# 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

Source: https://onco.cc/key-papers/paper-tejpar-tumour-location-crystal-fire3-jama-oncol-2017/  
OnCo record `paper-tejpar-tumour-location-crystal-fire3-jama-oncol-2017` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Two European randomised trials, analysed separately, each showed the same thing: cetuximab helps left-sided bowel cancers with no RAS mutation and adds little on the right.

## Summary

Patients with RAS wild-type metastatic colorectal cancer from the CRYSTAL and FIRE-3 trials were classified as left-sided (splenic flexure, descending colon, sigmoid colon or rectum) or right-sided (appendix, caecum, ascending colon, hepatic flexure or transverse colon). In both trials, patients with left-sided tumours (142 and 157) had markedly superior progression-free survival, overall survival and objective response rates compared with right-sided tumours (33 and 38). Among patients with left-sided tumours, FOLFIRI plus cetuximab significantly improved overall survival against the respective comparators, FOLFIRI in CRYSTAL and FOLFIRI plus bevacizumab in FIRE-3; in right-sided tumours the benefit of adding cetuximab was limited in CRYSTAL and outcomes were comparable between arms in FIRE-3. A significant interaction between primary tumour location and treatment was observed for overall survival in both studies (CRYSTAL hazard ratio 1.95; FIRE-3 hazard ratio 0.40) in multivariable models that included sex, prior adjuvant therapy and BRAF status.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: JAMA Oncology
- Year: 2017
- DOI: 10.1001/jamaoncol.2016.3797
- Authors: Tejpar S, Stintzing S, Ciardiello F, et al.
- Findings: Left-sided RAS wild-type tumours had markedly better progression-free survival, overall survival and response than right-sided in both trials.; Significant location-by-treatment interaction for overall survival in CRYSTAL (1.95) and FIRE-3 (0.40) after adjusting for BRAF status.
- What it means: It showed the sidedness effect is not an artefact of pooling and survives adjustment for BRAF, which is what made guideline committees act on it.
- Caveats: Retrospective subgroup analyses with small right-sided groups (33 and 38 patients).; The two trials had different comparators.; BRAF was adjusted for but the right-sided groups remain confounded by microsatellite status and other biology.

## Sources

- Tejpar et al., JAMA Oncol 2017: primary tumour location in the RAS wild-type populations of CRYSTAL and FIRE-3: https://doi.org/10.1001/jamaoncol.2016.3797
- PubMed: https://pubmed.ncbi.nlm.nih.gov/27722750/

## Connected records

- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/)
- targets: [BRAF](https://onco.cc/targets/braf/), [EGFR](https://onco.cc/targets/egfr/), [KRAS](https://onco.cc/targets/kras/)
- drugs: [Bevacizumab](https://onco.cc/drugs/bevacizumab/), [Cetuximab](https://onco.cc/drugs/cetuximab/)
- terms: [Sidedness (left vs right colon)](https://onco.cc/terms/sidedness/), [Wild-type (WT)](https://onco.cc/terms/wild-type/)
- trials: [CRYSTAL & FIRE-3](https://onco.cc/trials/crystal-fire3/)
- people: [Eric Van Cutsem](https://onco.cc/people/eric-van-cutsem/), [Heinz-Josef Lenz](https://onco.cc/people/heinz-josef-lenz/), [Volker Heinemann](https://onco.cc/people/volker-heinemann/)
- journals: [JAMA Oncology](https://onco.cc/journals/jama-oncology/)

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