Vol 17, No 2 (2021)
Review paper
Published online: 2021-04-07

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Clinical significance of primary tumour location in colorectal cancer — a review

Anna Janiak12, Joanna Połowinczak-Przybyłek12, Rafał Czyżykowski12, Piotr Potemski12
Oncol Clin Pract 2021;17(2):67-73.


Colorectal cancer (CRC) is one of the most common malignant neoplasms worldwide. The heterogeneous course of disease, as well as, genetic and molecular differences between tumours localized in different parts of the large intestine, resulted in an attempt to evaluate the significance of the primary tumour location and divide colorectal cancer into right- and left-sided. The results of the retrospective analyses of the phase III studies indicate that the right-sided location is a negative prognostic factor in stage IV and III of disease. The benefit of adding an anti-EGFR antibody to the first-line palliative chemotherapy was clearly demonstrated for patients with primary tumour located on the left side and the effect of treatment seems to be better than anti-VEGF therapy combined with chemotherapy. Treatement results of patients with right-sided primary tumour location are worse regardless of the type of treatment. In patients with right-sided cancer, it seems that bevacizumab treatment might be more beneficial in comparison with anti-EGFR therapy, although these suggestions are based on small groups of patients. The efficacy of bevacizumab seems to be independent of primary tumour location. It is still unclear whether the primary tumour location should be considered as an independent prognostic or predictive factor, or rather it is necessary to look for specific genetic and molecular disorders responsible for demonstrated and possible differences.

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  1. GLOBOCAN 2012. Estimated Cancer Incidence Mortality and Prevalence Worldwide in 2012. www.globocan.iarc.fr.
  2. NCCN Clinical Practice Guidelines in Oncology. Colon /Rectal Cancer 14. March 2018. www.nccn.org.
  3. Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012; 487(7407): 330–337.
  4. Budinska E, Popovici V, Tejpar S, et al. Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer. J Pathol. 2013; 231(1): 63–76.
  5. Schlicker A, Beran G, Chresta CM, et al. Subtypes of primary colorectal tumors correlate with response to targeted treatment in colorectal cell lines. BMC Med Genomics. 2012; 5: 66.
  6. Sadanandam A, Lyssiotis CA, Homicsko K, et al. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med. 2013; 19(5): 619–625.
  7. De Sousa E Melo F, Wang X, Jansen M, et al. Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions. Nat Med. 2013; 19(5): 614–618.
  8. Marisa L, de Reyniès A, Duval A, et al. Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. PLoS Med. 2013; 10(5): e1001453.
  9. Perez-Villamil B, Romera-Lopez A, Hernandez-Prieto S, et al. Colon cancer molecular subtypes identified by expression profiling and associated to stroma, mucinous type and different clinical behavior. BMC Cancer. 2012; 12: 260.
  10. Roepman P, Schlicker A, Tabernero J, et al. Colorectal cancer intrinsic subtypes predict chemotherapy benefit, deficient mismatch repair and epithelial-to-mesenchymal transition. Int J Cancer. 2014; 134(3): 552–562.
  11. Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015; 21(11): 1350–1356.
  12. 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): 1386–1422.
  13. Mik M, Berut M, Dziki L, et al. Right- and left-sided colon cancer - clinical and pathological differences of the disease entity in one organ. Arch Med Sci. 2017; 13(1): 157–162.
  14. Venook A. Right-Sided vs Left-Sided Colorectal Cancer. Clin Adv Hematol Oncol. 2017; 15(1): 22-24. https://www.hematologyandoncology.net/archives/january-2017/right-sided-vs-left-sided-colorectal-cancer/.
  15. Tejpar S, Stintzing S, Ciardiello 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.
  16. 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(8): 1862–1868.
  17. Loupakis F, Yang D, Yau L, et al. Primary tumor location as a prognostic factor in metastatic colorectal cancer. J Natl Cancer Inst. 2015; 107(3).
  18. Salem ME, Weinberg BA, Xiu J, et al. Comparative molecular analyses of left-sided colon, right-sided colon, and rectal cancers. Oncotarget. 2017; 8(49): 86356–86368.
  19. Shimada Y, Kameyama H, Nagahashi M, et al. Comprehensive genomic sequencing detects important genetic differences between right-sided and left-sided colorectal cancer. Oncotarget. 2017; 8(55): 93567–93579.
  20. Loree JM, Pereira AAL, Lam M, et al. Classifying Colorectal Cancer by Tumor Location Rather than Sidedness Highlights a Continuum in Mutation Profiles and Consensus Molecular Subtypes. Clin Cancer Res. 2018; 24(5): 1062–1072.
  21. Zhang L, Zhao Y, Dai Y, et al. Immune Landscape of Colorectal Cancer Tumor Microenvironment from Different Primary Tumor Location. Front Immunol. 2018; 9: 1578.
  22. Boeckx N, Toler A, Beeck Kde, et al. Primary tumor sidedness impacts on prognosis and treatment outcome: results from three randomized studies of panitumumab plus chemotherapy versus chemotherapy or chemotherapy plus bevacizumab in 1st and 2nd line RAS/BRAF WT mCRC. Ann Oncol. 2016; 27: vi27.
  23. Leijssen LGJ, Dinaux AM, Kunitake H, et al. Pathologic factors are more important than tumor location in long-term survival in colon cancer. Int J Colorectal Dis. 2018; 33(6): 709–717.
  24. Cremolini C, Antoniotti C, Lonardi S, et al. Primary tumor sidedness and benefit from FOLFOXIRI plus bevacizumab as initial therapy for metastatic colorectal cancer. Retrospective analysis of the TRIBE trial by GONO. Ann Oncol. 2018; 29(7): 1528–1534.
  25. Innocenti F, Ou FS, Qu X, et al. Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA. 2017; 317(23): 2392–2401.
  26. Venook A, Niedzwiecki D, Innocenti F, et al. Impact of primary (1º) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB/SWOG 80405 (Alliance). J Clin Oncol. 2016; 34(15_suppl): 3504.
  27. Ottaiano A, Stefano ADe, Capozzi M, et al. First biologic drug in the treatment of RAS wild-type metastatic colorectal cancer: anti-EGFR or bevacizumab? Results from a meta-analysis. Front Pharmacol. 2018; 9: 441.
  28. Saltz LB, Clarke S, Díaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008; 26(12): 2013–2019.
  29. You XH, Wen C, Xia ZJ, et al. Primary tumor sidedness predicts bevacizumab benefit in metastatic colorectal cancer patients. Front Oncol. 2019; 9: 723.
  30. Holch JW, Ricard I, Stintzing S, et al. 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.
  31. Wu CC, Wang JH, Lin PC, et al. Tumor sidedness and efficacy of first-line therapy in patients with RAS/BRAF wild-type metastatic colorectal cancer: A network meta-analysis. Crit Rev Oncol Hematol. 2020; 145: 102823.
  32. Lee-Ying R, Bosma N, Tang P. Impact of primary tumor sidedness on survival after resection of colorectal liver metastases (CRLM). J Clin Oncol. 2017; 35(4_suppl): 694.
  33. Creasy JM, Sadot E, Koerkamp BG, et al. The impact of primary tumor location on long-term survival in patients undergoing hepatic resection for metastatic colon cancer. Ann Surg Oncol. 2018; 25(2): 431–438.
  34. Marques MC, C Ribeiro HS, Costa WL, et al. Is primary sidedness a prognostic factor in patients with resected colon cancer liver metastases (CLM)? J Surg Oncol. 2018; 117(5): 858–863.
  35. McCracken EKE, Samsa GP, Fisher DA, et al. Prognostic significance of primary tumor sidedness in patients undergoing liver resection for metastatic colorectal cancer. HPB (Oxford). 2019; 21(12): 1667–1675.
  36. Gasser E, Braunwarth E, Riedmann M, et al. Primary tumour location affects survival after resection of colorectal liver metastases: A two-institutional cohort study with international validation, systematic meta-analysis and a clinical risk score. PLoS One. 2019; 14(5): e0217411.
  37. Jung MK, Shin UiS, Ki YJ, et al. Is the location of the tumor another prognostic factor for patients with colon cancer? Ann Coloproctol. 2017; 33(6): 210–218.
  38. Weiss JM, Pfau PR, O'Connor ES, et al. Mortality by stage for right- versus left-sided colon cancer: analysis of surveillance, epidemiology, and end results--Medicare data. J Clin Oncol. 2011; 29(33): 4401–4409.
  39. Zhang Y, Ma J, Zhang S, et al. A prognostic analysis of 895 cases of stage III colon cancer in different colon subsites. Int J Colorectal Dis. 2015; 30(9): 1173–1183.
  40. Schrag D, Weng S, Brooks G, et al. The relationship between primary tumor sidedness and prognosis in colorectal cancer. J Clin Oncol. 2016; 34(15_suppl): 3505.
  41. Karim S, Brennan K, Nanji S, et al. Association between prognosis and tumor laterality in early-stage colon cancer. JAMA Oncol. 2017; 3(10): 1386–1392.
  42. Brungs D, Aghmesheh M, de Souza P, et al. Sidedness is prognostic in locoregional colon cancer: an analysis of 9509 Australian patients. BMC Cancer. 2017; 17(1): 251.
  43. Ha GiW, Kim JH, Lee MRo. Oncologic effects of primary tumor-sidedness on patients with stages 1-3 colon cancer: a meta-analysis. Ann Surg Oncol. 2019; 26(5): 1366–1375.
  44. 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): 211–219.
  45. Grassadonia A, Di Marino P, Ficorella C, et al. Impact of primary tumor location in patients with RAS wild-type metastatic colon cancer treated with first-line chemotherapy plus anti-EGFR or anti-VEGF monoclonal antibodies: a retrospective multicenter study. J Cancer. 2019; 10(24): 5926–5934.
  46. Aggarwal H, Sheffield KM, Li Li, et al. Primary tumor location and survival in colorectal cancer: A retrospective cohort study. World J Gastrointest Oncol. 2020; 12(4): 405–423.
  47. Marques RP, Godinho AR, Heudtlass P, et al. Cetuximab versus bevacizumab in metastatic colorectal cancer: a comparative effectiveness study. J Cancer Res Clin Oncol. 2020; 146(5): 1321–1334.