Published online September 20, 2017 by JAMA Surgery Association of Primary Tumor Site with Mortality in Patients Receiving Bevacizumab and Cetuximab for Metastatic Colorectal Cancer Mayada Aljehani, DrPH Published online September 20, 2017 by JAMA Surgery

Introduction/ Background 4/8/2019 OUTLINE Conclusions Limitations Discussion Results Methods Introduction/ Background

4/8/2019 BACKGROUND Colorectal Cancer (CRC) is the 2nd leading cause of cancer deaths in U.S. About 20% of CRCs are stage IV at diagnosis (mCRC), predicting poor survival Treatment of mCRC includes systemic chemotherapy (SC) that recently is sometimes accompanied by targeted biologic therapy Biologic therapies anti-VEGF monoclonal antibodies such as bevacizumab and anti-EGFR monoclonal antibodies such as cetuximab are increasingly used to treat metastatic colorectal cancer (mCRC) Recent investigations have shown that primary tumor location as right or left impacts response to biologic therapy and survival in metastatic colorectal cancer Current NCCN recommendations do not differentiate between right and left mCRC Sources: Tejpar, et al. JAMA Oncol. 2017;3(2):194-201.

TARGETED BIOLOGIC THERAPY FOR mCRC The two most frequently used targeted biologic therapies for mCRC are two monoclonal antibodies Bevacizumab Vascular endothelial growth factor (VEGF) inhibitor Cetuximab Epidermal growth factor (EGFR) inhibitor

ANATOMIC SUBSITE (Location) Right colon Left colon ~45% ~55%

4/8/2019 BACKGROUND Recent clinical trial showed better survival for left-sided mCRC treated with SC + biologic therapy, relative to right-sided malignancies These findings have been challenged because of the highly select characteristics of patients in clinical trials that limit generalizability of findings Biologic therapies anti-VEGF monoclonal antibodies such as bevacizumab and anti-EGFR monoclonal antibodies such as cetuximab are increasingly used to treat metastatic colorectal cancer (mCRC) Recent investigations have shown that primary tumor location as right or left impacts response to biologic therapy and survival in metastatic colorectal cancer Current NCCN recommendations do not differentiate between right and left mCRC Sources: Tejpar, et al. JAMA Oncol. 2017;3(2):194-201.

4/8/2019 BACKGROUND Survival benefits from biologic therapy for mCRC influenced by tumor location (right vs. left) remains uncertain Current National Comprehensive Cancer Network (NCCN) treatment recommendations for mCRC are incomplete Biologic therapies anti-VEGF monoclonal antibodies such as bevacizumab and anti-EGFR monoclonal antibodies such as cetuximab are increasingly used to treat metastatic colorectal cancer (mCRC) Recent investigations have shown that primary tumor location as right or left impacts response to biologic therapy and survival in metastatic colorectal cancer Current NCCN recommendations do not differentiate between right and left mCRC

4/8/2019 OBJECTIVE To evaluate the impact of primary tumor location on mortality in a diverse population-based dataset among patients with mCRC receiving systemic chemotherapy and bevacizumab or cetuximab Our objective was to evaluate the impact of primary tumor location on mortality in a diverse population-based dataset among patients with metastatic colorectal cancer receiving systemic chemotherapy and either bevacizumab or cetuximab

4/8/2019 METHODS Retrospective review of statewide California Cancer Registry data Between 2004-2014 Stage IV colorectal adenocarcinoma Patients ages 40-85 that received systemic chemotherapy (SC) alone or SC and bevacizumab or cetuximab Single primary tumor classifiable as right (appendix to transverse colon) or left (splenic flexure to rectum) We performed a retrospective review of statewide California cancer registry data between 2004-2014 among patients with Stage IV colorectal adenocarcinoma. We included patients ages 40-85 that received systemic chemotherapy alone or systemic chemotherapy and either cetuximab or bevacizumab who also had a single primary tumor classifiable as right (defined as appendix to transverse colon) or left (defined as splenic flexure to rectum) Bevacizumab and cetuximab were selected as they are the most common monoclonal antibodies used in treatment for metastatic colorectal cancer.

OUTCOMES & COVARIATES Overall Survival: Time from date of diagnosis to death or to last date of study follow-up (December 31, 2014) Covariates: Adjusted for age, year of diagnosis, and SES as well as signet ring and mucinous histologies

STATISTICAL ANALYSES Univariable: Counts & percentages χ2 tests Median follow-up & survival: Kaplan-Meier Log-rank tests Multivariable: Propensity score weighting Cox regression Purposeful variable selection

STATISTICAL ANALYSES Subgroup Analyses: KRAS status wild-type patients diagnosed 2010-2014 Proportionality Assumption: Log-log plot Schoenfield’s residual correlation Significance level: Two sided α=0.05 (95%CI)

4/8/2019

DISCUSSION Survival differences for mCRC by location and biologic therapy type, like previous clinical trials, validating our findings and adding generalizability The importance of considering tumor location in decisions about mCRC treatment Right-sided mCRC is associated with poorer survival regardless of the biologic therapy type

LIMITATIONS Lack of genetic data (including MSI, BRAF, NRAS) Absence of information on tumor recurrence Unknown metastatic target tissues that define different survivals Does not utilize distinctions in types of chemotherapy used

CONCLUSIONS KRAS wild-type right-sided mCRC treated with cetuximab had poorer survival KRAS wild-type left-sided mCRC had better survival with cetuximab Further investigations are needed to understand the biologic differences that impact outcomes between right and left colon cancer

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