Purpose of Review
Colorectal cancer is the third most common cancer worldwide with a high mortality rate at the advanced stages of the disease. Treatment options are dependent on the stage of the disease, patients’ performance status, and the specific molecular makeup of the tumor. Adding an anti-epidermal growth factor receptor monoclonal antibody (anti-EGFR mAb) to conventional chemotherapy in molecularly selected patients (i.e., RAS wild-type) leads to a survival advantage. We aim to review the latest evidence on the influence of primary tumor location (PTL) on treatment response to chemotherapy combined with an anti-EGFR in patients with metastatic colorectal cancer (mCRC).
Colon cancer arising on the left side versus the right side of the colon portrays different outcomes, emerging PTL as an important characteristic in understanding the outcomes for patients with colorectal cancer. Patients with right-sided tumors have a worse prognosis than those with left-sided tumors. Primary tumor location may also be predictive of treatment benefit from targeted therapy with an anti-EGFR or anti-VEGF in the treatment of RAS wild-type mCRC. Although no benefit in overall survival (OS) has been demonstrated, available data up to now can endorse the use of an anti-EGFR in right-sided RAS wild-type advanced colorectal cancer if the therapy goal is tumor shrinkage (given the higher objective response rate). However, the majority of data on PTL has been obtained through retrospective analysis of clinical trials where PTL was neither part of the stratification nor pre-planned subgroup analysis, rendering it susceptible to recall bias.
There is a great necessity to improve our understanding of the molecular and histological variability in left versus right-sided colon cancer and its impact on future targeted therapy.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30.
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86.
Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016;27(8):1386e422.
Venook A, Niedzwiecki D, Innocenti F, et al. Impact of primary tumor location on overall survival and progression-free survival in patients with metastatic colorectal cancer: analysis of CALGB/SWOG 80405 (Alliance). J Clin Oncol. 2016;34. (suppl, abstr 3504:3504.
Karim S, Brennan K, Nanji S, Berry SR, Booth CM. Association between prognosis and tumor laterality in early-stage colon cancer. JAMA Oncol. 2017;3(10):1386–92.
• Bufill JA. Colorectal cancer: evidence for distinct genetic categories based on proximal or distal tumor location. Ann Intern Med. 1990;113(10):779–88. First proposed the concept that proximal and distal colons were 2 different entities.
Missiaglia E, Jacobs B, D’ario G, et al. Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features. Ann Oncol. 2014;25:1995–2001.
Sorich MJ, Wiese MD, Rowland A, Kichenadasse G, McKinnon RA, Karapetis CS. Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. Ann Oncol. 2015;26(1):13–21.
Tejpar S, Stintzing S, Ciardiello F, Tabernero J, van Cutsem E, Beier F, et al. Prognostic and predictive relevance of primary tumor location in patients with RAS wild-type metastatic colorectal cancer retrospective analyses of the CRYSTAL and FIRE-3 trials. JAMA Oncol. 2017;3(2):194–201.
Brule SY, Jonker DJ, Karapetis CS, et al. Location of colon cancer (right-sided versus left-sided) as a prognostic factor and predictor of benefit from cetuximab in NCIC CO.17. Eur J Cancer. 2015;51:1405–14.
Wang F, Bai L, Liu TS, Yu YY, He MM, Liu KY, et al. Right-sided colon cancer and left-sided colorectal cancers respond differently to cetuximab. Chin J Cancer. 2015;34(9):384–93.
Boeckx N, Koukakis R, Op de Beeck K, et al. Primary tumor sidedness has an impact on prognosis and treatment outcome in metastatic colorectal cancer: results from two randomized first-line panitumumab studies. Ann Oncol. 2017;28:1862–8.
Arnold D, Lueza B, Douillard JY, Peeters M, Lenz HJ, Venook A, et al. Prognostic and predictive value of primary tumor side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials. Ann Oncol. 2017;28:1713–29.
Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, al-Batran SE, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomized, open-label phase 3 trial. Lancet Oncol. 2014;15:1065–75.
Seligmann JF, Elliott F, Richman SD, et al. Primary tumour location (PTL) as a prognostic and predictive factor in advanced colorectal cancer: data from 2075 patients in randomised trials. Ann Oncol. 2014;25(suppl_4):iv167–209.
Moretto R, Cremolini C, Rossini D, Pietrantonio F, Battaglin F, Mennitto A, et al. Location of primary tumor and benefit from anti-epidermal growth factor receptor monoclonal antibodies in patients with RAS and BRAF wild-type metastatic colorectal cancer. Oncologist. 2016;21(8):988–94.
Holch JW, Ricard I, Stintzing S, Modest DP, Heinemann V. The relevance of primary tumour location in patients with metastatic colorectal cancer: a meta-analysis of first-line clinical trials. Eur J Cancer. 2017;70:87–98.
•• Petrelli F, Tomasello G, Borgonovo K, et al. Prognostic survival associated with left-sided vs right-sided colon cancer: a systematic review and meta-analysis. JAMA Oncol. 2017;3(2):211–9. Largest data set available on influence primary tumor location on overall survival.
Chang GJ, Gonen M. Prognostic and predictive ability of tumor sidedness: another vexing difference between localized and advanced colon cancer. JAMA Oncol. 2017;3(10):1314–5.
Lee GH, Malietzis G, Askari A, Bernardo D, al-Hassi HO, Clark SK. Is right-sided colon cancer different to left-sided colorectal cancer? A systematic review. Eur J Surg Oncol. 2015;41:300–8.
Van Cutsem E, Köhne CH, Láng I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29(15):2011–9.
Douillard J-Y, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369(11):1023–34.
Dienstmann R, Guinney J, Delorenzi M, de Reynies A, Roepman P, Sadanandam A, et al. Colorectal cancer subtyping consortium (CRCSC) identification of a consensus of molecular subtypes. J Clin Oncol. 2014;32(15_suppl):3511.
•• Maus MKH, Hanna DL, Stephens CL, et al. Distinct gene expression profiles of proximal and distal colorectal cancer: implications for cytotoxic and targeted therapy. Pharmacogenomics J. 2015;15(4):354–62. Highlighting the importance of specific genetic features and expression profiles according to primary tumor location. Important in future research.
Ulivi P, Scarpi E, Chiadini E, Marisi G, Valgiusti M, Capelli L, et al. Right- vs. left-sided metastatic colorectal cancer: difference in tumor biology and bevacizumab efficacy. Int J Mol Sci. 2017;18(6):1240.
Yaeger R, Chatila WK, Lipsyc MD. Clinical sequencing defines the genomic landscape of metastatic colorectal cancer. Cancer Cell. 2018;33:125–36.
Conflict of Interest
The authors declare that they have no conflicts of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article is part of the Topical Collection on Systemic Therapies in Colorectal Cancer
About this article
Cite this article
Triest, L., Debeuckelaere, C., Vandamme, T. et al. Should Anti-EGFR Agents Be Used in Right-Sided RAS Wild-type Advanced Colorectal Cancer?. Curr Colorectal Cancer Rep 15, 130–134 (2019). https://doi.org/10.1007/s11888-019-00439-x
- Metastatic colorectal cancer (mCRC)
- Targeted therapies
- EGFR (epidermal growth factor receptor)
- Anti-EGFR mAb
- RAS wild-type
- Primary tumor location (PTL)
- Overall survival (OS)
- Progression-free survival (PFS)
- Objective response rate (ORR)
- BRAF mutation
- Microsatellite instability (MSI)