{"entity":{"id":"paper-van-cutsem-crystal-cetuximab-folfiri-nejm-2009","kind":"paper","name":"Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer (CRYSTAL)","aka":[],"tldr":"The trial that added an EGFR antibody to first-line chemotherapy and, in the same paper, showed the benefit belongs only to patients whose KRAS gene is normal. It is the first negative predictive biomarker in bowel cancer.","summary":"Van Cutsem, Köhne, Hitre and colleagues randomly assigned patients with EGFR-positive colorectal cancer and unresectable metastases to FOLFIRI alone or with cetuximab, with progression-free survival as the primary end point, and sought associations between tumour KRAS mutation status and response. A total of 599 patients received cetuximab plus FOLFIRI and 599 received FOLFIRI alone.\n\nGrade 3 or 4 skin reactions occurred in 19.7 percent of the cetuximab group against 0.2 percent, infusion-related reactions in 2.5 against 0 percent and diarrhoea in 15.7 against 10.5 percent.","asOf":"2026-09-24","links":[{"label":"N Engl J Med 2009","url":"https://doi.org/10.1056/NEJMoa0805019"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/19339720/"}],"tags":["colorectal-evidence"],"related":["paper-kras-colorectal-j-clin-oncol-2011","paper-kras-colorectal-j-clin-oncol-2008","paper-douillard-prime-panitumumab-ras-nejm-2013"],"cancers":["colorectal"],"sections":["targeted-therapy"],"technologies":["monoclonal-antibody"],"targets":["egfr","kras"],"drugs":["cetuximab","folfiri","irinotecan","fluorouracil"],"companies":[],"institutions":[],"pathways":["ras-mapk"],"terms":["sidedness"],"trials":["crystal-fire3"],"people":["eric-van-cutsem"],"bottlenecks":["b-biomarker-validation"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2009,"doi":"10.1056/NEJMoa0805019","pmid":"19339720","authors":"Van Cutsem E, Köhne CH, Hitre E, et al.","paperType":"rct","findings":["Progression-free survival hazard ratio 0.85 (95 percent CI 0.72 to 0.99, p=0.048) overall.","No significant difference in overall survival overall (hazard ratio 0.93, 0.81 to 1.07, p=0.31).","Significant interaction between treatment and KRAS status for tumour response (p=0.03) but not for progression-free survival (p=0.07) or overall survival (p=0.44).","In KRAS wild-type tumours, progression-free survival hazard ratio 0.68 (0.50 to 0.94) in favour of cetuximab."],"whatItMeans":"Biomarker-directed treatment in colorectal cancer starts here: RAS testing became mandatory before an EGFR antibody, and the corpus's updated CRYSTAL analysis (paper-kras-colorectal-j-clin-oncol-2011) carries the mature survival figures in the wild-type group.","caveats":["The overall trial was positive only for progression-free survival, and narrowly; the important result is the subgroup defined by a biomarker tested retrospectively.","Only exon 2 KRAS was tested; the extended RAS analysis in PRIME four years later removed a further 17 percent of apparently eligible patients.","Sidedness, which turned out to matter more than the trial's own stratification factors, was not analysed."],"changedPractice":true,"participants":1198},"route":"/key-papers/paper-van-cutsem-crystal-cetuximab-folfiri-nejm-2009/","neighbours":{"paper":[{"id":"paper-kras-colorectal-j-clin-oncol-2011","kind":"paper","name":"Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status","route":"/key-papers/paper-kras-colorectal-j-clin-oncol-2011/"},{"id":"paper-hurwitz-bevacizumab-crc-nejm-2004","kind":"paper","name":"Hurwitz 2004: bevacizumab with chemotherapy for metastatic colorectal cancer, the first anti-angiogenic drug to extend life","route":"/key-papers/paper-hurwitz-bevacizumab-crc-nejm-2004/"},{"id":"paper-douillard-prime-panitumumab-ras-nejm-2013","kind":"paper","name":"Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer (PRIME)","route":"/key-papers/paper-douillard-prime-panitumumab-ras-nejm-2013/"},{"id":"paper-kras-colorectal-j-clin-oncol-2008","kind":"paper","name":"Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer","route":"/key-papers/paper-kras-colorectal-j-clin-oncol-2008/"}],"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"}],"section":[{"id":"targeted-therapy","kind":"section","name":"Targeted Therapy","route":"/fronts/targeted-therapy/"}],"technology":[{"id":"monoclonal-antibody","kind":"technology","name":"Monoclonal antibodies","route":"/technologies/monoclonal-antibody/"}],"target":[{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"}],"drug":[{"id":"cetuximab","kind":"drug","name":"Cetuximab","route":"/drugs/cetuximab/"},{"id":"fluorouracil","kind":"drug","name":"Fluorouracil (5-FU)","route":"/drugs/fluorouracil/"},{"id":"folfiri","kind":"drug","name":"FOLFIRI (5-FU, leucovorin, irinotecan)","route":"/drugs/folfiri/"},{"id":"irinotecan","kind":"drug","name":"Irinotecan (and liposomal irinotecan)","route":"/drugs/irinotecan/"}],"pathway":[{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"}],"term":[{"id":"sidedness","kind":"term","name":"Sidedness (left vs right colon)","route":"/terms/sidedness/"}],"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/"}],"bottleneck":[{"id":"b-biomarker-validation","kind":"bottleneck","name":"Biomarkers are not validated or standardised","route":"/bottlenecks/b-biomarker-validation/"}],"journal":[{"id":"nejm","kind":"journal","name":"New England Journal of Medicine","route":"/journals/nejm/"}],"roadmap":[{"id":"colorectal-roadmap","kind":"roadmap","name":"Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation","route":"/roadmaps/colorectal-roadmap/"}]}}