{"entity":{"id":"paper-tejpar-tumour-location-crystal-fire3-jama-oncol-2017","kind":"paper","name":"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","aka":[],"tldr":"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.","asOf":"2026-09-24","links":[{"label":"Tejpar et al., JAMA Oncol 2017: primary tumour location in the RAS wild-type populations of CRYSTAL and FIRE-3","url":"https://doi.org/10.1001/jamaoncol.2016.3797"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/27722750/"}],"tags":[],"related":[],"cancers":["colorectal"],"sections":[],"technologies":[],"targets":["egfr","kras","braf"],"drugs":["cetuximab","bevacizumab"],"companies":[],"institutions":[],"pathways":[],"terms":["sidedness","wild-type"],"trials":["crystal-fire3"],"people":["eric-van-cutsem","volker-heinemann","heinz-josef-lenz"],"bottlenecks":[],"keyPapers":[],"journals":["jama-oncology"],"dependsOn":[],"notes":[],"journal":"JAMA Oncology","year":2017,"doi":"10.1001/jamaoncol.2016.3797","pmid":"27722750","authors":"Tejpar S, Stintzing S, Ciardiello F, et al.","paperType":"rct","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."],"whatItMeans":"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."],"changedPractice":true},"route":"/key-papers/paper-tejpar-tumour-location-crystal-fire3-jama-oncol-2017/","neighbours":{"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"}],"target":[{"id":"braf","kind":"target","name":"BRAF","route":"/targets/braf/"},{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"}],"drug":[{"id":"bevacizumab","kind":"drug","name":"Bevacizumab","route":"/drugs/bevacizumab/"},{"id":"cetuximab","kind":"drug","name":"Cetuximab","route":"/drugs/cetuximab/"}],"term":[{"id":"sidedness","kind":"term","name":"Sidedness (left vs right colon)","route":"/terms/sidedness/"},{"id":"wild-type","kind":"term","name":"Wild-type (WT)","route":"/terms/wild-type/"}],"trial":[{"id":"crystal-fire3","kind":"trial","name":"CRYSTAL & FIRE-3","route":"/trials/crystal-fire3/"}],"person":[{"id":"eric-van-cutsem","kind":"person","name":"Eric Van Cutsem","route":"/people/eric-van-cutsem/"},{"id":"heinz-josef-lenz","kind":"person","name":"Heinz-Josef Lenz","route":"/people/heinz-josef-lenz/"},{"id":"volker-heinemann","kind":"person","name":"Volker Heinemann","route":"/people/volker-heinemann/"}],"journal":[{"id":"jama-oncology","kind":"journal","name":"JAMA Oncology","route":"/journals/jama-oncology/"}]}}