Elsevier

European Journal of Cancer

Volume 70, January 2017, Pages 87-98
European Journal of Cancer

Original Research
The relevance of primary tumour location in patients with metastatic colorectal cancer: A meta-analysis of first-line clinical trials

https://doi.org/10.1016/j.ejca.2016.10.007Get rights and content

Abstract

Background

Retrospective subgroup analyses suggest that primary tumour location (PTL) has a prognostic importance and relates to response to targeted therapy.

Methods

We conducted a meta-analysis of first-line clinical trials available up to October 2016, which assessed the relevance of PTL in patients with metastatic colorectal cancer (mCRC). Right- and left-sided colorectal cancers were differentiated (RC and LC).

Results

In 13 first-line randomised controlled trials and one prospective pharmacogenetic study, RC was associated with a significantly worse prognosis compared with LC (hazard ratio [HR] for overall survival: 1.56; 95% confidence interval [CI]: 1.43–1.70; P < 0.0001). A meta-analysis of PRIME and CRYSTAL study suggests that PTL was predictive of survival benefit from addition of anti-EGFR antibody to standard chemotherapy in patients with RAS wild-type tumour (overall survival, HR for LC: 0.69; 95% CI: 0.58–0.83; P < 0.0001 and HR for RC: 0.96; 95% CI: 0.68–1.35; P = 0.802). A meta-analysis of FIRE-3/AIO KRK0306, CALGB/SWOG 80405 and PEAK study indicates that patients with RAS wild-type LC had a significantly greater survival benefit from anti-EGFR treatment compared with anti-VEGF treatment when added to standard chemotherapy (HR 0.71; 95% CI: 0.58–0.85; P = 0.0003). By contrast, in patients with RC, benefit from standard therapy was poor and bevacizumab-based treatment was numerically associated with longer survival (HR 1.3; 95% CI: 0.97–1.74; P = 0.081).

Conclusions

The present meta-analysis demonstrates that PTL is prognostic in mCRC. Further, it supports the conclusion that patients with left-sided RAS wild-type mCRC should be preferentially treated with an anti-EGFR antibody. In right-sided mCRC, chemotherapy plus bevacizumab is a treatment option, but optimal treatment has yet to be defined.

Section snippets

Background

Tumours arising from different regions of the colon are clinically and molecularly distinct [1], [2], [3], [4], [5]. Beside differences in the luminal content (e.g. bacterial flora), this might reflect also the ontogenesis with left-sided colon tumours (LC) deriving from the embryonic hindgut and right-sided colon tumours (RC) deriving from the embryonic midgut [6], [7]. As the embryological demarcation line at the distal third of the colon transversum is difficult to determine in retrospective

Search strategy and selection criteria

A PubMed-based search including the following search terms was conducted in October 2016: colon cancer, colorectal cancer, metastatic colorectal cancer, mCRC as well as primary tumour location, left-sided tumour, right-sided tumour, sidedness. Relevant MeSH terms (Medical Subject Headings) were used where possible. No restrictions were placed on the searches. The titles and abstracts of all remaining citations were reviewed and irrelevant citations were discarded. Potentially relevant studies

Overview of the included trials

In a total of 13 first-line RCTs and one prospective pharmacogenetic study (PROVETTA), the role of PTL was investigated (Table 1). In these studies, the weighted overall HRs for PTL with regard to OS and PFS were evaluated (Fig. 1).

For a total of seven trials, the impact of PTL on OS and PFS within the different treatment arms was evaluable (Supplementary Fig. S1). Supplementary Table S1 shows the corresponding survival times.

Five trials reported detailed outcome of the differential treatment

Discussion

Previous reports have suggested that PTL has prognostic implications and impacts on response to targeted therapy in patients with mCRC. Nevertheless, these analyses are limited by sample size and heterogeneity of molecular subgroups and treatments. The presented meta-analysis summarises the available evidence from clinical studies and investigates the prognostic and predictive relevance of PTL.

The data clearly indicate that RC is associated with an inferior prognosis compared to LC. In the RE

Conflict of interest statement

Julian Walter Holch: None declared. Ingrid Ricard: None declared. Sebastian Stintzing has received honoraria from Merck, Roche, Amgen, Bayer, Sanofi-aventis
 and has served on advisory boards for Merck Serono, Roche
Travel support: Roche, Merck Serono, Sanofi-aventis. Dominik Paul Modest has received honoraria from Merck, Roche, Amgen, Bayer and has received research grant from Amgen (inst), Merck (inst), Roche (inst) and has received travel support from Amgen, Merck, Sanofi, Bayer and has

Acknowledgements

The authors thank all patients and families for participation in the studies, as well as all involved study centres, colleagues and nurses.

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