0.19, combined OR = 1.48, 95%CI = 1.13–1.96) subgroups. Improved survival of bevacizumab plus chemotherapy treated left-sided mCRC patients was observed in the overall population [ P h < 0.01, combined MSR = 1.09, 95%CI = 1.00–1.18 for PFS; P h < 0.01, combined MSR = 1.24, 95%CI = 1.13–1.36 for overall survival (OS)], especially in the RAS/BRAF wild-type ( P h = 0.09, combined MSR = 1.10, 95%CI = 1.03–1.19 for PFS; P h = 0.02, combined MSR = 1.34, 95%CI = 1.21–1.49 for OS). These findings indicate that primary tumor sidedness can predict clinical outcome of bevacizumab-treated RAS/BRAF wild-type mCRC patients and the left-sided patients may benefit more from bevacizumab plus FOLFIRI.

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Section: Discussionmentioning

confidence: 99%

Primary Tumor Sidedness Predicts Bevacizumab Benefit in Metastatic Colorectal Cancer Patients

et al. 2019

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“…Concerning maintenance therapy, our meta-analysis included only trials that compared bevacizumab or capecitabine plus bevacizumab to best supportive care (BSC). (Aparicio et al 2018;Goey et al 2017;Hegewisch-Becker et al 2015) A significant effect on overall survival was seen in neither RAS WT nor RAS MUT patients, while PFS trended to be improved in RAS WT mCRC. When stratified by substances, addition of anti angiogenic therapy alone did not improve outcome in the maintenance setting, while the combination of capecitabine and bevacizumab improved OS in patients with RAS wildtype tumors.…”

Section: Discussionmentioning

confidence: 99%

“…(Benvenuti et al 2007) Thus, RAS mutations were often associated with worse prognosis of mCRC-both due to different biology and due to lack of anti-EGFR targeted therapy. (Andreyev et al 2001(Andreyev et al , 1998Barault et al 2008;Cremolini et al 2015;Hegewisch-Becker et al 2018;Modest et al 2016;Richman et al 2009).…”

Section: Discussionmentioning

confidence: 99%

“…As EGF receptor inhibition is ineffective because of constitutive oncogenic signalling, (Benvenuti et al 2007) systemic treatment option in patients with a RAS MUT tumor currently include chemotherapy (fluoropyrimidines, 1 3 irinotecan, oxaliplatin) with or without anti angiogenic agents for two treatment lines, followed by later-line treatment such as trifluridine/tipiracil and regorafenib (Grothey et al 2013;Kubicka et al 2013;Van Cutsem et al 2018). For maintenance strategies following induction treatment, a combination of fluoropyrimidine and bevacizumab is usually recommended (Goey et al 2017;Hegewisch-Becker et al 2015;Van Cutsem et al 2016).…”

Section: Introductionmentioning

confidence: 99%

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Current treatment options in RAS mutant metastatic colorectal cancer patients: a meta-analysis of 14 randomized phase III trials

Stahler

Heinemann

Ricard

et al. 2020

J Cancer Res Clin Oncol

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Purpose Although biomarkers for patients with metastatic colorectal cancer exist, the benefit patients with RAS mutated tumors derive from established regimens is unclear. Methods Efficacy of therapeutic strategies available for RAS mutated patients (addition of chemotherapeutic agents and/or anti angiogenic agents) were investigated in fourteen randomized controlled phase III trials at trial level by meta-analysing individual study hazard ratios and 95% confidence intervals (95% CI) for overall survival (OS) and progression free survival (PFS). Results 6810 of 10,748 patients (63.3%) were available (48.5% RAS wildtype, 51.5% RAS mutated). Across all treatment lines, additional treatment efficacy (chemotherapy and/or anti angiogenic agents) was significantly smaller in RAS mutated compared to wildtype tumors for OS and PFS. In detail, patients with RAS mutated metastatic colorectal cancer derived significant benefit in PFS but not in OS by the addition of either chemotherapy or anti angiogenic agents to the respective comparator. In patients with RAS wildtype metastatic colorectal cancer, PFS and OS were improved by the addition of chemotherapy or anti angiogenic agent. Conclusion The therapeutic benefit of additional substances is less distinct in patients with RAS mutated as compared to RAS wildtype metastatic colorectal cancer, especially with regard to OS.

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“…Further, since RAS is mutated (RAS mt) in about 55% of the mCRC cases, these patients need to be treated with bevacizumab 26 . However, the majority of recently published studies with randomised trials have focused on the RAS wt subpopulation alone; hence, data on treatment with bevacizumab for RAS mt mCRC involving the two primary tumour locations are limited 16,27,28 . Moreover, while several clinical studies have suggested that the tumour location does not predict benefit from bevacizumab treatment in patients with mCRC harbouring KRAS wt 16,29 and undetermined RAS status 30 , other reports indicate better outcomes in left-than right-sided mCRC, with unselected RAS status, treated with bevacizumab 13,17,30 .…”

Section: Discussionmentioning

confidence: 99%

Clinical impact of primary tumour location, early tumour shrinkage, and depth of response in the treatment of metastatic colorectal cancer with first-line chemotherapy plus cetuximab or bevacizumab

Sagawa¹,

Sato

Hirakawa³

et al. 2020

Sci Rep

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The primary tumour location is an important prognostic factor for previously untreated metastatic colorectal cancer (mCRC). However, the predictive efficacies of primary tumour location, early tumour shrinkage (ETS), and depth of response (DpR) on mCRC treatment has not been fully evaluated. This study aimed to investigate the predictive efficacies of these traits in mCRC patients treated with first-line 5-fluorouracil-based chemotherapy plus biologic agents, namely, cetuximab and bevacizumab. This was a retrospective analysis of the medical records of 110 patients with pathology-documented unresectable mCRC. Patients with left-sided mCRC receiving any first-line regimen showed better overall survival (OS) than those with right-sided mCRC [33.3 vs 16.3 months; hazard ratio (HR) 0.44; 95% confidence interval (CI) 0.27–0.74; p < 0.001]. In patients with left-sided tumours, treatment with chemotherapy plus cetuximab yielded longer OS than chemotherapy plus bevacizumab (50.6 vs 27.8 months, HR 0.55; 95% CI 0.32–0.97; p = 0.0378). mCRC patients with ETS and high DpR showed better OS than those lacking ETS and with low DpR (33.5 vs 19.6 months, HR 0.50, 95% CI 0.32–0.79, p = 0.023 and 38.3 vs 19.0 months, HR 0.43, 95% CI 0.28–0.68, p < 0.001, respectively). Moreover, ETS and/or high DpR achieved in patients with right-sided mCRC receiving chemotherapy plus cetuximab were associated with significantly better OS than in those lacking ETS and with low DpR (34.3 vs 10.4 months, HR 0.19, 95% CI 0.04–0.94, p = 0.025 and 34.3 vs 10.4 months, HR 0.19, 95% CI 0.04–0.94, p = 0.0257, respectively). Taken together, our study demonstrates that primary tumour location is not only a well-known prognostic factor but also a relevant predictive factor in patients with mCRC receiving chemotherapy plus cetuximab. Additionally, both ETS and DpR could predict treatment outcomes and also potentially guide cetuximab treatment even in right-sided mCRCs.

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Impact of primary tumour location and RAS/BRAF mutational status in metastatic colorectal cancer treated with first-line regimens containing oxaliplatin and bevacizumab: Prognostic factors from the AIO KRK0207 first-line and maintenance therapy trial

Cited by 21 publications

References 23 publications

Primary Tumor Sidedness Predicts Bevacizumab Benefit in Metastatic Colorectal Cancer Patients

Primary Tumor Sidedness Predicts Bevacizumab Benefit in Metastatic Colorectal Cancer Patients

Current treatment options in RAS mutant metastatic colorectal cancer patients: a meta-analysis of 14 randomized phase III trials

Clinical impact of primary tumour location, early tumour shrinkage, and depth of response in the treatment of metastatic colorectal cancer with first-line chemotherapy plus cetuximab or bevacizumab

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