Published online Apr 15, 2020. doi: 10.4251/wjgo.v12.i4.405
Peer-review started: September 19, 2019
First decision: October 18, 2019
Revised: December 10, 2019
Accepted: December 23, 2019
Article in press: December 23, 2019
Published online: April 15, 2020
Metastatic colorectal cancer (mCRC) is a heterogeneous disease with differing outcomes and clinical responses, in part due to differences in chromosomal and molecular profiles between primary tumors that arise from the left (distal) and right (proximal) sides of the colon. Primary tumor location has been shown to be a prognostic factor, with left-sided primary tumor location (LPTL) demonstrating significantly longer survival than right-sided primary tumor location (RPTL). Additionally, primary tumor location may be a predictive factor of survival outcomes associated with cetuximab or bevacizumab in combination with 5-fluorouracil-based chemotherapy. Current first-line treatment recommendations for mCRC per the National Comprehensive Cancer Network are cetuximab or panitumumab only for patients with LPTL RAS wild-type (WT) disease or bevacizumab for patients with RPTL RAS WT disease; second-line treatment recommendations for subsequent lines are cetuximab or panitumumab for all patients with RAS WT tumors. However, most of the studies that investigated the effect of primary tumor location on biologic therapy efficacy and that led to treatment recommendations were post hoc analyses of large randomized controlled trials (such as CALGB/SWOG 80405, FIRE-3, CRYSTAL, PEAK, PRIME and others) not designed to examine tumor sidedness, or were single institution analyses of small cohorts. Consequently, there is a need for real-world evidence from large mCRC populations describing the association of primary tumor location with survival outcomes from biologic therapy, which is the aim of the current study.
This study was conducted to evaluate the prognostic and/or predictive roles of primary tumor location in real-world mCRC patients treated with cetuximab or bevacizumab plus 5-fluorouracil-based chemotherapy. The findings of this study are important because they contribute to the growing body of literature describing the potential impact of primary tumor location on survival benefit associated with biologic therapy for patients with mCRC.
The main objectives of this study were to evaluate the prognostic and predictive role of primary tumor location and its association with survival benefit in real-world patients with KRAS WT mCRC who initiated first-line therapy with cetuximab plus 5-fluorouracil/leucovorin/irinotecan (FOLFIRI) or 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) vs with bevacizumab plus FOLFIRI or FOLFOX in the United States. The analysis of this real-world cohort of mCRC KRAS WT patients who received first-line treatment found a prognostic effect by primary tumor location, but not a predictive effect for survival by biologic agent given with 5-fluoroucil-based chemotherapy. The difference in these real-world results regarding predictive findings compared with published post hoc analyses of randomized clinical trials highlights challenges with the generalizability of clinical trial findings and the need for further research to elucidate tumor, patient, and treatment factors that contributed to these real-world findings, as well as differences between real-world and clinical trial populations that may have contributed to the divergent results.
This retrospective cohort study selected patients with KRAS wild-type mCRC who initiated first-line therapy with cetuximab or bevacizumab in combination with FOLFIRI or FOLFOX between January 2013 and April 2017 from the Flatiron Health electronic health record derived database of de-identified patient-level data in the United States. Primary tumor location was abstracted from patients’ charts. LPTL was defined as tumors that originated in the splenic flexure, descending colon, sigmoid colon, or rectum; RPTL was defined as tumors that originated from the appendix, cecum, ascending colon, hepatic flexure, or transverse colon. Propensity score matching was used to balance the baseline demographic and clinical characteristics between patients treated with cetuximab and patients treated with bevacizumab. Kaplan-Meier and Cox regression methods were used for survival analyses.
In this retrospective cohort study of real-world patients from clinical practice in the United States, median OS was significantly longer for mCRC KRAS WT patients with LPTL than for those with RPTL, regardless of first-line treatment, substantiating the prognostic effect of primary tumor location reported in previous studies. Primary tumor location was not predictive of treatment effect for cetuximab compared with bevacizumab in this study; there was no significant difference in median OS between patients who received cetuximab and those who received bevacizumab by primary tumor location. However, subgroup analyses by chemotherapy backbone showed a significant treatment benefit for cetuximab compared with bevacizumab, regardless of primary tumor location, in patients who received FOLFOX as the chemotherapy backbone. Factors that may have affected treatment-related findings include that cetuximab patients were more likely to receive FOLFIRI vs bevacizumab patients; cetuximab RPTL patients were more likely to have stage III disease while bevacizumab RPTL patients were more likely to have stage IV disease; and cetuximab RPTL patients were more likely to have a documented history of adjuvant chemotherapy vs bevacizumab RPTL patients. In addition, mutations in NRAS and KRAS exons 3 and 4 may have impacted the study results, yet approximately 70% of patients were not evaluated for expanded RAS mutations in this study. Future research should examine these treatment factors further.
Although the analysis of this real-world cohort of mCRC KRAS WT patients who received first-line treatment found a prognostic effect by primary tumor location, it did not confirm a predictive effect for survival by biologic agent given with 5-fluoroucil-based chemotherapy as expected from previous post hoc analyses of clinical trials and treatment guidelines. Possible reasons for this divergence from previously reported findings, current guidelines, and current practice regarding treatment recommendations for mCRC by primary tumor location may include limitations of post hoc analyses; the potential impact of chemotherapy backbone on survival benefit associated with biologic therapy; tumor, patient, and treatment factors that contributed to these real-world findings; and differences between real-world and clinical trial populations. Future research is needed to definitively confirm these reasons in order to optimize treatment for patients with mCRC.
These findings confirmed primary tumor location as a prognostic factor in mCRC but did not confirm its predictive effect in contrast with previous findings. Chemotherapy backbone may contribute to outcomes, either alone, by interacting with the biologic agent, or as a proxy for disease biology if the backbone choice is driven by clinical history: Stage at initial diagnosis and features of prior adjuvant chemotherapy (use, regimen choice, disease response, and the time since completion of adjuvant therapy). Future research is needed to better understand if biologic treatment recommendations by side of colon should incorporate the potential impact of chemotherapy backbone and other factors, such as expanded RAS and BRAF mutations, and history of adjuvant chemotherapy. Furthermore, additional studies are required to elucidate tumor, patient, and treatment factors that contributed to these real-world findings, as well as differences between real-world and clinical trial populations.