{"entity":{"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","aka":["Colorectal cancer history","Bowel cancer roadmap","CRC evidence roadmap","Colon and rectal cancer roadmap"],"tldr":"Bowel cancer grows from a polyp over years, so removing the polyp prevents it. This roadmap follows the evidence from that discovery through the stool tests and scopes that built the screening programmes, the operation that changed rectal cancer, the chemotherapy and antibody era, immunotherapy that dissolves some tumours without surgery, and the unexplained rise in young adults, to 2032.","summary":"Colorectal cancer is the cancer with the best-understood natural history. Vogelstein and Fearon's 172 tumours (1988) showed that it accumulates mutations as an adenoma grows, and the National Polyp Study (2012) showed that cutting the adenoma out halves the death rate two decades later. That logic built the screening programmes: the Nottingham (1996), Funen (1996) and Minnesota (1993) stool-blood trials, the UK flexible sigmoidoscopy trial (2010, 17-year follow-up 2017) and finally NordICC (2022), the first randomised trial of colonoscopy itself, whose modest 18 percent reduction in incidence turned on the fact that only 42 percent of those invited came.\n\nTreatment moved on two tracks. In the rectum the change was surgical: Heald's total mesorectal excision (1982) cut pelvic recurrence from a quarter of patients to a few percent, and the Swedish (1997), Dutch TME (2001) and MRC CR07 (2009) trials settled that radiotherapy before the operation buys local control rather than survival. In the colon the change was chemical: fluorouracil with levamisole (1990), oxaliplatin added in MOSAIC (2004), then a long de-escalation as QUASAR (2007) measured how small the stage II benefit is, the IDEA collaboration (2018) halved the duration for lower-risk stage III disease and FOxTROT (2023) moved six weeks of it before the operation.\n\nThe metastatic era began with bevacizumab (2004) and cetuximab (CRYSTAL, 2009), and immediately produced the field's first negative predictive biomarker: the EGFR antibodies work only when RAS is normal (PRIME's extended testing, 2013) and, as the pooled analysis of six trials showed (2017), only when the primary tumour is on the left. Refractory lines arrived with regorafenib (2013), trifluridine-tipiracil (2015), the combination with bevacizumab (SUNLIGHT, 2023) and fruquintinib (2023), each measured in weeks.\n\nThen the disease split in two. Le's 41 patients (2015) showed that mismatch repair-deficient tumours respond to PD-1 blockade and proficient ones do not, KEYNOTE-177 (2020) made immunotherapy the first-line standard for that 5 percent, CheckMate 8HW (2024) added the CTLA-4 antibody, NICHE-2 (2024) produced 68 percent pathological complete responses before surgery and Cercek's dostarlimab series (2022, 2025) made surgery unnecessary in every mismatch repair-deficient rectal cancer treated. BRAF V600E disease got a targeted doublet (BEACON, 2019) and then a first-line triplet, HER2 got three regimens, KRAS G12C got sotorasib with panitumumab (2023). Circulating tumour DNA became the first reliable measure of residual disease in a solid tumour (Tie 2016), and DYNAMIC (2022) used it to halve chemotherapy in stage II without losing recurrence-free survival.\n\nWhat has not been solved: 95 percent of metastatic disease is microsatellite stable and still ignores immunotherapy, screening uptake rather than test performance sets what programmes achieve, and incidence in people under 50 is rising by about 3 percent a year in the United States and by 1.6 to 7.9 percent a year across Europe for reasons nobody can name, with colibactin-producing gut bacteria the strongest current lead.","asOf":"2026-09-24","links":[{"label":"NICE NG151: colorectal cancer (published 29 January 2020)","url":"https://www.nice.org.uk/guidance/ng151"},{"label":"NICE NG12: suspected cancer, recognition and referral","url":"https://www.nice.org.uk/guidance/ng12"},{"label":"ESMO clinical practice guidelines: gastrointestinal cancers","url":"https://www.esmo.org/guidelines/esmo-clinical-practice-guidelines-gastrointestinal-cancers"},{"label":"NCCN guidelines: colon cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"},{"label":"NCCN guidelines: rectal cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1461"},{"label":"National Bowel Cancer Audit (NATCAN)","url":"https://www.natcan.org.uk/audits/bowel/"},{"label":"ClinicalTrials.gov NCT05174169","url":"https://clinicaltrials.gov/study/NCT05174169"},{"label":"ClinicalTrials.gov NCT05253651","url":"https://clinicaltrials.gov/study/NCT05253651"}],"tags":["colorectal","gi","roadmap","colorectal-evidence"],"related":["early-detection-roadmap","surgery-roadmap","chemotherapy-roadmap","immunotherapy-roadmap","kras-roadmap","ctdna-tests","neoadjuvant-io-dmmr","anti-egfr-left-sided","idea-ctdna-guided-adjuvant-crc","idea-immunotherapy-mss-crc","idea-crc-early-onset-cause-hunt","idea-crc-screening-uptake-and-age-extension","idea-crc-ctdna-de-escalation-beyond-stage-ii","idea-crc-organ-preservation-randomised-in-pmmr-rectal","idea-crc-mss-immunotherapy-by-biomarker-not-by-line","idea-crc-peritoneal-disease-found-early-and-treated-in-networks","idea-crc-exercise-as-a-funded-treatment","idea-crc-uk-colonoscopy-capacity-and-fit-threshold","idea-crc-uk-young-patient-referral-and-diagnostic-interval"],"cancers":["colorectal","colon-cancer","rectal-cancer","msi-high-colorectal","braf-v600e-colorectal","her2-amplified-colorectal","kras-g12c-colorectal","early-onset-colorectal"],"sections":["early-detection","prevention","surgery","radiation","chemotherapy","targeted-therapy","immunotherapy","diagnostics"],"technologies":["colorectal-screening","colonoscopy","liquid-biopsy","mrd-testing","signatera","checkpoint-inhibitor","monoclonal-antibody","kras-inhibitors","cytotoxic-chemotherapy","radiotherapy","robotic-surgery","hipec","wes-wgs","exercise-oncology"],"targets":["apc","kras","braf","tp53","egfr","her2","pd1","ctla4"],"drugs":["fluorouracil","oxaliplatin","irinotecan","folfox","folfiri","capox","bevacizumab","cetuximab","panitumumab","trifluridine-tipiracil","encorafenib","pembrolizumab","dostarlimab","tucatinib","sotorasib","botensilimab"],"companies":["merck","bms","amgen","pfizer","servier","gsk","natera","unicancer","alliance-oncology"],"institutions":["esmo","nice","cruk","mskcc","nki","johns-hopkins","ncc-japan","iarc"],"pathways":["wnt","ras-mapk","microbiome-tumour"],"terms":["msi","mmr","sidedness","cms-subtypes","lynch-syndrome","fit-test","ctdna","mrd","total-mesorectal-excision","organ-preservation","clinical-complete-response","total-neoadjuvant-therapy","folfox-family","gut-microbiome-diversity"],"trials":["nordicc","keynote-177","checkmate-8hw","niche-2","atomic","azur-1","breakwater","paradigm","crystal-fire3","beacon-crc","mountaineer","codebreak-300","rapido","prodige-23","opra","dynamic","circulate-japan"],"people":["bert-vogelstein","thierry-andre","andrea-cercek","myriam-chalabi","julio-garcia-aguilar","scott-kopetz","eric-van-cutsem","jeanne-tie","michael-bretthauer","dung-le"],"bottlenecks":["b-early-detection","b-prevention-adoption","b-immunotherapy-response","b-dormancy-mrd","b-resistance","b-surgery-radiation-innovation","b-toxicity-qol","b-workforce","b-care-fragmentation","b-global-access"],"keyPapers":["paper-vogelstein-genetic-alterations-colorectal-tumor-development-nejm-1988","paper-tcga-colon-rectal-molecular-characterization-nature-2012","paper-cms-guinney-nat-med-2015","paper-zauber-national-polyp-study-colonoscopic-polypectomy-nejm-2012","paper-atkin-flexible-sigmoidoscopy-17-year-follow-up-lancet-2017","paper-bretthauer-nordicc-colonoscopy-screening-nejm-2022","paper-heald-mesorectum-rectal-cancer-surgery-br-j-surg-1982","paper-kapiteijn-dutch-tme-preoperative-radiotherapy-nejm-2001","paper-mosaic-oxaliplatin-adjuvant-colon-nejm-2004","paper-idea-duration-adjuvant-stage-iii-colon-nejm-2018","paper-van-cutsem-crystal-cetuximab-folfiri-nejm-2009","paper-arnold-primary-tumour-side-ras-wild-type-ann-oncol-2017","paper-le-pd1-blockade-mismatch-repair-deficiency-nejm-2015","paper-andre-keynote-177-pembrolizumab-msi-high-nejm-2020","paper-cercek-nonoperative-management-mismatch-repair-deficient-tumours-nejm-2025","paper-kopetz-beacon-encorafenib-braf-colorectal-nejm-2019","paper-tie-dynamic-ctdna-guided-adjuvant-stage-ii-colon-nejm-2022","paper-garcia-aguilar-opra-organ-preservation-jco-2022","paper-siegel-colorectal-incidence-birth-cohort-jnci-2017","paper-diaz-gay-colibactin-geographic-age-mutational-processes-nature-2025"],"journals":[],"dependsOn":[],"notes":["Dates in 'What to watch' are quoted from the registry as read on 2026-09-24 and are not predictions; estimated completion dates move.","Papers that already had a record here are linked rather than rewritten: Fearon and Vogelstein 1990, Guinney's consensus molecular subtypes, the Minnesota faecal occult blood trial, Sauer's German chemoradiotherapy trial, Hurwitz on bevacizumab, Amado and Van Cutsem on KRAS and anti-EGFR therapy, Galon's immune contexture, NICHE-2 and Cercek 2022.","A few trials and glossary entries named on this page have no record of their own yet and appear here as text only.","UK and NHS specifics (screening programme ages and uptake, the symptomatic FIT threshold in NG12, NICE NG151 positions, Cancer Drugs Fund status, endoscopy capacity, audit indicators and trial access) are on the UK and NHS page for colorectal cancer and are not restated here."],"steps":[{"era":"1975-1990","title":"A cancer with a visible precursor, and the first proof that finding it early saves lives","description":"Vogelstein, Fearon and colleagues looked for four genetic changes in 172 colorectal specimens spanning adenoma to carcinoma (1988) and found they accumulated in step with clinical progression: ras mutations in 58 percent of adenomas over 1 cm but 9 percent of those under 1 cm, chromosome 18 deletions in 73 percent of carcinomas against 11 to 13 percent of early adenomas, chromosome 17p loss almost only in carcinomas. Fearon and Vogelstein set the model out in Cell in 1990. If cancer grows out of a polyp over years, then screening can prevent it rather than merely bring diagnosis forward, and the Minnesota trial (1993) had already shown that annual stool-blood testing cut colorectal cancer deaths by a third.","refs":["paper-vogelstein-genetic-alterations-colorectal-tumor-development-nejm-1988","paper-fearon-cell","paper-minnesota-fobt-nejm-1993","apc","kras","tp53"],"status":"historic"},{"era":"1982-2009","title":"Total mesorectal excision, and radiotherapy before the operation","description":"Heald, Husband and Ryall found tumour deposits in the fatty envelope around the rectum centimetres below the tumour and began removing the whole envelope intact: 50 curative operations followed two years with no pelvic or staple-line recurrence (1982). The randomised trials then asked what radiotherapy adds on top. The Swedish Rectal Cancer Trial (1997, 1,168 patients) cut five-year local recurrence from 27 to 11 percent and improved survival from 48 to 58 percent, but against surgery that was not standardised. The Dutch TME trial (2001, 1,861 patients) repeated the question against quality-controlled total mesorectal excision: local recurrence fell from 8.2 to 2.4 percent at two years and survival did not change at all. MRC CR07 (2009, 1,350 patients) settled the timing, cutting local recurrence by 61 percent when everyone had short-course radiotherapy before surgery rather than selective chemoradiotherapy after it. Sauer's German trial (2004) made the same case for long-course chemoradiotherapy.","refs":["paper-heald-mesorectum-rectal-cancer-surgery-br-j-surg-1982","paper-swedish-rectal-cancer-trial-preoperative-radiotherapy-nejm-1997","paper-kapiteijn-dutch-tme-preoperative-radiotherapy-nejm-2001","paper-sebag-montefiore-cr07-preoperative-radiotherapy-lancet-2009","paper-sauer-preoperative-chemoradiotherapy-rectal-nejm-2004","total-mesorectal-excision","radiotherapy","cornelis-van-de-velde"],"status":"historic"},{"era":"1990-2007","title":"Chemotherapy after the operation, and how small the benefit is when the nodes are clear","description":"Moertel's 1,296 patients (1990) showed that a year of fluorouracil with levamisole cut recurrence by 41 percent and death by 33 percent in node-positive colon cancer, the first adjuvant standard in the disease. MOSAIC (2004, 2,246 patients) added oxaliplatin and raised three-year disease-free survival from 72.9 to 78.2 percent, at the price of grade 3 sensory neuropathy in 12.4 percent during treatment. QUASAR (2007, 3,239 patients, 91 percent node-negative) then measured what chemotherapy is worth when the nodes are clear: a relative risk of death of 0.82, which the authors translated into an absolute survival gain of 3.6 percent. That number is why stage II treatment has been a conversation rather than a rule ever since, and why a blood test that could pick out the 3.6 percent was worth building.","refs":["paper-moertel-levamisole-fluorouracil-adjuvant-colon-nejm-1990","paper-mosaic-oxaliplatin-adjuvant-colon-nejm-2004","paper-quasar-adjuvant-chemotherapy-vs-observation-lancet-2007","folfox","oxaliplatin","fluorouracil"],"status":"historic"},{"era":"1993-2022","title":"The screening programmes, and the discovery that uptake is the whole game","description":"Nottingham (1996, 152,850 people) and Funen (1996, 61,933) confirmed Minnesota in Europe: biennial stool-blood testing cut colorectal cancer mortality by 15 and 18 percent, with 40 percent of the Nottingham screening group never completing a single test. The National Polyp Study's 23-year follow-up (2012) showed that removing adenomas halved colorectal cancer deaths against the general population, and the UK flexible sigmoidoscopy trial showed one look at the left colon at 55 to 64 cut incidence 23 percent and mortality 31 percent (2010), still holding at 17 years (2017). Then NordICC (2022) randomised invitations to colonoscopy itself in 84,585 people and got an 18 percent reduction in ten-year incidence, because only 42 percent attended. Kaminski (2010) had already shown that who does the colonoscopy matters: endoscopists finding adenomas in under 20 percent of people left their patients around ten times more likely to develop an interval cancer. Multitarget stool DNA (2014) found 92 percent of cancers against 74 percent for the faecal immunochemical test, but only 42 percent of advanced precancerous lesions and with lower specificity.","refs":["paper-hardcastle-nottingham-faecal-occult-blood-lancet-1996","paper-kronborg-funen-faecal-occult-blood-lancet-1996","paper-zauber-national-polyp-study-colonoscopic-polypectomy-nejm-2012","paper-atkin-once-only-flexible-sigmoidoscopy-lancet-2010","paper-atkin-flexible-sigmoidoscopy-17-year-follow-up-lancet-2017","paper-bretthauer-nordicc-colonoscopy-screening-nejm-2022","nordicc","colorectal-screening","colonoscopy"],"status":"current"},{"era":"2004-2017","title":"Antibodies, and the two things that decide whether they work","description":"Hurwitz (2004) put bevacizumab into first-line chemotherapy and CRYSTAL (2009, 1,198 patients) put cetuximab into FOLFIRI, with a progression-free survival hazard ratio of 0.85 overall and 0.68 in KRAS wild-type tumours: the first negative predictive biomarker in the disease. PRIME's extended RAS analysis (2013) found that a further 17 percent of apparently eligible patients carried KRAS or NRAS mutations outside exon 2 and did worse on the antibody, so testing widened to all of KRAS and NRAS exons 2, 3 and 4. Then FIRE-3 (2014) and CALGB/SWOG 80405 (2017) compared the two antibodies head to head and disagreed: 28.7 against 25.0 months favouring cetuximab in Germany, 30.0 against 29.0 months and no difference in North America. Pooling 2,159 patients across six trials (Arnold 2017) reconciled them: the EGFR antibody helps on the left (overall survival hazard ratio 0.75) and not at all on the right (1.12), interaction p<0.001. PARADIGM confirmed it prospectively in 2022. For patients who need a response and cannot have an EGFR antibody, TRIBE (2015) showed the three-drug FOLFOXIRI backbone with bevacizumab reaches 29.8 months.","refs":["paper-hurwitz-bevacizumab-crc-nejm-2004","paper-van-cutsem-crystal-cetuximab-folfiri-nejm-2009","paper-kras-colorectal-j-clin-oncol-2008","paper-douillard-prime-panitumumab-ras-nejm-2013","paper-heinemann-fire-3-cetuximab-vs-bevacizumab-lancet-oncol-2014","paper-venook-calgb-80405-cetuximab-vs-bevacizumab-jama-2017","paradigm","crystal-fire3","cetuximab"],"status":"current"},{"era":"2012-2017","title":"The genome, the subtypes and the hypermutated sixth","description":"The Cancer Genome Atlas read 276 colorectal tumours (2012) and found colon and rectal cancers genomically alike once the hypermutated 16 percent were set aside: three-quarters of those were microsatellite unstable with MLH1 silencing and a quarter carried mismatch-repair or POLE mutations. Twenty-four genes were significantly mutated, and the network flagged amplifications of ERBB2, which is where every HER2 trial in this disease begins. Guinney's consensus molecular subtypes (2015) then sorted expression profiles into four groups, CMS1 immune, CMS2 canonical, CMS3 metabolic and CMS4 mesenchymal, giving the field a shared vocabulary for why right-sided and left-sided tumours behave differently and why stromal tumours resist.","refs":["paper-tcga-colon-rectal-molecular-characterization-nature-2012","paper-cms-guinney-nat-med-2015","cms-subtypes","msi","mmr"],"status":"historic"},{"era":"2013-2023","title":"Refractory lines measured in weeks, and de-escalation measured in months of chemotherapy avoided","description":"CORRECT (2013, 760 patients) gave regorafenib a median survival of 6.4 against 5.0 months with hand-foot skin reaction in 17 percent; RECOURSE (2015, 800 patients) gave trifluridine-tipiracil 7.1 against 5.3 months; SUNLIGHT (2023, 492 patients) added bevacizumab to the tablet and reached 10.8 against 7.5 months, the largest gain the refractory setting has seen; FRESCO-2 (2023, 691 patients) added fruquintinib at 7.4 against 4.8 months. In the curative setting the movement went the other way. The IDEA collaboration pooled six trials and 12,834 patients (2018): three months of CAPOX was non-inferior to six in T1-T3 N1 disease (83.1 against 83.3 percent three-year disease-free survival) while six months of FOLFOX stayed standard for T4 or N2 disease. FOxTROT (2023, 1,053 patients) moved six weeks of chemotherapy before the operation and cut two-year residual or recurrent disease from 21.5 to 16.9 percent with more complete resections.","refs":["paper-grothey-correct-regorafenib-lancet-2013","paper-mayer-recourse-tas-102-nejm-2015","paper-prager-sunlight-trifluridine-tipiracil-bevacizumab-nejm-2023","paper-dasari-fresco-2-fruquintinib-lancet-2023","paper-idea-duration-adjuvant-stage-iii-colon-nejm-2018","paper-foxtrot-preoperative-chemotherapy-colon-jco-2023","sunlight","fresco-2","regorafenib"],"status":"current"},{"era":"2015-2025","title":"Immunotherapy takes mismatch repair-deficient disease apart","description":"Le's 41 patients (2015) gave a 40 percent response in mismatch repair-deficient colorectal cancer and 0 percent in proficient disease, with 1,782 somatic mutations per tumour against 73; the 12-tumour expansion (2017) produced the first tumour-agnostic approval. KEYNOTE-177 (2020, 307 patients) made pembrolizumab the first-line standard for metastatic mismatch repair-deficient disease (16.5 against 8.2 months progression-free, grade 3 toxicity 22 against 66 percent) and reported 77.5 months median survival at five years. CheckMate 8HW (2024) took 24-month progression-free survival to 72 percent against 14 percent with chemotherapy. In curable disease NICHE-2 (2024) gave four weeks of nivolumab and one dose of ipilimumab before surgery and found 68 percent pathological complete responses with no relapses at three years, and ATOMIC (2025) halved recurrence by adding a year of atezolizumab to adjuvant FOLFOX. Then Cercek removed the operation altogether: every mismatch repair-deficient rectal cancer treated with six months of dostarlimab had a clinical complete response (2022, 2025), with 82 of 103 patients across both cohorts avoiding surgery and two-year recurrence-free survival of 92 percent.","refs":["paper-le-pd1-blockade-mismatch-repair-deficiency-nejm-2015","paper-le-mismatch-repair-deficiency-pd1-solid-tumours-science-2017","paper-andre-keynote-177-pembrolizumab-msi-high-nejm-2020","paper-andre-checkmate-8hw-nivolumab-ipilimumab-nejm-2024","paper-niche-2-neoadjuvant-colon-nejm-2024","paper-cercek-dmmr-rectal-nejm-2022","keynote-177","checkmate-8hw","niche-2"],"status":"current"},{"era":"2016-2024","title":"BRAF, HER2 and the first KRAS allele","description":"BRAF V600E disease had a median survival of 13.4 months in TRIBE's molecular analysis and four to six months after first-line failure. BEACON CRC (2019, 665 patients) blocked BRAF and EGFR together and reached 9.0 against 5.4 months with the triplet and 8.4 months with the doublet; BREAKWATER later moved encorafenib and cetuximab into first line with chemotherapy and doubled survival to 30.3 against 15.1 months. HER2 took a different route: HERACLES (2016) screened 914 patients to find 48 amplified and treated 27, with a 30 percent response to trastuzumab and lapatinib; DESTINY-CRC01 (2021) gave trastuzumab deruxtecan a 45.3 percent response with two deaths from interstitial lung disease; MOUNTAINEER (2023) gave tucatinib and trastuzumab a 38.1 percent response and the first United States approval of a HER2 regimen in this disease. CodeBreaK 300 (2023) showed that a KRAS G12C inhibitor needs an EGFR antibody beside it: 5.6 against 2.2 months progression-free with sotorasib plus panitumumab.","refs":["paper-kopetz-beacon-encorafenib-braf-colorectal-nejm-2019","paper-sartore-bianchi-heracles-trastuzumab-lapatinib-lancet-oncol-2016","paper-siena-destiny-crc01-trastuzumab-deruxtecan-lancet-oncol-2021","paper-strickler-mountaineer-tucatinib-trastuzumab-lancet-oncol-2023","paper-fakih-codebreak-300-sotorasib-panitumumab-nejm-2023","beacon-crc","breakwater","mountaineer"],"status":"current"},{"era":"2016-2026","title":"A blood test for the disease that is left behind","description":"Tie's 230 stage II patients (2016) showed circulating tumour DNA after surgery carried a hazard ratio of 18 for recurrence, the first reliable measure of minimal residual disease in a solid tumour. DYNAMIC (2022, 455 patients) turned it into a randomised strategy: chemotherapy fell from 28 to 15 percent of patients with two-year recurrence-free survival of 93.5 against 92.4 percent, non-inferior. GALAXY, the observational arm of CIRCULATE-Japan (2023, 1,039 patients), found a hazard ratio of 10.0 for recurrence at four weeks after surgery and showed the test picks out who benefits from adjuvant chemotherapy (hazard ratio 6.59). What no trial has shown is the other half: that escalating treatment for a positive result improves anything, which is what CIRCULATE-US and the European CIRCULATE trials are built to answer.","refs":["paper-tie-ctdna-minimal-residual-disease-stage-ii-colon-sci-transl-med-2016","paper-tie-dynamic-ctdna-guided-adjuvant-stage-ii-colon-nejm-2022","paper-kotani-galaxy-molecular-residual-disease-nat-med-2023","dynamic","circulate-japan","mrd-testing"],"status":"current"},{"era":"2004-2026","title":"Keeping the rectum, and what surgery still has to carry","description":"Habr-Gama simply watched the patients whose rectal cancers vanished after chemoradiotherapy: 71 of 265, with ten-year overall survival of 97.7 percent across the series (2004). Total neoadjuvant therapy made that outcome plannable. RAPIDO (2021, 920 patients) cut three-year disease-related treatment failure from 30.4 to 23.7 percent by moving all the chemotherapy in front of surgery after one week of radiotherapy; PRODIGE 23 (2021, 461 patients) raised three-year disease-free survival from 69 to 76 percent with FOLFIRINOX before chemoradiotherapy and halved the serious adverse events of adjuvant treatment; OPRA (2022, 324 patients) planned watch and wait from the start and kept the rectum in 53 percent of the consolidation-chemotherapy group with no apparent cost in disease-free survival. Elsewhere surgery held its ground the hard way: Verwaal (2003) established cytoreduction with heated intraperitoneal chemotherapy for peritoneal disease at 22.3 against 12.6 months, and PRODIGE 7 (2021) then removed the heated chemotherapy and found the survival unchanged at 41.7 against 41.2 months, so the benefit had always been the operation. CHALLENGE (2025, 889 patients) showed a three-year structured exercise programme after adjuvant chemotherapy improved disease-free survival with a hazard ratio of 0.72.","refs":["paper-habr-gama-nonoperative-stage-0-rectal-ann-surg-2004","paper-bahadoer-rapido-short-course-radiotherapy-lancet-oncol-2021","paper-conroy-prodige-23-neoadjuvant-folfirinox-rectal-lancet-oncol-2021","paper-garcia-aguilar-opra-organ-preservation-jco-2022","paper-verwaal-cytoreduction-hipec-peritoneal-colorectal-jco-2003","paper-quenet-prodige-7-hipec-peritoneal-colorectal-lancet-oncol-2021","rapido","prodige-23","opra"],"status":"current"},{"era":"2017-2026","title":"The disease is moving younger, and nobody can say why","description":"Siegel's age-period-cohort analysis of 490,305 United States cases (2017) showed the rise in young adults is a birth-cohort effect: someone born around 1990 has double the colon cancer risk and quadruple the rectal cancer risk of someone born around 1950, and the proportion of rectal cancers diagnosed under 55 doubled from 14.6 to 29.2 percent in 23 years. Vuik found the same pattern across 20 European countries and 143.7 million people (2019), with incidence rising 7.9 percent a year in 20 to 29-year-olds. By 2023 one in five new United States cases was in someone under 55, and 60 percent of cases were advanced at diagnosis against 52 percent in the mid-2000s, the stage shift screening had bought going into reverse. The United States lowered the screening start age to 45 in 2021. The strongest mechanistic lead came in 2025, when 981 genomes from 11 countries showed the colibactin signatures SBS88 and ID18 are 3.3 times more common in cancers diagnosed before 40 than after 70, are imprinted early in tumour development and account for about a quarter of APC driver indels where they are present.","refs":["paper-siegel-colorectal-incidence-birth-cohort-jnci-2017","paper-vuik-early-onset-colorectal-europe-gut-2019","paper-siegel-colorectal-cancer-statistics-ca-2023","paper-hur-sugar-sweetened-beverages-early-onset-colorectal-gut-2021","paper-diaz-gay-colibactin-geographic-age-mutational-processes-nature-2025","early-onset-colorectal","microbiome-tumour","idea-crc-early-onset-cause-hunt"],"status":"current"},{"era":"2026-2032","title":"What the registry says is coming","description":"The immunotherapy question moves into curable disease: AZUR-1 (dostarlimab alone for untreated mismatch repair-deficient rectal cancer, 154 participants, actual; active, not recruiting) has a primary completion date of 2 November 2026, and its randomised sibling in colon cancer (perioperative dostarlimab for T4N0 or stage III mismatch repair-deficient disease, 892 estimated participants; recruiting) of 19 March 2029; the NICHE platform runs to 1 March 2032. The ctDNA question moves from prognosis to strategy: CIRCULATE-US (NRG-GI008, 1,912 estimated participants; recruiting) has a primary completion date of 10 March 2029 and the French CIRCULATE (PRODIGE 70, 1,980 estimated participants; recruiting) of March 2032, while COBRA (NRG-GI005, 635 participants, actual) completes on 21 June 2026. HER2 moves first line with MOUNTAINEER-03 (400 estimated participants; recruiting), primary completion 31 December 2027, and BREAKWATER completes on 28 December 2027. Microsatellite stable disease has its first randomised test of Fc-enhanced CTLA-4 blockade (botensilimab and balstilimab, 234 participants, actual; active, not recruiting), primary completion September 2027. Screening's own long game continues: NordICC, with 95,000 participants actual, has a primary completion date of June 2026 and a study completion date of July 2036, which is when the 15-year mortality answer arrives.","refs":["azur-1","circulate-japan","nordicc","mountaineer","breakwater","dostarlimab","mrd-testing","idea-crc-ctdna-de-escalation-beyond-stage-ii","idea-crc-mss-immunotherapy-by-biomarker-not-by-line"],"status":"emerging"},{"era":"What sets the pace","title":"Uptake, capacity, the microsatellite stable majority and who gets to the operating table","description":"Four things no trial on this page has fixed. First, uptake: NordICC's 18 percent reduction in incidence is what a health system gets when 42 percent of invitations are accepted, and Nottingham's 40 percent who never returned a kit are the same problem thirty years earlier. Second, capacity and quality: every positive stool test needs a colonoscopy, and Kaminski showed a tenfold difference in interval cancer risk between endoscopists at either end of the adenoma detection distribution. Third, the microsatellite stable majority: 95 percent of metastatic colorectal cancer responds to none of the immunotherapy on this page, and the best signal so far is a 17 percent response rate in a single-arm phase 1. 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