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Primary Tumor Sidedness Predicts Bevacizumab Benefit in Metastatic Colorectal Cancer Patients.

ABSTRACT: 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.

SUBMITTER: You XH

PROVIDER: S-EPMC6702298 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Primary Tumor Sidedness Predicts Bevacizumab Benefit in Metastatic Colorectal Cancer Patients.

You Xia-Hong XH Wen Can C Xia Zi-Jin ZJ Sun Fan F Li Yao Y Wang Wei W Fang Zhou Z Chen Qing-Gen QG Zhang Lei L Jiang Yu-Huang YH Wang Xiao-Zhong XZ Ying Hou-Qun HQ Zong Zhen Z

Frontiers in oncology 20190814

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 (<i>p</i> ...[more]

PMID: 31475100

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Project description:ImportanceBiologic therapy (BT) (eg, bevacizumab or cetuximab) is increasingly used to treat metastatic colorectal cancer (mCRC). Recent investigations have suggested that right- or left-sided primary tumor origin affects survival and response to BT.ObjectiveTo evaluate the association of tumor origin with mortality in a diverse population-based data set of patients receiving systemic chemotherapy (SC) and bevacizumab or cetuximab for mCRC.Design, setting, and participantsThis population-based nonconcurrent cohort study of statewide California Cancer Registry data included all patients aged 40 to 85 years diagnosed with mCRC and treated with SC only or SC plus bevacizumab or cetuximab from January 1, 2004, through December 31, 2014. Patients were stratified by tumor origin in the left vs right sides.InterventionsTreatment with SC or SC plus bevacizumab or cetuximab.Main outcomes and measuresMortality hazards by tumor origin (right vs left sides) were assessed for patients receiving SC alone or SC plus bevacizumab or cetuximab. Subgroup analysis for patients with wild-type KRAS tumors was also performed.ResultsA total of 11 905 patients with mCRC (6713 men [56.4%] and 5192 women [43.6%]; mean [SD] age, 60.0 [10.9] years) were eligible for the study. Among these, 4632 patients received SC and BT. Compared with SC alone, SC plus bevacizumab reduced mortality among patients with right- and left-sided mCRC, whereas SC plus cetuximab reduced mortality only among patients with left-sided tumors and was associated with significantly higher mortality for right-sided tumors (hazard ratio [HR], 1.31; 95% CI, 1.14-1.51; P < .001). Among patients treated with SC plus BT, right-sided tumor origin was associated with higher mortality among patients receiving bevacizumab (HR, 1.31; 95% CI, 1.25-1.36; P < .001) and cetuximab (HR, 1.88; 95% CI, 1.68-2.12; P < .001) BT, compared with left-sided tumor origin. In patients with wild-type KRAS tumors (n = 668), cetuximab was associated with reduced mortality among only patients with left-sided mCRC compared with bevacizumab (HR, 0.75; 95% CI, 0.63-0.90; P = .002), whereas patients with right-sided mCRC had more than double the mortality compared with those with left-sided mCRC (HR, 2.44; 95% CI, 1.83-3.25, P < .001).Conclusions and relevancePrimary tumor site is associated with response to BT in mCRC. Right-sided primary tumor location is associated with higher mortality regardless of BT type. In patients with wild-type KRAS tumors, treatment with cetuximab benefited only those with left-sided mCRC and was associated with significantly poorer survival among those with right-sided mCRC. Our results underscore the importance of stratification by tumor site for current treatment guidelines and future clinical trials.

Project description:Background: Colorectal cancer (CRC) has been reconsidered as a heterogeneous disease. Among advances of genomic analysis in CRC, the sidedness of tumors (left-sided colon vs. right-sided colon) and microsatellite instability (MSI)-high (H) tumors have been highlighted. Methods: We analyzed 153 CRC patients who were available for evaluation of MSI status and had been treated with cetuximab-containing chemotherapy between April 2008 and January 2013. KRAS mutational status was available in all 153 patients, but BRAF mutational status was only available in 72 patients (47.1%). We evaluated the impact of microsatellite instability status and location of the primary colon tumor on the effect of cetuximab-containing chemotherapy in patients with metastatic colorectal cancer. Results: MSI-H was detected in 3.9% of analyzed patients. Characteristics of patients, with the exception of BRAF mutational status, were generally similar between those with right and left-sided tumors. Right-sided tumors were significantly associated with a BRAF mutation (p=0.023). In addition, patient characteristics with an MSS tumor were not different from those with an MSI-H tumor. For all 153 patients, the most commonly used regimen that included cetuximab was irinotecan alone, irrespective of treatment line. There was no significant difference in treatment efficacy in either RR or disease control rate (DCR) between the MSI-H and MSS groups. There was also no difference in RR and DCR according to the location of the primary tumor (left side vs. right side). No significant difference in PFS was observed between the MSI-H and MSS groups (4.80 months vs. 5.80 months; p=0.238) or the left-side and right-side groups (6.10 months vs. 4.20 months; p=0.278). In a subgroup-analysis of 140 patients with wild-type KRAS, there was no difference in PFS following cetuximab-containing therapy based on MSI status or the location of the primary tumor. Conclusions: MSI status and the location of the primary tumor were not novel biomarkers for response to cetuximab-containing therapy in metastatic CRC. Further prospective validation of the prognostic or predictive capacity of MSI status and the sidedness of tumors is warranted.

Dataset Information

Primary Tumor Sidedness Predicts Bevacizumab Benefit in Metastatic Colorectal Cancer Patients.

Publications

Primary Tumor Sidedness Predicts Bevacizumab Benefit in Metastatic Colorectal Cancer Patients.

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