Understanding the role of primary tumour localisation in colorectal cancer treatment and outcomes

Abstract

Metastatic colorectal carcinoma (mCRC) is a heterogeneous disease with differing outcomes and clinical responses and poor prognosis. CRCs can be characterised by their primary tumour location within the colon. The left-sided colon, derived from the hindgut, includes the distal third of the transverse colon, splenic flexure, descending colon, sigmoid colon and rectum. The right-sided colon, derived from the midgut, includes the proximal two-thirds of the transverse colon, ascending colon and caecum. Sometimes, the rectum is described separately, despite originating from the hindgut, and in many clinical series, the left-sided colon includes only tumours within and distal to the splenic flexure. Differences in the microbiome, clinical characteristics and chromosomal and molecular characteristics have been reported between the right and left side of the colon, regardless of how this is defined. There is now strong evidence from clinical studies in patients with mCRC for the prognostic effect of primary tumour location. The impact of primary colonic tumour location on response to treatment is now under investigation in a large number of clinical studies in patients with mCRC. In this review, we summarise the microbiome, clinical, chromosomal and molecular differences associated with the primary location of CRC. We present an overview of the proven prognostic impact of primary tumour location for patients with mCRC and discuss emerging data for the predictive impact of primary tumour location on clinical outcome.

Keywords: Colon; Colorectal carcinoma; Hindgut; Metastatic; Midgut; Predictive; Prognostic.

Fig. 1.

Schematic diagram of the most commonly used definition of left- and right-sided regions of the colon and rectum.

Fig. 2.

A) Molecular characteristics of CRC [32] [Reproduced from Gut 2012, ‘Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum’, Yamauchi M et al, 61, 847–54, copyright 2017 with permission from BMJ Publishing Group Ltd.] and B) frequency of molecular alterations, according to primary tumour location [11] [Reproduced from Clin Cancer Res 2015, ‘Analysis of molecular markers by anatomic tumor site in Stage III colon carcinomas from adjuvant chemotherapy trial NCCTG N0147 (Alliance)’ Sinicrope FA et al, 21(23), 5294–5304, copyright 2017 with permission from AACR]. CIMP, CpG island methylator phenotype; CRC, colorectal carcinoma; MSI, microsatellite instability; MSS, microsatellite stability.

Fig. 3.

Clinical outcome of patients with stage III CRC according to tumour localisation: A) overall survival and B) time-to-recurrence [11] [Reproduced from Clin Cancer Res 2015, ‘Analysis of molecular markers by anatomic tumor site in Stage III colon carcinomas from adjuvant chemotherapy trial NCCTG N0147 (Alliance)’ Sinicrope FA et al, 21(23), 5294–5304, copyright 2017 with permission from AACR]. CI, confidence intervals; CRC, colorectal carcinoma; HR, hazard ratio; OS, overall survival; Ref., reference group; TTR, time-to-response.