{"id":"colorectal-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/","eras":[{"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.","status":"historic","refs":[{"id":"paper-vogelstein-genetic-alterations-colorectal-tumor-development-nejm-1988","kind":"paper","name":"Genetic alterations during colorectal-tumor development","route":"/key-papers/paper-vogelstein-genetic-alterations-colorectal-tumor-development-nejm-1988/","tldr":"The 1988 study of 172 bowel tumours that showed cancer is not one mutation but a sequence of them, accumulating as a polyp grows into a cancer. It is the origin of the idea that cancer develops step by step."},{"id":"paper-fearon-cell","kind":"paper","name":"A genetic model for colorectal tumorigenesis","route":"/key-papers/paper-fearon-cell/","tldr":"Paper cited by one term page, indexed on Europe PMC as PubMed record 2188735 and published in Cell; the citing page links this DOI, which is how the record was matched."},{"id":"paper-minnesota-fobt-nejm-1993","kind":"paper","name":"Minnesota trial: a yearly stool blood test cuts bowel cancer deaths by a third","route":"/key-papers/paper-minnesota-fobt-nejm-1993/","tldr":"Annual faecal occult blood testing followed by colonoscopy for positives reduced colorectal cancer deaths by 33% over 13 years, the first proof that bowel cancer screening saves lives."},{"id":"apc","kind":"target","name":"APC","route":"/targets/apc/","tldr":"APC (Adenomatous polyposis coli protein) is a gene whose normal job is to hold cell growth in check. The public catalogues list it as a drug target, an oncogene driver, a tumour suppressor and a biomarker, and an approved or late-stage drug is recorded against it. Tied to Colorectal cancer, Gastric & gastro-oesophageal junction cancer, Hepatocellular carcinoma and 5 more."},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/","tldr":"KRAS is the most commonly mutated cancer gene, called 'undruggable' for 40 years until 2021."},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/","tldr":"TP53 is the 'guardian of the genome', broken in half of all cancers. Fixing it directly has so far defeated every attempt, so drugs exploit what its loss makes cancers depend on."}],"trials":[],"papers":[{"id":"paper-vogelstein-genetic-alterations-colorectal-tumor-development-nejm-1988","name":"Genetic alterations during colorectal-tumor development","route":"/key-papers/paper-vogelstein-genetic-alterations-colorectal-tumor-development-nejm-1988/","journal":"New England Journal of Medicine","year":1988,"whatItMeans":"Every screening programme rests on this paper: if cancer arrives through a polyp that takes years to progress, then finding and removing polyps prevents cancer rather than merely catching it early."},{"id":"paper-fearon-cell","name":"A genetic model for colorectal tumorigenesis","route":"/key-papers/paper-fearon-cell/","journal":"Cell","year":1990,"whatItMeans":"One term page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand."},{"id":"paper-minnesota-fobt-nejm-1993","name":"Minnesota trial: a yearly stool blood test cuts bowel cancer deaths by a third","route":"/key-papers/paper-minnesota-fobt-nejm-1993/","journal":"New England Journal of Medicine","year":1993,"whatItMeans":"A cheap home stool test, repeated yearly or every two years and followed by colonoscopy when positive, prevents bowel cancer deaths. This is what national bowel screening programmes do today, with FIT replacing the older guaiac test."}]},{"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.","status":"historic","refs":[{"id":"paper-heald-mesorectum-rectal-cancer-surgery-br-j-surg-1982","kind":"paper","name":"The mesorectum in rectal cancer surgery: the clue to pelvic recurrence?","route":"/key-papers/paper-heald-mesorectum-rectal-cancer-surgery-br-j-surg-1982/","tldr":"Bill Heald noticed cancer cells hiding in the fatty envelope around the rectum, centimetres below the tumour, and started removing the whole envelope intact. Pelvic recurrence fell from a quarter of patients to almost none."},{"id":"paper-swedish-rectal-cancer-trial-preoperative-radiotherapy-nejm-1997","kind":"paper","name":"Improved survival with preoperative radiotherapy in resectable rectal cancer (Swedish Rectal Cancer Trial)","route":"/key-papers/paper-swedish-rectal-cancer-trial-preoperative-radiotherapy-nejm-1997/","tldr":"Five days of radiotherapy before the operation more than halved the chance of the cancer coming back in the pelvis, and was the first rectal cancer trial to show that radiotherapy also helps people live longer."},{"id":"paper-kapiteijn-dutch-tme-preoperative-radiotherapy-nejm-2001","kind":"paper","name":"Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer (Dutch TME trial)","route":"/key-papers/paper-kapiteijn-dutch-tme-preoperative-radiotherapy-nejm-2001/","tldr":"The trial that asked whether radiotherapy still helps once the surgery is done properly. It does for local control, cutting two-year pelvic recurrence from 8.2 to 2.4 percent, but it did not lengthen life."},{"id":"paper-sebag-montefiore-cr07-preoperative-radiotherapy-lancet-2009","kind":"paper","name":"Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016)","route":"/key-papers/paper-sebag-montefiore-cr07-preoperative-radiotherapy-lancet-2009/","tldr":"The British trial that settled the timing question: giving everyone a short course of radiotherapy before surgery beats operating first and irradiating only those whose margins turn out to be involved."},{"id":"paper-sauer-preoperative-chemoradiotherapy-rectal-nejm-2004","kind":"paper","name":"Sauer 2004: chemoradiotherapy before rather than after surgery for rectal cancer (CAO/ARO/AIO-94)","route":"/key-papers/paper-sauer-preoperative-chemoradiotherapy-rectal-nejm-2004/","tldr":"Giving chemotherapy and radiotherapy before surgery rather than after halved local recurrences of rectal cancer, caused less toxicity and let more patients keep their anal sphincter, without changing overall survival."},{"id":"total-mesorectal-excision","kind":"term","name":"Total mesorectal excision (TME)","route":"/terms/total-mesorectal-excision/","tldr":"The standard rectal cancer operation: the rectum is removed together with its surrounding fatty envelope (the mesorectum) in one intact package, which is where local recurrences used to come from."},{"id":"radiotherapy","kind":"term","name":"Radiotherapy","route":"/terms/radiotherapy/","tldr":"Using high-energy X-rays or particles to damage the DNA of cancer cells in a precisely aimed volume of the body. On its own it cures early prostate, larynx, cervix and skin cancers, it is combined with chemotherapy in head and neck, lung, oesophageal and rectal cancers, and about half of all cancer patients receive it."},{"id":"cornelis-van-de-velde","kind":"person","name":"Cornelis J. H. van de Velde","route":"/people/cornelis-van-de-velde/","tldr":"Surgeon who led the Dutch TME trial, proving standardised rectal surgery with radiotherapy cuts local recurrence."}],"trials":[],"papers":[{"id":"paper-heald-mesorectum-rectal-cancer-surgery-br-j-surg-1982","name":"The mesorectum in rectal cancer surgery: the clue to pelvic recurrence?","route":"/key-papers/paper-heald-mesorectum-rectal-cancer-surgery-br-j-surg-1982/","journal":"British Journal of Surgery","year":1982,"whatItMeans":"The single largest improvement in rectal cancer outcomes came from a change in surgical technique, not a drug. Every radiotherapy trial since has had to show it adds something on top of a properly performed total mesorectal excision."},{"id":"paper-swedish-rectal-cancer-trial-preoperative-radiotherapy-nejm-1997","name":"Improved survival with preoperative radiotherapy in resectable rectal cancer (Swedish Rectal Cancer Trial)","route":"/key-papers/paper-swedish-rectal-cancer-trial-preoperative-radiotherapy-nejm-1997/","journal":"New England Journal of Medicine","year":1997,"whatItMeans":"The origin of short-course preoperative radiotherapy, still the standard schedule across northern Europe and the backbone of the RAPIDO regimen 24 years later."},{"id":"paper-kapiteijn-dutch-tme-preoperative-radiotherapy-nejm-2001","name":"Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer (Dutch TME trial)","route":"/key-papers/paper-kapiteijn-dutch-tme-preoperative-radiotherapy-nejm-2001/","journal":"New England Journal of Medicine","year":2001,"whatItMeans":"The modern basis for offering short-course radiotherapy selectively: it buys local control, not survival, so the decision turns on the predicted recurrence risk from MRI against the long-term bowel and sexual morbidity of pelvic irradiation."},{"id":"paper-sebag-montefiore-cr07-preoperative-radiotherapy-lancet-2009","name":"Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016)","route":"/key-papers/paper-sebag-montefiore-cr07-preoperative-radiotherapy-lancet-2009/","journal":"The Lancet","year":2009,"whatItMeans":"The trial that made preoperative rather than postoperative radiotherapy the UK standard, and the one whose circumferential resection margin pathology protocol, led by Quirke, became the quality measure for rectal surgery worldwide."},{"id":"paper-sauer-preoperative-chemoradiotherapy-rectal-nejm-2004","name":"Sauer 2004: chemoradiotherapy before rather than after surgery for rectal cancer (CAO/ARO/AIO-94)","route":"/key-papers/paper-sauer-preoperative-chemoradiotherapy-rectal-nejm-2004/","journal":"New England Journal of Medicine","year":2004,"whatItMeans":"This trial made preoperative chemoradiotherapy the standard for locally advanced rectal cancer worldwide and is the foundation on which total neoadjuvant therapy and watch-and-wait organ preservation were later built."}]},{"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.","status":"historic","refs":[{"id":"paper-moertel-levamisole-fluorouracil-adjuvant-colon-nejm-1990","kind":"paper","name":"Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma","route":"/key-papers/paper-moertel-levamisole-fluorouracil-adjuvant-colon-nejm-1990/","tldr":"The 1990 trial that first showed chemotherapy after a colon cancer operation stops the cancer coming back. It cut recurrences by 41 percent and deaths by a third in node-positive disease."},{"id":"paper-mosaic-oxaliplatin-adjuvant-colon-nejm-2004","kind":"paper","name":"Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer (MOSAIC)","route":"/key-papers/paper-mosaic-oxaliplatin-adjuvant-colon-nejm-2004/","tldr":"Adding oxaliplatin to chemotherapy after a colon cancer operation cut recurrences by 23 percent. It made FOLFOX the standard, and gave a generation of patients the numb fingers that go with it."},{"id":"paper-quasar-adjuvant-chemotherapy-vs-observation-lancet-2007","kind":"paper","name":"Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study (QUASAR)","route":"/key-papers/paper-quasar-adjuvant-chemotherapy-vs-observation-lancet-2007/","tldr":"The trial that measured how small the benefit of chemotherapy is for node-negative bowel cancer: about 3.6 people in every 100 avoid dying, which is why the decision is a conversation rather than a rule."},{"id":"folfox","kind":"drug","name":"FOLFOX (5-FU, leucovorin, oxaliplatin)","route":"/drugs/folfox/","status":"standard-of-care","tldr":"FOLFOX is the workhorse chemotherapy combination for bowel cancer, used after surgery to cure and in advanced disease as the backbone that targeted drugs are added to."},{"id":"oxaliplatin","kind":"drug","name":"Oxaliplatin","route":"/drugs/oxaliplatin/","status":"approved","tldr":"The platinum drug that works in bowel cancer where cisplatin does not, the 'OX' in FOLFOX and CAPOX; its cost is nerve damage in hands and feet."},{"id":"fluorouracil","kind":"drug","name":"Fluorouracil (5-FU)","route":"/drugs/fluorouracil/","status":"approved","tldr":"The 1957 chemotherapy that remains the backbone of treatment for bowel, stomach, pancreatic, anal, head and neck and breast cancers, and as a cream for skin precancers."}],"trials":[],"papers":[{"id":"paper-moertel-levamisole-fluorouracil-adjuvant-colon-nejm-1990","name":"Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma","route":"/key-papers/paper-moertel-levamisole-fluorouracil-adjuvant-colon-nejm-1990/","journal":"New England Journal of Medicine","year":1990,"whatItMeans":"The start of adjuvant treatment for colon cancer. Levamisole was later dropped, but fluorouracil with folinic acid remained the backbone that oxaliplatin was added to in MOSAIC fourteen years later."},{"id":"paper-mosaic-oxaliplatin-adjuvant-colon-nejm-2004","name":"Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer (MOSAIC)","route":"/key-papers/paper-mosaic-oxaliplatin-adjuvant-colon-nejm-2004/","journal":"New England Journal of Medicine","year":2004,"whatItMeans":"FOLFOX after surgery for stage III colon cancer, still the standard 22 years later, and the reason every later adjuvant trial in this disease is an oxaliplatin trial."},{"id":"paper-quasar-adjuvant-chemotherapy-vs-observation-lancet-2007","name":"Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study (QUASAR)","route":"/key-papers/paper-quasar-adjuvant-chemotherapy-vs-observation-lancet-2007/","journal":"The Lancet","year":2007,"whatItMeans":"The number every stage II conversation still uses. It is also the baseline against which ctDNA-guided de-escalation is judged: DYNAMIC halved chemotherapy use in exactly this group without losing recurrence-free survival."}]},{"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.","status":"current","refs":[{"id":"paper-hardcastle-nottingham-faecal-occult-blood-lancet-1996","kind":"paper","name":"Randomised controlled trial of faecal-occult-blood screening for colorectal cancer (Nottingham)","route":"/key-papers/paper-hardcastle-nottingham-faecal-occult-blood-lancet-1996/","tldr":"The British trial, in 152,850 people around Nottingham, that showed offering a home stool test for hidden blood every two years cut deaths from bowel cancer by 15 percent. It is the trial the NHS Bowel Cancer Screening Programme was built on."},{"id":"paper-kronborg-funen-faecal-occult-blood-lancet-1996","kind":"paper","name":"Randomised study of screening for colorectal cancer with faecal-occult-blood test (Funen)","route":"/key-papers/paper-kronborg-funen-faecal-occult-blood-lancet-1996/","tldr":"The Danish twin of the Nottingham trial: 61,933 people on the island of Funen, stool tests every two years for ten years, and an 18 percent fall in deaths from bowel cancer."},{"id":"paper-zauber-national-polyp-study-colonoscopic-polypectomy-nejm-2012","kind":"paper","name":"Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths (National Polyp Study)","route":"/key-papers/paper-zauber-national-polyp-study-colonoscopic-polypectomy-nejm-2012/","tldr":"Twenty-three years after having their adenomas removed at colonoscopy, 2,602 people in the National Polyp Study had half the bowel cancer deaths expected for the general population. This is the evidence that removing a polyp prevents a death."},{"id":"paper-atkin-once-only-flexible-sigmoidoscopy-lancet-2010","kind":"paper","name":"Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial","route":"/key-papers/paper-atkin-once-only-flexible-sigmoidoscopy-lancet-2010/","tldr":"One look at the lower bowel with a short scope, offered once between 55 and 64, cut bowel cancer cases by a quarter and deaths by a third in a UK trial of 170,432 people."},{"id":"paper-atkin-flexible-sigmoidoscopy-17-year-follow-up-lancet-2017","kind":"paper","name":"Long term effects of once-only flexible sigmoidoscopy screening after 17 years of follow-up","route":"/key-papers/paper-atkin-flexible-sigmoidoscopy-17-year-follow-up-lancet-2017/","tldr":"Seventeen years after a single flexible sigmoidoscopy, the protection was still there: a quarter fewer bowel cancers and a third fewer deaths."},{"id":"paper-bretthauer-nordicc-colonoscopy-screening-nejm-2022","kind":"paper","name":"Effect of colonoscopy screening on risks of colorectal cancer and related death (NordICC)","route":"/key-papers/paper-bretthauer-nordicc-colonoscopy-screening-nejm-2022/","tldr":"The first randomised trial of screening colonoscopy itself. Inviting people to one colonoscopy cut bowel cancer cases by 18 percent over ten years, less than expected, largely because only 42 percent of those invited turned up."},{"id":"nordicc","kind":"trial","name":"NordICC (Nordic-European Initiative on Colorectal Cancer)","route":"/trials/nordicc/","status":"mixed","tldr":"The first randomised trial of colonoscopy screening: being invited cut the risk of bowel cancer by about a fifth, but fewer than half of those invited attended, so the effect on deaths was small."},{"id":"colorectal-screening","kind":"technology","name":"Colorectal cancer screening (colonoscopy, FIT, stool DNA, blood)","route":"/technologies/colorectal-screening/","status":"standard-of-care","tldr":"Finding and removing polyps before they become cancer. Colonoscopy prevents cancer; stool and blood tests catch it early and get more people screened."},{"id":"colonoscopy","kind":"term","name":"Colonoscopy","route":"/terms/colonoscopy/","tldr":"Examining the whole large bowel with a flexible camera; polyps found on the way are removed (polypectomy), which prevents most bowel cancers."}],"trials":[{"id":"nordicc","name":"NordICC (Nordic-European Initiative on Colorectal Cancer)","route":"/trials/nordicc/","outcomes":[{"endpoint":"Colorectal cancer incidence at 10 years (intention to screen)","primary":true,"unit":"%","arms":[{"name":"Invited to colonoscopy","value":0.98},{"name":"Usual care","value":1.2}],"hr":0.82,"ci":[0.7,0.93],"source":"https://doi.org/10.1056/NEJMoa2208375"},{"endpoint":"Colorectal cancer death at 10 years","unit":"%","arms":[{"name":"Invited to colonoscopy","value":0.28},{"name":"Usual care","value":0.31}],"hr":0.9,"ci":[0.64,1.16],"source":"https://doi.org/10.1056/NEJMoa2208375"}],"setting":"Population-based randomised trial of invitation to a single screening colonoscopy versus no invitation in Poland, Norway and Sweden, adults aged 55 to 64","enrolled":84585,"enrolledNote":"ClinicalTrials.gov lists 95,000 participants (actual); the NEJM 2022 analysis covers the 84,585 participants in Poland, Norway and Sweden with follow-up data (28,220 invited, 56,365 usual care).","enrolledBasis":"analysed"}],"papers":[{"id":"paper-hardcastle-nottingham-faecal-occult-blood-lancet-1996","name":"Randomised controlled trial of faecal-occult-blood screening for colorectal cancer (Nottingham)","route":"/key-papers/paper-hardcastle-nottingham-faecal-occult-blood-lancet-1996/","journal":"The Lancet","year":1996,"whatItMeans":"The evidence that a cheap home test posted to a whole population saves lives, and the reason England, Scotland, Wales and Northern Ireland all run bowel screening programmes; the 40 percent who never did the test are the reason uptake is still the biggest lever."},{"id":"paper-kronborg-funen-faecal-occult-blood-lancet-1996","name":"Randomised study of screening for colorectal cancer with faecal-occult-blood test (Funen)","route":"/key-papers/paper-kronborg-funen-faecal-occult-blood-lancet-1996/","journal":"The Lancet","year":1996,"whatItMeans":"The second randomised trial to show the same effect in a different health system; together with Nottingham and Minnesota it made biennial stool testing an accepted public health intervention across Europe."},{"id":"paper-zauber-national-polyp-study-colonoscopic-polypectomy-nejm-2012","name":"Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths (National Polyp Study)","route":"/key-papers/paper-zauber-national-polyp-study-colonoscopic-polypectomy-nejm-2012/","journal":"New England Journal of Medicine","year":2012,"whatItMeans":"The clinical proof of Vogelstein's sequence: interrupting the adenoma-carcinoma pathway with a snare prevents the cancer, which is why colonoscopy is the only screening test that both detects and prevents."},{"id":"paper-atkin-once-only-flexible-sigmoidoscopy-lancet-2010","name":"Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial","route":"/key-papers/paper-atkin-once-only-flexible-sigmoidoscopy-lancet-2010/","journal":"The Lancet","year":2010,"whatItMeans":"The trial behind England's short-lived bowel scope screening programme, and the clearest demonstration that one endoscopic look, by removing adenomas, prevents cancer rather than only advancing its diagnosis."},{"id":"paper-atkin-flexible-sigmoidoscopy-17-year-follow-up-lancet-2017","name":"Long term effects of once-only flexible sigmoidoscopy screening after 17 years of follow-up","route":"/key-papers/paper-atkin-flexible-sigmoidoscopy-17-year-follow-up-lancet-2017/","journal":"The Lancet","year":2017,"whatItMeans":"Durability is what makes endoscopic screening cost-effective: one procedure at 55 buys nearly two decades of protection, which is the argument for long intervals rather than frequent tests."},{"id":"paper-bretthauer-nordicc-colonoscopy-screening-nejm-2022","name":"Effect of colonoscopy screening on risks of colorectal cancer and related death (NordICC)","route":"/key-papers/paper-bretthauer-nordicc-colonoscopy-screening-nejm-2022/","journal":"New England Journal of Medicine","year":2022,"whatItMeans":"Colonoscopy screening works, but the effect a health system gets is the effect of the invitation, not of the procedure; uptake, not test performance, is the binding constraint, and this is the trial that made that argument unavoidable."}]},{"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.","status":"current","refs":[{"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/","tldr":"Adding the VEGF antibody bevacizumab to irinotecan-based chemotherapy prolonged survival in first-line metastatic colorectal cancer, the first time blocking a tumour's blood supply had been shown to help patients."},{"id":"paper-van-cutsem-crystal-cetuximab-folfiri-nejm-2009","kind":"paper","name":"Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer (CRYSTAL)","route":"/key-papers/paper-van-cutsem-crystal-cetuximab-folfiri-nejm-2009/","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."},{"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/","tldr":"Phase 2 or 3 results paper on KRAS in Colorectal cancer, in Journal of Clinical Oncology (2008), one of the most cited Europe PMC records with KRAS in its title."},{"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/","tldr":"Looking beyond the one KRAS exon everyone tested found that a further 17 percent of patients carried a RAS mutation and were harmed rather than helped by the antibody. Testing widened overnight."},{"id":"paper-heinemann-fire-3-cetuximab-vs-bevacizumab-lancet-oncol-2014","kind":"paper","name":"FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3)","route":"/key-papers/paper-heinemann-fire-3-cetuximab-vs-bevacizumab-lancet-oncol-2014/","tldr":"A head-to-head of the two antibodies. They tied on response and progression, but patients on the EGFR antibody lived 3.7 months longer, a result nobody had predicted from the primary endpoint."},{"id":"paper-venook-calgb-80405-cetuximab-vs-bevacizumab-jama-2017","kind":"paper","name":"Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in KRAS wild-type advanced or metastatic colorectal cancer (CALGB/SWOG 80405)","route":"/key-papers/paper-venook-calgb-80405-cetuximab-vs-bevacizumab-jama-2017/","tldr":"The American head-to-head of the same two antibodies, in 1,137 patients, found no difference: 30.0 against 29.0 months. Read next to FIRE-3, it is why sidedness had to be invoked."},{"id":"paradigm","kind":"trial","name":"PARADIGM","route":"/trials/paradigm/","status":"positive","tldr":"Proved that for RAS-normal tumours starting on the left side of the colon, an EGFR antibody beats the VEGF antibody as first partner for chemotherapy."},{"id":"crystal-fire3","kind":"trial","name":"CRYSTAL & FIRE-3","route":"/trials/crystal-fire3/","status":"positive","tldr":"The trials that established EGFR antibodies in bowel cancer and discovered they only work when the RAS gene is normal."},{"id":"cetuximab","kind":"drug","name":"Cetuximab","route":"/drugs/cetuximab/","status":"approved","tldr":"Cetuximab is a chimeric antibody that blocks the EGFR growth receptor. It is used with FOLFIRI or FOLFOX in RAS wild-type, left-sided bowel cancer, with encorafenib in BRAF V600E disease, with KRAS G12C inhibitors, and with radiation or chemotherapy in head and neck cancer; RAS-mutant tumours gain nothing and may be harmed, so RAS testing comes first."}],"trials":[{"id":"paradigm","name":"PARADIGM","route":"/trials/paradigm/","outcomes":[{"endpoint":"Overall survival, left-sided","primary":true,"unit":"months","arms":[{"name":"Panitumumab + mFOLFOX6","value":37.9},{"name":"Bevacizumab + mFOLFOX6","value":34.3}],"hr":0.82,"ci":[0.68,0.99],"p":"0.031","source":"https://ascopubs.org/doi/10.1200/JCO.2022.40.17_suppl.LBA1"}],"setting":"First-line RAS wild-type metastatic colorectal cancer: panitumumab + mFOLFOX6 vs bevacizumab + mFOLFOX6","enrolled":823,"enrolledBasis":"registry"},{"id":"crystal-fire3","name":"CRYSTAL & FIRE-3","route":"/trials/crystal-fire3/","outcomes":[{"endpoint":"Overall survival, KRAS wild-type (CRYSTAL)","unit":"months","arms":[{"name":"FOLFIRI + cetuximab","value":23.5},{"name":"FOLFIRI","value":20}],"hr":0.8,"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa0805019"},{"endpoint":"CRYSTAL: progression-free survival (KRAS wild-type)","unit":"hazard ratio","arms":[{"name":"FOLFIRI plus cetuximab","value":0.68},{"name":"FOLFIRI","value":1}],"hr":0.68,"ci":[0.5,0.94],"source":"https://doi.org/10.1056/NEJMoa0805019"},{"endpoint":"FIRE-3: overall survival (KRAS exon 2 wild-type)","unit":"months","arms":[{"name":"FOLFIRI plus cetuximab","n":297,"value":28.7},{"name":"FOLFIRI plus bevacizumab","n":295,"value":25}],"hr":0.77,"ci":[0.62,0.96],"p":"0.017","source":"https://doi.org/10.1016/S1470-2045(14)70330-4"},{"endpoint":"FIRE-3: objective response (primary endpoint)","primary":true,"unit":"percent","arms":[{"name":"FOLFIRI plus cetuximab","n":297,"value":62},{"name":"FOLFIRI plus bevacizumab","n":295,"value":58}],"p":"0.18","source":"https://doi.org/10.1016/S1470-2045(14)70330-4"}],"setting":"First-line metastatic colorectal cancer: FOLFIRI ± cetuximab (CRYSTAL); FOLFIRI + cetuximab vs FOLFIRI + bevacizumab (FIRE-3)","enrolled":1198,"enrolledNote":"Two trials under one record: CRYSTAL (NCT00154102) randomised 1,198 patients, 599 per arm, and FIRE-3 (NCT00433927) treated 592 patients with KRAS exon 2 wild-type tumours.","enrolledBasis":"randomised"}],"papers":[{"id":"paper-hurwitz-bevacizumab-crc-nejm-2004","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/","journal":"New England Journal of Medicine","year":2004,"whatItMeans":"This trial opened anti-angiogenic therapy as a class, and bevacizumab went on to approvals in lung, kidney, ovarian, cervical and brain cancers. It also set the pattern of modest but real survival gains from adding a biologic to chemotherapy, and introduced hypertension, proteinuria and perforation as the signature side effects clinicians now monitor."},{"id":"paper-van-cutsem-crystal-cetuximab-folfiri-nejm-2009","name":"Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer (CRYSTAL)","route":"/key-papers/paper-van-cutsem-crystal-cetuximab-folfiri-nejm-2009/","journal":"New England Journal of Medicine","year":2009,"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."},{"id":"paper-kras-colorectal-j-clin-oncol-2008","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/","journal":"Journal of Clinical Oncology","year":2008,"whatItMeans":"One of the most cited trial reports Europe PMC returns for KRAS in Colorectal cancer, so it is a natural first reading for anyone weighing the idea it is linked from. The record was linked automatically by title and abstract; read the abstract above and the paper itself before relying on any figure."},{"id":"paper-douillard-prime-panitumumab-ras-nejm-2013","name":"Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer (PRIME)","route":"/key-papers/paper-douillard-prime-panitumumab-ras-nejm-2013/","journal":"New England Journal of Medicine","year":2013,"whatItMeans":"Extended RAS testing (KRAS and NRAS exons 2, 3 and 4) became the standard before any EGFR antibody, and about one in six patients who would previously have been treated is now spared a drug that would have made things worse."},{"id":"paper-heinemann-fire-3-cetuximab-vs-bevacizumab-lancet-oncol-2014","name":"FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3)","route":"/key-papers/paper-heinemann-fire-3-cetuximab-vs-bevacizumab-lancet-oncol-2014/","journal":"The Lancet Oncology","year":2014,"whatItMeans":"Together with PARADIGM it makes the EGFR antibody the preferred first partner for chemotherapy in left-sided RAS wild-type disease; the survival gain without a progression-free survival gain remains one of the field's unexplained results."},{"id":"paper-venook-calgb-80405-cetuximab-vs-bevacizumab-jama-2017","name":"Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in KRAS wild-type advanced or metastatic colorectal cancer (CALGB/SWOG 80405)","route":"/key-papers/paper-venook-calgb-80405-cetuximab-vs-bevacizumab-jama-2017/","journal":"JAMA","year":2017,"whatItMeans":"The negative counterweight to FIRE-3. The two trials are reconciled only by primary tumour side, which is why the sidedness analysis rather than either trial is what guidelines now cite."}]},{"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.","status":"historic","refs":[{"id":"paper-tcga-colon-rectal-molecular-characterization-nature-2012","kind":"paper","name":"Comprehensive molecular characterization of human colon and rectal cancer","route":"/key-papers/paper-tcga-colon-rectal-molecular-characterization-nature-2012/","tldr":"The Cancer Genome Atlas read 276 bowel cancers end to end and found that colon and rectal tumours are genetically the same disease, that one in six is hypermutated, and that a few carry a HER2 amplification that a drug could hit."},{"id":"paper-cms-guinney-nat-med-2015","kind":"paper","name":"The consensus molecular subtypes of colorectal cancer","route":"/key-papers/paper-cms-guinney-nat-med-2015/","tldr":"An international consortium reconciled six competing gene-expression classifications of colorectal cancer into four consensus subtypes, from immune-active microsatellite-unstable tumours to mesenchymal tumours with the worst outlook."},{"id":"cms-subtypes","kind":"term","name":"Consensus molecular subtypes (CMS1-4)","route":"/terms/cms-subtypes/","tldr":"The consensus molecular subtypes are four gene-expression groups of bowel cancer: immune (CMS1), canonical (CMS2), metabolic (CMS3), and mesenchymal (CMS4), with different prognoses."},{"id":"msi","kind":"term","name":"Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)","route":"/terms/msi/","tldr":"Microsatellite instability is the mark of a broken DNA spell-checker (loss of MLH1, MSH2, MSH6 or PMS2) that leaves thousands of mutations, so the tumour displays abnormal proteins that T cells can recognise. It is found in a fraction of colorectal and endometrial cancers and was the basis of the first tumour-agnostic approval, pembrolizumab in 2017."},{"id":"mmr","kind":"target","name":"Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)","route":"/targets/mmr/","tldr":"The four mismatch repair proteins proofread newly copied DNA; when a tumour loses one of them its DNA fills with small errors, and that state (dMMR or MSI-high) is what lets immunotherapy work across many cancers."}],"trials":[],"papers":[{"id":"paper-tcga-colon-rectal-molecular-characterization-nature-2012","name":"Comprehensive molecular characterization of human colon and rectal cancer","route":"/key-papers/paper-tcga-colon-rectal-molecular-characterization-nature-2012/","journal":"Nature","year":2012,"whatItMeans":"The paper that put HER2 on the colorectal map (HERACLES, MOUNTAINEER and DESTINY-CRC follow from it) and that showed the hypermutated group, later the immunotherapy-responsive group, is defined by two distinct mechanisms."},{"id":"paper-cms-guinney-nat-med-2015","name":"The consensus molecular subtypes of colorectal cancer","route":"/key-papers/paper-cms-guinney-nat-med-2015/","journal":"Nature Medicine","year":2015,"whatItMeans":"The CMS framework organises colorectal cancer biology and trial stratification; BRAF V600E tumours cluster in CMS1, and CMS4's poor prognosis and stromal signalling are targets of ongoing research."}]},{"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.","status":"current","refs":[{"id":"paper-grothey-correct-regorafenib-lancet-2013","kind":"paper","name":"Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT)","route":"/key-papers/paper-grothey-correct-regorafenib-lancet-2013/","tldr":"The first pill to extend life after every standard treatment had failed, by 1.4 months, at the price of hand-foot skin reaction in one patient in six."},{"id":"paper-mayer-recourse-tas-102-nejm-2015","kind":"paper","name":"Randomized trial of TAS-102 for refractory metastatic colorectal cancer (RECOURSE)","route":"/key-papers/paper-mayer-recourse-tas-102-nejm-2015/","tldr":"An oral chemotherapy that works where fluorouracil no longer does, adding 1.8 months after everything else has failed, and delaying the slide in performance status by nearly two months."},{"id":"paper-prager-sunlight-trifluridine-tipiracil-bevacizumab-nejm-2023","kind":"paper","name":"Trifluridine-tipiracil and bevacizumab in refractory metastatic colorectal cancer (SUNLIGHT)","route":"/key-papers/paper-prager-sunlight-trifluridine-tipiracil-bevacizumab-nejm-2023/","tldr":"Adding a cheap old antibody to the refractory-line tablet took median survival from 7.5 to 10.8 months, the largest gain in this setting since the setting existed."},{"id":"paper-dasari-fresco-2-fruquintinib-lancet-2023","kind":"paper","name":"Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2)","route":"/key-papers/paper-dasari-fresco-2-fruquintinib-lancet-2023/","tldr":"A selective VEGF receptor pill, first approved in China, repeated its effect in a global trial of 691 heavily treated patients: 7.4 against 4.8 months."},{"id":"paper-idea-duration-adjuvant-stage-iii-colon-nejm-2018","kind":"paper","name":"Duration of adjuvant chemotherapy for stage III colon cancer (the IDEA collaboration)","route":"/key-papers/paper-idea-duration-adjuvant-stage-iii-colon-nejm-2018/","tldr":"Six trials pooled 12,834 patients to ask whether three months of chemotherapy is as good as six. For lower-risk tumours treated with CAPOX it is, and the nerve damage is far less."},{"id":"paper-foxtrot-preoperative-chemotherapy-colon-jco-2023","kind":"paper","name":"Preoperative chemotherapy for operable colon cancer: mature results of an international randomized controlled trial (FOxTROT)","route":"/key-papers/paper-foxtrot-preoperative-chemotherapy-colon-jco-2023/","tldr":"Six weeks of chemotherapy before the colon cancer operation, rather than all of it afterwards, shrank tumours, left fewer incomplete resections and cut two-year recurrence from 21.5 to 16.9 percent."},{"id":"sunlight","kind":"trial","name":"SUNLIGHT","route":"/trials/sunlight/","status":"positive","tldr":"Adding the old blood-vessel antibody to a late-line chemotherapy pill extended survival by three months in patients who had exhausted standard options."},{"id":"fresco-2","kind":"trial","name":"FRESCO-2","route":"/trials/fresco-2/","status":"positive","tldr":"A selective VEGF-receptor pill gave a modest but real survival gain in patients with no remaining standard treatment."},{"id":"regorafenib","kind":"drug","name":"Regorafenib","route":"/drugs/regorafenib/","status":"approved","tldr":"A sorafenib successor that became the first second-line drug proven to prolong life in liver cancer (2017)."}],"trials":[{"id":"sunlight","name":"SUNLIGHT","route":"/trials/sunlight/","outcomes":[{"endpoint":"Overall survival","primary":true,"unit":"months","arms":[{"name":"Trifluridine/tipiracil + bevacizumab","n":246,"value":10.8},{"name":"Trifluridine/tipiracil","n":246,"value":7.5}],"hr":0.61,"ci":[0.49,0.77],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2214963"}],"setting":"Refractory metastatic colorectal cancer: trifluridine/tipiracil + bevacizumab vs trifluridine/tipiracil","enrolled":492,"enrolledBasis":"registry"},{"id":"fresco-2","name":"FRESCO-2","route":"/trials/fresco-2/","outcomes":[{"endpoint":"Overall survival","primary":true,"unit":"months","arms":[{"name":"Fruquintinib","n":461,"value":7.4},{"name":"Placebo","n":230,"value":4.8}],"hr":0.66,"ci":[0.55,0.8],"source":"https://www.takedaoncology.com/newsroom/news-releases/2023/hutchmed-fresco2-lancet-results/"}],"setting":"Refractory metastatic colorectal cancer after all standard therapies: fruquintinib vs placebo","enrolled":691,"enrolledBasis":"registry"}],"papers":[{"id":"paper-grothey-correct-regorafenib-lancet-2013","name":"Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT)","route":"/key-papers/paper-grothey-correct-regorafenib-lancet-2013/","journal":"The Lancet","year":2013,"whatItMeans":"The start of the refractory-line era in colorectal cancer: a survival benefit measured in weeks, with real toxicity, which is why dose-escalation strategies and patient selection have occupied the field since."},{"id":"paper-mayer-recourse-tas-102-nejm-2015","name":"Randomized trial of TAS-102 for refractory metastatic colorectal cancer (RECOURSE)","route":"/key-papers/paper-mayer-recourse-tas-102-nejm-2015/","journal":"New England Journal of Medicine","year":2015,"whatItMeans":"Trifluridine-tipiracil became the other refractory-line standard alongside regorafenib, and the backbone that SUNLIGHT later improved on by adding bevacizumab."},{"id":"paper-prager-sunlight-trifluridine-tipiracil-bevacizumab-nejm-2023","name":"Trifluridine-tipiracil and bevacizumab in refractory metastatic colorectal cancer (SUNLIGHT)","route":"/key-papers/paper-prager-sunlight-trifluridine-tipiracil-bevacizumab-nejm-2023/","journal":"New England Journal of Medicine","year":2023,"whatItMeans":"Trifluridine-tipiracil with bevacizumab is the refractory-line standard, and a reminder that combining two drugs already on the shelf can beat anything new in the same line."},{"id":"paper-dasari-fresco-2-fruquintinib-lancet-2023","name":"Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2)","route":"/key-papers/paper-dasari-fresco-2-fruquintinib-lancet-2023/","journal":"The Lancet","year":2023,"whatItMeans":"A third refractory-line option, and the clearest example in colorectal cancer of a drug developed and approved in China going on to a global registration trial."},{"id":"paper-idea-duration-adjuvant-stage-iii-colon-nejm-2018","name":"Duration of adjuvant chemotherapy for stage III colon cancer (the IDEA collaboration)","route":"/key-papers/paper-idea-duration-adjuvant-stage-iii-colon-nejm-2018/","journal":"New England Journal of Medicine","year":2018,"whatItMeans":"The largest de-escalation exercise in adjuvant oncology, and the reason a patient with a T3 N1 colon cancer is now offered four cycles of CAPOX rather than twelve of FOLFOX, with a fraction of the neuropathy."},{"id":"paper-foxtrot-preoperative-chemotherapy-colon-jco-2023","name":"Preoperative chemotherapy for operable colon cancer: mature results of an international randomized controlled trial (FOxTROT)","route":"/key-papers/paper-foxtrot-preoperative-chemotherapy-colon-jco-2023/","journal":"Journal of Clinical Oncology","year":2023,"whatItMeans":"A UK-led trial that moved part of colon cancer chemotherapy in front of the operation, and showed that tumour regression grade after six weeks predicts recurrence, which is the basis for using the response itself to choose what follows."}]},{"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.","status":"current","refs":[{"id":"paper-le-pd1-blockade-mismatch-repair-deficiency-nejm-2015","kind":"paper","name":"PD-1 blockade in tumors with mismatch-repair deficiency","route":"/key-papers/paper-le-pd1-blockade-mismatch-repair-deficiency-nejm-2015/","tldr":"Forty-one patients settled a decade of argument: colorectal cancers with a broken DNA spell-checker responded to immunotherapy in 40 percent of cases, and those without responded in none."},{"id":"paper-le-mismatch-repair-deficiency-pd1-solid-tumours-science-2017","kind":"paper","name":"Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade","route":"/key-papers/paper-le-mismatch-repair-deficiency-pd1-solid-tumours-science-2017/","tldr":"The follow-up that took the same test across 12 different cancers and found the same answer, producing the first drug approval in history based on a molecular feature rather than an organ."},{"id":"paper-andre-keynote-177-pembrolizumab-msi-high-nejm-2020","kind":"paper","name":"Pembrolizumab in microsatellite-instability-high advanced colorectal cancer (KEYNOTE-177)","route":"/key-papers/paper-andre-keynote-177-pembrolizumab-msi-high-nejm-2020/","tldr":"The randomised trial that replaced chemotherapy with a single antibody as the first treatment for the 5 percent of metastatic bowel cancers with a broken DNA spell-checker: 16.5 against 8.2 months without progression, and a quarter of the severe side effects."},{"id":"paper-andre-checkmate-8hw-nivolumab-ipilimumab-nejm-2024","kind":"paper","name":"Nivolumab plus ipilimumab in microsatellite-instability-high metastatic colorectal cancer (CheckMate 8HW)","route":"/key-papers/paper-andre-checkmate-8hw-nivolumab-ipilimumab-nejm-2024/","tldr":"Two immunotherapy drugs together kept 72 percent of patients progression-free at two years against 14 percent on chemotherapy, the largest effect size of any first-line trial in colorectal cancer."},{"id":"paper-niche-2-neoadjuvant-colon-nejm-2024","kind":"paper","name":"NICHE-2: a single dose of ipilimumab and two of nivolumab before surgery clears dMMR colon cancer in most patients","route":"/key-papers/paper-niche-2-neoadjuvant-colon-nejm-2024/","tldr":"In NICHE-2, four weeks of checkpoint blockade before surgery eliminated nearly all tumour in 95% of patients with mismatch-repair-deficient colon cancer, and none had relapsed at three years."},{"id":"paper-cercek-dmmr-rectal-nejm-2022","kind":"paper","name":"Dostarlimab alone cures mismatch-repair-deficient rectal cancer without surgery or radiotherapy","route":"/key-papers/paper-cercek-dmmr-rectal-nejm-2022/","tldr":"Six months of the PD-1 antibody dostarlimab made every tumour disappear in a small group of patients with mismatch-repair-deficient rectal cancer, allowing them to avoid chemotherapy, radiotherapy and surgery."},{"id":"keynote-177","kind":"trial","name":"KEYNOTE-177","route":"/trials/keynote-177/","status":"positive","tldr":"The trial that made immunotherapy alone, with no chemotherapy, the first treatment for the 5% of bowel cancers with a broken DNA spell-checker. Over half of patients were alive at five years."},{"id":"checkmate-8hw","kind":"trial","name":"CheckMate 8HW","route":"/trials/checkmate-8hw/","status":"positive","tldr":"Showed that a two-drug immunotherapy combination controls mismatch-repair-deficient bowel cancer for over four years on average, and beats immunotherapy alone."},{"id":"niche-2","kind":"trial","name":"NICHE-2","route":"/trials/niche-2/","status":"positive","tldr":"In NICHE-2, four weeks of immunotherapy before surgery wiped out most mismatch-repair-deficient colon cancers, and nobody had relapsed three years later."}],"trials":[{"id":"keynote-177","name":"KEYNOTE-177","route":"/trials/keynote-177/","outcomes":[{"endpoint":"Progression-free survival","primary":true,"unit":"months","arms":[{"name":"Pembrolizumab","n":153,"value":16.5},{"name":"Chemotherapy","n":154,"value":8.2}],"hr":0.6,"ci":[0.45,0.8],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2017699"},{"endpoint":"Overall survival (5-year follow-up)","unit":"months","arms":[{"name":"Pembrolizumab","n":153,"value":77.5},{"name":"Chemotherapy","n":154,"value":36.7}],"hr":0.73,"source":"https://www.annalsofoncology.org/article/S0923-7534(24)04949-4/fulltext"}],"setting":"First-line MSI-H/dMMR metastatic colorectal cancer: pembrolizumab vs investigator-choice chemotherapy","enrolled":307,"enrolledBasis":"registry"},{"id":"checkmate-8hw","name":"CheckMate 8HW","route":"/trials/checkmate-8hw/","outcomes":[{"endpoint":"Progression-free survival, first line","primary":true,"unit":"months","arms":[{"name":"Nivolumab + ipilimumab","n":202,"value":54.1},{"name":"Chemotherapy","n":101,"value":5.9}],"hr":0.21,"source":"https://dailynews.ascopubs.org/do/updated-checkmate-8hw-results-nivolumab-ipilimumab-shows-sustained-pfs-benefit-msi-h"},{"endpoint":"Progression-free survival, all lines: combination vs nivolumab","arms":[{"name":"Nivolumab + ipilimumab","n":296},{"name":"Nivolumab","n":286}],"hr":0.62,"source":"https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)02848-4/abstract"}],"setting":"MSI-H/dMMR metastatic colorectal cancer, all lines: nivolumab + ipilimumab vs nivolumab vs chemotherapy","enrolled":839,"enrolledBasis":"registry"},{"id":"niche-2","name":"NICHE-2","route":"/trials/niche-2/","outcomes":[{"endpoint":"Pathologic complete response","primary":true,"unit":"percent","arms":[{"name":"Neoadjuvant nivolumab + ipilimumab","n":111,"value":68}],"source":"https://www.nejm.org/doi/abs/10.1056/NEJMoa2400634"},{"endpoint":"3-year disease-free survival","unit":"percent","arms":[{"name":"Neoadjuvant nivolumab + ipilimumab","n":111,"value":100}],"source":"https://www.annalsofoncology.org/article/S0923-7534(24)03843-2/fulltext"}],"setting":"Locally advanced (mostly stage III) dMMR colon cancer: 4 weeks of neoadjuvant nivolumab + one dose ipilimumab, then surgery","enrolled":115,"enrolledNote":"ClinicalTrials.gov lists an estimated 353 participants for the amended NICHE protocol, which is still recruiting to further cohorts; the NEJM 2024 NICHE-2 analysis enrolled 115 patients, 111 of them in the efficacy analysis.","enrolledBasis":"registered"}],"papers":[{"id":"paper-le-pd1-blockade-mismatch-repair-deficiency-nejm-2015","name":"PD-1 blockade in tumors with mismatch-repair deficiency","route":"/key-papers/paper-le-pd1-blockade-mismatch-repair-deficiency-nejm-2015/","journal":"New England Journal of Medicine","year":2015,"whatItMeans":"The paper that split colorectal cancer into two diseases for immunotherapy purposes, and the direct ancestor of the first tumour-agnostic drug approval two years later."},{"id":"paper-le-mismatch-repair-deficiency-pd1-solid-tumours-science-2017","name":"Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade","route":"/key-papers/paper-le-mismatch-repair-deficiency-pd1-solid-tumours-science-2017/","journal":"Science","year":2017,"whatItMeans":"The first tumour-agnostic approval, and the reason every patient with metastatic colorectal cancer has mismatch repair status tested regardless of where the tumour started."},{"id":"paper-andre-keynote-177-pembrolizumab-msi-high-nejm-2020","name":"Pembrolizumab in microsatellite-instability-high advanced colorectal cancer (KEYNOTE-177)","route":"/key-papers/paper-andre-keynote-177-pembrolizumab-msi-high-nejm-2020/","journal":"New England Journal of Medicine","year":2020,"whatItMeans":"First-line chemotherapy-free treatment for mismatch repair-deficient metastatic colorectal cancer, approved in June 2020; the five-year follow-up published in 2024 reported median overall survival of 77.5 months despite 62 percent crossover."},{"id":"paper-andre-checkmate-8hw-nivolumab-ipilimumab-nejm-2024","name":"Nivolumab plus ipilimumab in microsatellite-instability-high metastatic colorectal cancer (CheckMate 8HW)","route":"/key-papers/paper-andre-checkmate-8hw-nivolumab-ipilimumab-nejm-2024/","journal":"New England Journal of Medicine","year":2024,"whatItMeans":"Combination checkpoint blockade became a first-line standard for mismatch repair-deficient metastatic colorectal cancer in 2025; the later all-lines comparison against nivolumab alone showed the CTLA-4 antibody adds to the PD-1 antibody, the first phase 3 to prove that in this disease."},{"id":"paper-niche-2-neoadjuvant-colon-nejm-2024","name":"NICHE-2: a single dose of ipilimumab and two of nivolumab before surgery clears dMMR colon cancer in most patients","route":"/key-papers/paper-niche-2-neoadjuvant-colon-nejm-2024/","journal":"New England Journal of Medicine","year":2024,"whatItMeans":"NICHE-2 shows that a month of immunotherapy before surgery can effectively cure locally advanced dMMR colon cancer, where chemotherapy after surgery has limited benefit. It is changing guidelines towards neoadjuvant checkpoint blockade for this group and raises the question of whether surgery can be omitted altogether, as in dMMR rectal cancer. Whether the same applies to MMR-proficient tumours is being tested but is not established."},{"id":"paper-cercek-dmmr-rectal-nejm-2022","name":"Dostarlimab alone cures mismatch-repair-deficient rectal cancer without surgery or radiotherapy","route":"/key-papers/paper-cercek-dmmr-rectal-nejm-2022/","journal":"New England Journal of Medicine","year":2022,"whatItMeans":"Patients with rectal cancer whose tumour is mismatch-repair deficient (about 5-10% of rectal cancers) can now be offered immunotherapy alone with the realistic expectation of avoiding surgery, radiotherapy and a permanent stoma. This requires mismatch repair testing on the diagnostic biopsy, close endoscopic and MRI surveillance, and treatment in an experienced centre. It does not apply to the 90% of rectal cancers that are mismatch-repair proficient."}]},{"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.","status":"current","refs":[{"id":"paper-kopetz-beacon-encorafenib-braf-colorectal-nejm-2019","kind":"paper","name":"Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer (BEACON CRC)","route":"/key-papers/paper-kopetz-beacon-encorafenib-braf-colorectal-nejm-2019/","tldr":"BRAF V600E bowel cancer had a median survival of four to six months after first-line failure. Blocking BRAF and EGFR together took it to nine, and made the doublet a standard."},{"id":"paper-sartore-bianchi-heracles-trastuzumab-lapatinib-lancet-oncol-2016","kind":"paper","name":"Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES)","route":"/key-papers/paper-sartore-bianchi-heracles-trastuzumab-lapatinib-lancet-oncol-2016/","tldr":"A trial designed from mouse avatars: screening 914 patients found 48 with HER2-amplified bowel cancer, and blocking HER2 two ways shrank tumours in 30 percent of the 27 who were treated."},{"id":"paper-siena-destiny-crc01-trastuzumab-deruxtecan-lancet-oncol-2021","kind":"paper","name":"Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01)","route":"/key-papers/paper-siena-destiny-crc01-trastuzumab-deruxtecan-lancet-oncol-2021/","tldr":"An antibody carrying a chemotherapy payload shrank 45 percent of HER2-positive bowel cancers that had already failed two or more treatments, including tumours that had progressed on other HER2 drugs."},{"id":"paper-strickler-mountaineer-tucatinib-trastuzumab-lancet-oncol-2023","kind":"paper","name":"Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER)","route":"/key-papers/paper-strickler-mountaineer-tucatinib-trastuzumab-lancet-oncol-2023/","tldr":"A HER2 pill with an antibody gave a 38 percent response rate in chemotherapy-refractory HER2-positive bowel cancer, and became the first HER2-directed regimen approved for the disease."},{"id":"paper-fakih-codebreak-300-sotorasib-panitumumab-nejm-2023","kind":"paper","name":"Sotorasib plus panitumumab in refractory colorectal cancer with mutated KRAS G12C (CodeBreaK 300)","route":"/key-papers/paper-fakih-codebreak-300-sotorasib-panitumumab-nejm-2023/","tldr":"KRAS G12C inhibitors alone barely work in bowel cancer because the tumour switches EGFR back on. Blocking both at once more than doubled progression-free survival against standard refractory treatment."},{"id":"beacon-crc","kind":"trial","name":"BEACON CRC","route":"/trials/beacon-crc/","status":"positive","tldr":"BEACON was the first trial to show that blocking BRAF works in bowel cancer once the escape route through EGFR is blocked too: encorafenib with cetuximab lengthened life and shrank ten times as many tumours as chemotherapy."},{"id":"breakwater","kind":"trial","name":"BREAKWATER","route":"/trials/breakwater/","status":"positive","tldr":"Doubled survival, from about 15 to about 30 months, in the worst-prognosis genetic subtype of bowel cancer by adding two targeted drugs to first-line chemotherapy."},{"id":"mountaineer","kind":"trial","name":"MOUNTAINEER","route":"/trials/mountaineer/","status":"completed","tldr":"A HER2 pill plus antibody gave durable responses in the 3-5% of bowel cancers driven by HER2, and is now being tested as first-line treatment."}],"trials":[{"id":"beacon-crc","name":"BEACON CRC","route":"/trials/beacon-crc/","outcomes":[{"endpoint":"Overall survival (updated analysis)","primary":true,"unit":"months","arms":[{"name":"Encorafenib + binimetinib + cetuximab","n":224,"value":9.3},{"name":"Encorafenib + cetuximab","n":220,"value":9.3},{"name":"Chemotherapy + cetuximab","n":221,"value":5.9}],"source":"https://doi.org/10.1200/JCO.20.02088"},{"endpoint":"Confirmed objective response rate","unit":"%","arms":[{"name":"Encorafenib + binimetinib + cetuximab","n":224,"value":27},{"name":"Encorafenib + cetuximab","n":220,"value":20},{"name":"Chemotherapy + cetuximab","n":221,"value":2}],"source":"https://doi.org/10.1200/JCO.20.02088"}],"setting":"BRAF V600E-mutant metastatic colorectal cancer after one or two prior lines: encorafenib plus cetuximab with or without binimetinib, versus irinotecan-based chemotherapy plus cetuximab","enrolled":665,"enrolledBasis":"registry"},{"id":"breakwater","name":"BREAKWATER","route":"/trials/breakwater/","outcomes":[{"endpoint":"Overall survival (EC + mFOLFOX6)","unit":"months","arms":[{"name":"Encorafenib + cetuximab + mFOLFOX6","value":30.3},{"name":"Chemotherapy ± bevacizumab","value":15.1}],"hr":0.49,"source":"https://ascopubs.org/doi/10.1200/JCO.2025.43.17_suppl.LBA3500"},{"endpoint":"Progression-free survival (EC + mFOLFOX6)","primary":true,"unit":"months","arms":[{"name":"Encorafenib + cetuximab + mFOLFOX6","value":12.8},{"name":"Chemotherapy ± bevacizumab","value":7.1}],"source":"https://ascopubs.org/doi/10.1200/JCO.2025.43.17_suppl.LBA3500"},{"endpoint":"Progression-free survival (EC + FOLFIRI cohort)","unit":"months","arms":[{"name":"Encorafenib + cetuximab + FOLFIRI"},{"name":"Chemotherapy ± bevacizumab"}],"hr":0.44,"source":"https://ascopubs.org/doi/10.1200/JCO.2026.44.17_suppl.LBA3503"}],"setting":"First-line BRAF V600E-mutant metastatic colorectal cancer: encorafenib + cetuximab + mFOLFOX6 (or FOLFIRI) vs chemotherapy ± bevacizumab","enrolledBasis":"registry"},{"id":"mountaineer","name":"MOUNTAINEER","route":"/trials/mountaineer/","outcomes":[{"endpoint":"Objective response rate (phase 2)","primary":true,"unit":"percent","arms":[{"name":"Tucatinib + trastuzumab","n":84,"value":38.1}],"source":"https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.3509"}],"setting":"Chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer: tucatinib plus trastuzumab (cohorts A and B) or tucatinib alone (cohort C)","enrolledBasis":"registry"}],"papers":[{"id":"paper-kopetz-beacon-encorafenib-braf-colorectal-nejm-2019","name":"Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer (BEACON CRC)","route":"/key-papers/paper-kopetz-beacon-encorafenib-braf-colorectal-nejm-2019/","journal":"New England Journal of Medicine","year":2019,"whatItMeans":"Encorafenib with cetuximab became the standard second-line treatment for BRAF V600E disease, and the platform BREAKWATER later moved into first line with chemotherapy added, doubling survival again."},{"id":"paper-sartore-bianchi-heracles-trastuzumab-lapatinib-lancet-oncol-2016","name":"Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES)","route":"/key-papers/paper-sartore-bianchi-heracles-trastuzumab-lapatinib-lancet-oncol-2016/","journal":"The Lancet Oncology","year":2016,"whatItMeans":"The first demonstration that HER2 is actionable in colorectal cancer, and the trial that defined the colorectal-specific HER2 scoring criteria every later trial has used."},{"id":"paper-siena-destiny-crc01-trastuzumab-deruxtecan-lancet-oncol-2021","name":"Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01)","route":"/key-papers/paper-siena-destiny-crc01-trastuzumab-deruxtecan-lancet-oncol-2021/","journal":"The Lancet Oncology","year":2021,"whatItMeans":"The antibody-drug conjugate route into HER2-positive colorectal cancer, extended by DESTINY-CRC02 at a lower dose; interstitial lung disease is the class risk that defines how the drug is monitored."},{"id":"paper-strickler-mountaineer-tucatinib-trastuzumab-lancet-oncol-2023","name":"Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER)","route":"/key-papers/paper-strickler-mountaineer-tucatinib-trastuzumab-lancet-oncol-2023/","journal":"The Lancet Oncology","year":2023,"whatItMeans":"The first United States approval of a HER2-directed regimen in colorectal cancer, and the basis for MOUNTAINEER-03, which is testing the combination with chemotherapy in the first line."},{"id":"paper-fakih-codebreak-300-sotorasib-panitumumab-nejm-2023","name":"Sotorasib plus panitumumab in refractory colorectal cancer with mutated KRAS G12C (CodeBreaK 300)","route":"/key-papers/paper-fakih-codebreak-300-sotorasib-panitumumab-nejm-2023/","journal":"New England Journal of Medicine","year":2023,"whatItMeans":"The proof that a RAS inhibitor in colorectal cancer needs an EGFR antibody beside it, a principle that now shapes the trials of the pan-RAS and G12D inhibitors following behind."}]},{"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.","status":"current","refs":[{"id":"paper-tie-ctdna-minimal-residual-disease-stage-ii-colon-sci-transl-med-2016","kind":"paper","name":"Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer","route":"/key-papers/paper-tie-ctdna-minimal-residual-disease-stage-ii-colon-sci-transl-med-2016/","tldr":"Traces of tumour DNA in blood after a colon cancer operation identified the patients who would relapse with a hazard ratio of 18. It is the observation the whole ctDNA field is built on."},{"id":"paper-tie-dynamic-ctdna-guided-adjuvant-stage-ii-colon-nejm-2022","kind":"paper","name":"Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer (DYNAMIC)","route":"/key-papers/paper-tie-dynamic-ctdna-guided-adjuvant-stage-ii-colon-nejm-2022/","tldr":"The first randomised trial to let a blood test decide who gets chemotherapy. It halved chemotherapy use in stage II colon cancer with no loss of recurrence-free survival."},{"id":"paper-kotani-galaxy-molecular-residual-disease-nat-med-2023","kind":"paper","name":"Molecular residual disease and efficacy of adjuvant chemotherapy in patients with colorectal cancer (GALAXY, CIRCULATE-Japan)","route":"/key-papers/paper-kotani-galaxy-molecular-residual-disease-nat-med-2023/","tldr":"In 1,039 Japanese patients, tumour DNA in blood four weeks after surgery was the strongest predictor of recurrence ever measured in this disease, and picked out exactly the patients whose chemotherapy did some good."},{"id":"dynamic","kind":"trial","name":"DYNAMIC","route":"/trials/dynamic/","status":"positive","tldr":"Showed that a blood test can safely halve the number of colon cancer patients given chemotherapy after surgery."},{"id":"circulate-japan","kind":"trial","name":"CIRCULATE-Japan (GALAXY / VEGA / ALTAIR)","route":"/trials/circulate-japan/","status":"active","tldr":"Japan's national programme tests whether a blood test after surgery should decide who gets chemotherapy, and whether treating a positive test early helps."},{"id":"mrd-testing","kind":"technology","name":"MRD / molecular residual disease testing","route":"/technologies/mrd-testing/","status":"established","tldr":"An ultra-sensitive blood test after surgery that detects leftover cancer months before a scan would."}],"trials":[{"id":"dynamic","name":"DYNAMIC","route":"/trials/dynamic/","outcomes":[{"endpoint":"Recurrence-free survival at 2 years (non-inferiority)","primary":true,"unit":"%","arms":[{"name":"ctDNA-guided management","n":302,"value":93.5,"note":"Non-inferiority met (margin −8.5 points)"},{"name":"Standard management","n":153,"value":92.4}],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2200075"},{"endpoint":"Patients receiving adjuvant chemotherapy","unit":"%","arms":[{"name":"ctDNA-guided management","value":15},{"name":"Standard management","value":28}],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2200075"}],"setting":"Stage II colon cancer: ctDNA-guided adjuvant chemotherapy vs standard management","enrolled":455,"enrolledBasis":"registry"},{"id":"circulate-japan","name":"CIRCULATE-Japan (GALAXY / VEGA / ALTAIR)","route":"/trials/circulate-japan/","outcomes":[{"endpoint":"GALAXY (observational): recurrence risk by post-operative ctDNA status (4 weeks after surgery)","arms":[{"name":"ctDNA-positive","note":"n = 1,039 resectable stage II-IV CRC; ctDNA positivity was the strongest prognostic factor and identified who benefited from adjuvant chemotherapy (HR 6.59)"},{"name":"ctDNA-negative"}],"hr":10,"p":"<0.0001","source":"https://doi.org/10.1038/s41591-022-02115-4"},{"endpoint":"ALTAIR (randomised phase 3): disease-free survival in post-adjuvant ctDNA-positive patients","primary":true,"unit":"months","arms":[{"name":"Trifluridine/tipiracil","n":122,"value":9.3,"note":"Primary endpoint not met"},{"name":"Placebo","n":121,"value":5.55}],"hr":0.79,"ci":[0.6,1.05],"p":"0.107","source":"https://doi.org/10.1038/s41591-026-04428-0"}],"setting":"Resected stage II-IV colorectal cancer: ctDNA (Signatera) to guide adjuvant chemotherapy de-escalation (VEGA) or escalation with trifluridine/tipiracil (ALTAIR)","enrolledBasis":"registry"}],"papers":[{"id":"paper-tie-ctdna-minimal-residual-disease-stage-ii-colon-sci-transl-med-2016","name":"Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer","route":"/key-papers/paper-tie-ctdna-minimal-residual-disease-stage-ii-colon-sci-transl-med-2016/","journal":"Science Translational Medicine","year":2016,"whatItMeans":"Minimal residual disease became measurable in solid tumours, and the DYNAMIC and CIRCULATE trials that followed turned the measurement into a treatment decision."},{"id":"paper-tie-dynamic-ctdna-guided-adjuvant-stage-ii-colon-nejm-2022","name":"Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer (DYNAMIC)","route":"/key-papers/paper-tie-dynamic-ctdna-guided-adjuvant-stage-ii-colon-nejm-2022/","journal":"New England Journal of Medicine","year":2022,"whatItMeans":"De-escalation guided by a blood test is now proven in stage II colon cancer, and is the template for the stage III and rectal trials that follow; the unsolved half is what to do for the positives, whose recurrence-free survival remains the worst in the trial even after chemotherapy."},{"id":"paper-kotani-galaxy-molecular-residual-disease-nat-med-2023","name":"Molecular residual disease and efficacy of adjuvant chemotherapy in patients with colorectal cancer (GALAXY, CIRCULATE-Japan)","route":"/key-papers/paper-kotani-galaxy-molecular-residual-disease-nat-med-2023/","journal":"Nature Medicine","year":2023,"whatItMeans":"The predictive half of the ctDNA case: chemotherapy after surgery helps the patients whose blood test is positive and appears to do little for those whose test is negative, which is the rationale for the randomised CIRCULATE trials now running in Japan, the United States and Europe."}]},{"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.","status":"current","refs":[{"id":"paper-habr-gama-nonoperative-stage-0-rectal-ann-surg-2004","kind":"paper","name":"Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results","route":"/key-papers/paper-habr-gama-nonoperative-stage-0-rectal-ann-surg-2004/","tldr":"In São Paulo, Angelita Habr-Gama simply watched the patients whose rectal cancers had disappeared after chemoradiotherapy instead of operating. Ten-year survival was 98 percent, and she had invented watch and wait."},{"id":"paper-bahadoer-rapido-short-course-radiotherapy-lancet-oncol-2021","kind":"paper","name":"Short-course radiotherapy followed by chemotherapy before total mesorectal excision versus preoperative chemoradiotherapy in locally advanced rectal cancer (RAPIDO)","route":"/key-papers/paper-bahadoer-rapido-short-course-radiotherapy-lancet-oncol-2021/","tldr":"Moving all the chemotherapy in front of the operation, after one week of radiotherapy, cut three-year treatment failure from 30.4 to 23.7 percent in high-risk rectal cancer."},{"id":"paper-conroy-prodige-23-neoadjuvant-folfirinox-rectal-lancet-oncol-2021","kind":"paper","name":"Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23)","route":"/key-papers/paper-conroy-prodige-23-neoadjuvant-folfirinox-rectal-lancet-oncol-2021/","tldr":"Six cycles of a three-drug chemotherapy before the usual chemoradiotherapy raised three-year disease-free survival from 69 to 76 percent, and left patients with less nerve damage than giving the chemotherapy afterwards."},{"id":"paper-garcia-aguilar-opra-organ-preservation-jco-2022","kind":"paper","name":"Organ preservation in patients with rectal adenocarcinoma treated with total neoadjuvant therapy (OPRA)","route":"/key-papers/paper-garcia-aguilar-opra-organ-preservation-jco-2022/","tldr":"Planning for watch and wait from the start, rather than stumbling into it, let half of 324 rectal cancer patients keep their rectum with no loss of disease-free survival."},{"id":"paper-verwaal-cytoreduction-hipec-peritoneal-colorectal-jco-2003","kind":"paper","name":"Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer","route":"/key-papers/paper-verwaal-cytoreduction-hipec-peritoneal-colorectal-jco-2003/","tldr":"The Dutch trial that put heated chemotherapy into the abdomen after stripping out all visible tumour, and nearly doubled median survival from 12.6 to 22.3 months. Eight percent of patients died of the treatment."},{"id":"paper-quenet-prodige-7-hipec-peritoneal-colorectal-lancet-oncol-2021","kind":"paper","name":"Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7)","route":"/key-papers/paper-quenet-prodige-7-hipec-peritoneal-colorectal-lancet-oncol-2021/","tldr":"The trial that took the heated chemotherapy away and found the survival was the same: 41.7 against 41.2 months. The benefit had always been in the surgery."},{"id":"rapido","kind":"trial","name":"RAPIDO","route":"/trials/rapido/","status":"positive","tldr":"RAPIDO showed that giving one week of radiotherapy and then all the chemotherapy before surgery cuts distant spread and doubles complete responses in high-risk rectal cancer, establishing total neoadjuvant therapy."},{"id":"prodige-23","kind":"trial","name":"PRODIGE 23","route":"/trials/prodige-23/","status":"positive","tldr":"PRODIGE 23 showed that six cycles of intensive chemotherapy before chemoradiation improves disease-free survival in rectal cancer and, on longer follow-up, overall survival, the second pillar of total neoadjuvant therapy."},{"id":"opra","kind":"trial","name":"OPRA","route":"/trials/opra/","status":"positive","tldr":"OPRA showed that about half of people with rectal cancer who receive all their chemotherapy and radiotherapy before surgery can keep their rectum without any drop in the chance of cure, and that giving the chemotherapy after the radiotherapy preserves more rectums."}],"trials":[{"id":"rapido","name":"RAPIDO","route":"/trials/rapido/","outcomes":[{"endpoint":"Disease-related treatment failure at 3 years","primary":true,"unit":"%","arms":[{"name":"Total neoadjuvant therapy","n":462,"value":23.7},{"name":"Standard chemoradiation","n":450,"value":30.4}]}],"setting":"High-risk locally advanced rectal cancer: short-course radiotherapy then chemotherapy before surgery (total neoadjuvant therapy) versus standard chemoradiation, surgery and optional adjuvant chemotherapy","enrolled":920,"enrolledBasis":"registry"},{"id":"prodige-23","name":"PRODIGE 23","route":"/trials/prodige-23/","outcomes":[{"endpoint":"Disease-free survival at 3 years","primary":true,"unit":"%","arms":[{"name":"Induction mFOLFIRINOX then chemoradiation","n":231,"value":76},{"name":"Chemoradiation first","n":230,"value":69}]}],"setting":"Locally advanced rectal cancer: induction mFOLFIRINOX then chemoradiation, surgery and adjuvant chemotherapy, versus chemoradiation, surgery and adjuvant chemotherapy","enrolled":461,"enrolledBasis":"registry"},{"id":"opra","name":"OPRA","route":"/trials/opra/","outcomes":[{"endpoint":"Survival without total mesorectal excision at 3 years","primary":true,"unit":"%","arms":[{"name":"Induction chemotherapy then chemoradiation","n":158,"value":41},{"name":"Chemoradiation then consolidation chemotherapy","n":166,"value":53}],"source":"https://doi.org/10.1200/JCO.22.00032"},{"endpoint":"Disease-free survival at 3 years","unit":"%","arms":[{"name":"Induction chemotherapy then chemoradiation","n":158,"value":76},{"name":"Chemoradiation then consolidation chemotherapy","n":166,"value":76}],"source":"https://doi.org/10.1200/JCO.22.00032"}],"setting":"Stage II or III rectal adenocarcinoma: total neoadjuvant therapy as induction chemotherapy then chemoradiation, or chemoradiation then consolidation chemotherapy, with watch and wait offered to patients whose tumour disappeared","enrolled":324,"enrolledBasis":"registry"}],"papers":[{"id":"paper-habr-gama-nonoperative-stage-0-rectal-ann-surg-2004","name":"Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results","route":"/key-papers/paper-habr-gama-nonoperative-stage-0-rectal-ann-surg-2004/","journal":"Annals of Surgery","year":2004,"whatItMeans":"The origin of organ preservation in rectal cancer. Twenty years later OPRA made it a planned strategy and the dostarlimab series made it the expected outcome in mismatch repair-deficient disease."},{"id":"paper-bahadoer-rapido-short-course-radiotherapy-lancet-oncol-2021","name":"Short-course radiotherapy followed by chemotherapy before total mesorectal excision versus preoperative chemoradiotherapy in locally advanced rectal cancer (RAPIDO)","route":"/key-papers/paper-bahadoer-rapido-short-course-radiotherapy-lancet-oncol-2021/","journal":"The Lancet Oncology","year":2021,"whatItMeans":"The first total neoadjuvant therapy trial to change practice in high-risk rectal cancer, and the schedule that makes organ preservation possible by giving the tumour months rather than weeks to respond."},{"id":"paper-conroy-prodige-23-neoadjuvant-folfirinox-rectal-lancet-oncol-2021","name":"Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23)","route":"/key-papers/paper-conroy-prodige-23-neoadjuvant-folfirinox-rectal-lancet-oncol-2021/","journal":"The Lancet Oncology","year":2021,"whatItMeans":"The second total neoadjuvant therapy schedule to change practice, and the one that shows the advantage is partly deliverability: chemotherapy given before an operation is completed by far more patients than chemotherapy given after one."},{"id":"paper-garcia-aguilar-opra-organ-preservation-jco-2022","name":"Organ preservation in patients with rectal adenocarcinoma treated with total neoadjuvant therapy (OPRA)","route":"/key-papers/paper-garcia-aguilar-opra-organ-preservation-jco-2022/","journal":"Journal of Clinical Oncology","year":2022,"whatItMeans":"Organ preservation became a plan rather than an accident: consolidation chemotherapy after chemoradiotherapy gives the best chance of keeping the rectum, and salvage surgery after regrowth does not appear to cost survival."},{"id":"paper-verwaal-cytoreduction-hipec-peritoneal-colorectal-jco-2003","name":"Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer","route":"/key-papers/paper-verwaal-cytoreduction-hipec-peritoneal-colorectal-jco-2003/","journal":"Journal of Clinical Oncology","year":2003,"whatItMeans":"The trial that created peritoneal surface malignancy as a speciality, and the reason patients with limited peritoneal disease are referred to designated centres; PRODIGE 7 later showed the benefit belongs to the surgery, not to the heated chemotherapy."},{"id":"paper-quenet-prodige-7-hipec-peritoneal-colorectal-lancet-oncol-2021","name":"Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7)","route":"/key-papers/paper-quenet-prodige-7-hipec-peritoneal-colorectal-lancet-oncol-2021/","journal":"The Lancet Oncology","year":2021,"whatItMeans":"Complete cytoreductive surgery with modern systemic chemotherapy gives a median survival over 40 months in selected patients with peritoneal metastases, and the heated intraperitoneal oxaliplatin adds only late complications."}]},{"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.","status":"current","refs":[{"id":"paper-siegel-colorectal-incidence-birth-cohort-jnci-2017","kind":"paper","name":"Colorectal cancer incidence patterns in the United States, 1974-2013","route":"/key-papers/paper-siegel-colorectal-incidence-birth-cohort-jnci-2017/","tldr":"The analysis that showed the rise in bowel cancer in young adults is a birth-cohort effect: someone born in 1990 has twice the colon cancer risk and four times the rectal cancer risk of someone born in 1950 at the same age."},{"id":"paper-vuik-early-onset-colorectal-europe-gut-2019","kind":"paper","name":"Increasing incidence of colorectal cancer in young adults in Europe over the last 25 years","route":"/key-papers/paper-vuik-early-onset-colorectal-europe-gut-2019/","tldr":"The same rise is happening in Europe. Across 20 countries and 143.7 million people, bowel cancer in 20 to 29-year-olds rose by 7.9 percent a year from 2004 to 2016."},{"id":"paper-siegel-colorectal-cancer-statistics-ca-2023","kind":"paper","name":"Colorectal cancer statistics, 2023","route":"/key-papers/paper-siegel-colorectal-cancer-statistics-ca-2023/","tldr":"The American Cancer Society's three-yearly stocktake: overall deaths are still falling, but one in five new cases is now in someone under 55, and more cancers are being found after they have spread than twenty years ago."},{"id":"paper-hur-sugar-sweetened-beverages-early-onset-colorectal-gut-2021","kind":"paper","name":"Sugar-sweetened beverage intake in adulthood and adolescence and risk of early-onset colorectal cancer among women","route":"/key-papers/paper-hur-sugar-sweetened-beverages-early-onset-colorectal-gut-2021/","tldr":"In 95,464 nurses followed for 24 years, women who drank two or more sugary drinks a day had double the risk of bowel cancer before 50, and each daily drink in adolescence raised it by a third."},{"id":"paper-diaz-gay-colibactin-geographic-age-mutational-processes-nature-2025","kind":"paper","name":"Geographic and age variations in mutational processes in colorectal cancer","route":"/key-papers/paper-diaz-gay-colibactin-geographic-age-mutational-processes-nature-2025/","tldr":"Reading 981 bowel cancer genomes from 11 countries found that the fingerprint of colibactin, a DNA-damaging toxin made by some gut bacteria, is more than three times as common in people diagnosed under 40 as over 70, and is stamped on the tumour early in life. It is the strongest lead yet on why bowel cancer is rising in young adults."},{"id":"early-onset-colorectal","kind":"cancer","name":"Early-onset colorectal cancer (under 50)","route":"/cancers/early-onset-colorectal/","tldr":"Bowel cancer is rising in people under 50, for reasons that are still not understood, and it is usually found late because neither patients nor doctors expect it. Treatment is the same as in older adults and works as well stage for stage; the changes are earlier screening, genetic testing for everyone diagnosed young, and attention to fertility, work and family."},{"id":"microbiome-tumour","kind":"pathway","name":"Microbiome-tumour interactions","route":"/pathways/microbiome-tumour/","tldr":"The bacteria in the gut, and even inside tumours, influence whether cancer starts and whether immunotherapy works. Transplanting stool from responders has made some non-responders respond."},{"id":"idea-crc-early-onset-cause-hunt","kind":"idea","name":"Find out what is driving early-onset bowel cancer, starting with colibactin, before extending screening any further","route":"/ideas/idea-crc-early-onset-cause-hunt/","tldr":"Bowel cancer in people under 50 is rising by 2 to 8 percent a year on both sides of the Atlantic and nobody knows why. The strongest lead is a toxin made by some gut bacteria whose damage signature is three times more common in young patients and is stamped on the colon early in life. If that is the cause, the fix is in childhood, not in a screening programme."}],"trials":[],"papers":[{"id":"paper-siegel-colorectal-incidence-birth-cohort-jnci-2017","name":"Colorectal cancer incidence patterns in the United States, 1974-2013","route":"/key-papers/paper-siegel-colorectal-incidence-birth-cohort-jnci-2017/","journal":"JNCI: Journal of the National Cancer Institute","year":2017,"whatItMeans":"The paper that turned early-onset colorectal cancer from an anecdote into a policy problem, and the direct evidence behind lowering the screening start age from 50 to 45 in the United States."},{"id":"paper-vuik-early-onset-colorectal-europe-gut-2019","name":"Increasing incidence of colorectal cancer in young adults in Europe over the last 25 years","route":"/key-papers/paper-vuik-early-onset-colorectal-europe-gut-2019/","journal":"Gut","year":2019,"whatItMeans":"The European counterpart to Siegel 2017, and the evidence a UK screening age extension has to be argued against: the fastest relative rise is in people two decades below any screening programme's start age."},{"id":"paper-siegel-colorectal-cancer-statistics-ca-2023","name":"Colorectal cancer statistics, 2023","route":"/key-papers/paper-siegel-colorectal-cancer-statistics-ca-2023/","journal":"CA: A Cancer Journal for Clinicians","year":2023,"whatItMeans":"The numbers behind the argument that the screening programme is working for the people it covers and failing everyone below its start age; the stage shift going into reverse is the most uncomfortable figure on this roadmap."},{"id":"paper-hur-sugar-sweetened-beverages-early-onset-colorectal-gut-2021","name":"Sugar-sweetened beverage intake in adulthood and adolescence and risk of early-onset colorectal cancer among women","route":"/key-papers/paper-hur-sugar-sweetened-beverages-early-onset-colorectal-gut-2021/","journal":"Gut","year":2021,"whatItMeans":"One of the few modifiable exposures with a plausible adolescent window to match the birth-cohort pattern; it is the kind of hypothesis a cohort can generate but not settle."},{"id":"paper-diaz-gay-colibactin-geographic-age-mutational-processes-nature-2025","name":"Geographic and age variations in mutational processes in colorectal cancer","route":"/key-papers/paper-diaz-gay-colibactin-geographic-age-mutational-processes-nature-2025/","journal":"Nature","year":2025,"whatItMeans":"If a childhood exposure to colibactin-producing Escherichia coli writes APC mutations into the colon decades before a tumour appears, then the rise in early-onset bowel cancer may be preventable by something done in childhood rather than by screening alone."}]},{"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.","status":"emerging","refs":[{"id":"azur-1","kind":"trial","name":"AZUR-1","route":"/trials/azur-1/","status":"positive","tldr":"AZUR-1 is the registrational trial of the 'no surgery, no radiation, no chemo' approach for mismatch-repair-deficient rectal cancer, built on the MSK study where every patient had a complete response."},{"id":"circulate-japan","kind":"trial","name":"CIRCULATE-Japan (GALAXY / VEGA / ALTAIR)","route":"/trials/circulate-japan/","status":"active","tldr":"Japan's national programme tests whether a blood test after surgery should decide who gets chemotherapy, and whether treating a positive test early helps."},{"id":"nordicc","kind":"trial","name":"NordICC (Nordic-European Initiative on Colorectal Cancer)","route":"/trials/nordicc/","status":"mixed","tldr":"The first randomised trial of colonoscopy screening: being invited cut the risk of bowel cancer by about a fifth, but fewer than half of those invited attended, so the effect on deaths was small."},{"id":"mountaineer","kind":"trial","name":"MOUNTAINEER","route":"/trials/mountaineer/","status":"completed","tldr":"A HER2 pill plus antibody gave durable responses in the 3-5% of bowel cancers driven by HER2, and is now being tested as first-line treatment."},{"id":"breakwater","kind":"trial","name":"BREAKWATER","route":"/trials/breakwater/","status":"positive","tldr":"Doubled survival, from about 15 to about 30 months, in the worst-prognosis genetic subtype of bowel cancer by adding two targeted drugs to first-line chemotherapy."},{"id":"dostarlimab","kind":"drug","name":"Dostarlimab","route":"/drugs/dostarlimab/","status":"approved","tldr":"Dostarlimab is a PD-1 blocker famous for making rectal cancer disappear without surgery in every patient with a mismatch-repair-deficient tumour."},{"id":"mrd-testing","kind":"technology","name":"MRD / molecular residual disease testing","route":"/technologies/mrd-testing/","status":"established","tldr":"An ultra-sensitive blood test after surgery that detects leftover cancer months before a scan would."},{"id":"idea-crc-ctdna-de-escalation-beyond-stage-ii","kind":"idea","name":"Take ctDNA-guided de-escalation beyond stage II, and stop escalating on a positive result until a trial says it helps","route":"/ideas/idea-crc-ctdna-de-escalation-beyond-stage-ii/","tldr":"A blood test after surgery already lets stage II colon cancer patients skip chemotherapy safely. The same test in stage III would spare far more people, and the unproven half, giving more chemotherapy to those who test positive, has so far changed nothing."},{"id":"idea-crc-mss-immunotherapy-by-biomarker-not-by-line","kind":"idea","name":"Select microsatellite stable patients for immunotherapy by a measured immune biomarker, not by how many treatments they have already failed","route":"/ideas/idea-crc-mss-immunotherapy-by-biomarker-not-by-line/","tldr":"Ninety-five percent of advanced bowel cancers ignore immunotherapy, and the only real signal so far came in patients without active liver secondaries. Trials keep enrolling by treatment line rather than by immune biology, which guarantees the responders are diluted away."}],"trials":[{"id":"azur-1","name":"AZUR-1","route":"/trials/azur-1/","outcomes":[{"endpoint":"Sustained clinical complete response at 12 months (independent central review)","primary":true,"unit":"%","arms":[{"name":"Dostarlimab monotherapy (single arm)","note":"Primary endpoint met at the interim analysis per the sponsor (13 July 2026); the rate itself is pending congress presentation. Single-arm registrational phase 2."}],"source":"https://www.cancernetwork.com/view/dostarlimab-yields-sustained-complete-responses-in-dmmr-msi-h-rectal-cancer"}],"setting":"Untreated stage II/III dMMR/MSI-H locally advanced rectal cancer: dostarlimab monotherapy for 6 months, no surgery or radiation if complete response","enrolled":154,"enrolledBasis":"registry"},{"id":"circulate-japan","name":"CIRCULATE-Japan (GALAXY / VEGA / ALTAIR)","route":"/trials/circulate-japan/","outcomes":[{"endpoint":"GALAXY (observational): recurrence risk by post-operative ctDNA status (4 weeks after surgery)","arms":[{"name":"ctDNA-positive","note":"n = 1,039 resectable stage II-IV CRC; ctDNA positivity was the strongest prognostic factor and identified who benefited from adjuvant chemotherapy (HR 6.59)"},{"name":"ctDNA-negative"}],"hr":10,"p":"<0.0001","source":"https://doi.org/10.1038/s41591-022-02115-4"},{"endpoint":"ALTAIR (randomised phase 3): disease-free survival in post-adjuvant ctDNA-positive patients","primary":true,"unit":"months","arms":[{"name":"Trifluridine/tipiracil","n":122,"value":9.3,"note":"Primary endpoint not met"},{"name":"Placebo","n":121,"value":5.55}],"hr":0.79,"ci":[0.6,1.05],"p":"0.107","source":"https://doi.org/10.1038/s41591-026-04428-0"}],"setting":"Resected stage II-IV colorectal cancer: ctDNA (Signatera) to guide adjuvant chemotherapy de-escalation (VEGA) or escalation with trifluridine/tipiracil (ALTAIR)","enrolledBasis":"registry"},{"id":"nordicc","name":"NordICC (Nordic-European Initiative on Colorectal Cancer)","route":"/trials/nordicc/","outcomes":[{"endpoint":"Colorectal cancer incidence at 10 years (intention to screen)","primary":true,"unit":"%","arms":[{"name":"Invited to colonoscopy","value":0.98},{"name":"Usual care","value":1.2}],"hr":0.82,"ci":[0.7,0.93],"source":"https://doi.org/10.1056/NEJMoa2208375"},{"endpoint":"Colorectal cancer death at 10 years","unit":"%","arms":[{"name":"Invited to colonoscopy","value":0.28},{"name":"Usual care","value":0.31}],"hr":0.9,"ci":[0.64,1.16],"source":"https://doi.org/10.1056/NEJMoa2208375"}],"setting":"Population-based randomised trial of invitation to a single screening colonoscopy versus no invitation in Poland, Norway and Sweden, adults aged 55 to 64","enrolled":84585,"enrolledNote":"ClinicalTrials.gov lists 95,000 participants (actual); the NEJM 2022 analysis covers the 84,585 participants in Poland, Norway and Sweden with follow-up data (28,220 invited, 56,365 usual care).","enrolledBasis":"analysed"},{"id":"mountaineer","name":"MOUNTAINEER","route":"/trials/mountaineer/","outcomes":[{"endpoint":"Objective response rate (phase 2)","primary":true,"unit":"percent","arms":[{"name":"Tucatinib + trastuzumab","n":84,"value":38.1}],"source":"https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.3509"}],"setting":"Chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer: tucatinib plus trastuzumab (cohorts A and B) or tucatinib alone (cohort C)","enrolledBasis":"registry"},{"id":"breakwater","name":"BREAKWATER","route":"/trials/breakwater/","outcomes":[{"endpoint":"Overall survival (EC + mFOLFOX6)","unit":"months","arms":[{"name":"Encorafenib + cetuximab + mFOLFOX6","value":30.3},{"name":"Chemotherapy ± bevacizumab","value":15.1}],"hr":0.49,"source":"https://ascopubs.org/doi/10.1200/JCO.2025.43.17_suppl.LBA3500"},{"endpoint":"Progression-free survival (EC + mFOLFOX6)","primary":true,"unit":"months","arms":[{"name":"Encorafenib + cetuximab + mFOLFOX6","value":12.8},{"name":"Chemotherapy ± bevacizumab","value":7.1}],"source":"https://ascopubs.org/doi/10.1200/JCO.2025.43.17_suppl.LBA3500"},{"endpoint":"Progression-free survival (EC + FOLFIRI cohort)","unit":"months","arms":[{"name":"Encorafenib + cetuximab + FOLFIRI"},{"name":"Chemotherapy ± bevacizumab"}],"hr":0.44,"source":"https://ascopubs.org/doi/10.1200/JCO.2026.44.17_suppl.LBA3503"}],"setting":"First-line BRAF V600E-mutant metastatic colorectal cancer: encorafenib + cetuximab + mFOLFOX6 (or FOLFIRI) vs chemotherapy ± bevacizumab","enrolledBasis":"registry"}],"papers":[]},{"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. Fourth, who gets treated at all: organ preservation, peritoneal surgery and total neoadjuvant therapy each require an MRI service, a specialist multidisciplinary team and a high-volume centre, and the trials that established them enrolled fit patients under 75.","status":"current","refs":[{"id":"paper-bretthauer-nordicc-colonoscopy-screening-nejm-2022","kind":"paper","name":"Effect of colonoscopy screening on risks of colorectal cancer and related death (NordICC)","route":"/key-papers/paper-bretthauer-nordicc-colonoscopy-screening-nejm-2022/","tldr":"The first randomised trial of screening colonoscopy itself. Inviting people to one colonoscopy cut bowel cancer cases by 18 percent over ten years, less than expected, largely because only 42 percent of those invited turned up."},{"id":"paper-kaminski-adenoma-detection-rate-interval-cancer-nejm-2010","kind":"paper","name":"Quality indicators for colonoscopy and the risk of interval cancer","route":"/key-papers/paper-kaminski-adenoma-detection-rate-interval-cancer-nejm-2010/","tldr":"Patients examined by endoscopists who find adenomas in fewer than one in five people are around ten times more likely to develop a cancer before their next scheduled test. Who does the colonoscopy matters as much as whether it is done."},{"id":"paper-bullock-botensilimab-balstilimab-mss-colorectal-nat-med-2024","kind":"paper","name":"Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial","route":"/key-papers/paper-bullock-botensilimab-balstilimab-mss-colorectal-nat-med-2024/","tldr":"The first immunotherapy signal in the 95 percent of bowel cancers that have always ignored it: an engineered CTLA-4 antibody plus a PD-1 antibody shrank tumours in 17 percent of 101 heavily treated patients."},{"id":"paper-quenet-prodige-7-hipec-peritoneal-colorectal-lancet-oncol-2021","kind":"paper","name":"Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7)","route":"/key-papers/paper-quenet-prodige-7-hipec-peritoneal-colorectal-lancet-oncol-2021/","tldr":"The trial that took the heated chemotherapy away and found the survival was the same: 41.7 against 41.2 months. The benefit had always been in the surgery."},{"id":"b-early-detection","kind":"bottleneck","name":"The hardest cancers are found late","route":"/bottlenecks/b-early-detection/","tldr":"Screening exists for only a few cancers. Pancreatic, ovarian, liver, oesophageal and most lung cancers are found when cure is unlikely."},{"id":"b-workforce","kind":"bottleneck","name":"Not enough oncologists, nurses, pathologists, physicists","route":"/bottlenecks/b-workforce/","tldr":"The number of people with cancer is rising faster than the workforce trained to treat them."},{"id":"idea-crc-screening-uptake-and-age-extension","kind":"idea","name":"Treat screening uptake, not test sensitivity, as the thing to optimise, and settle the age extension with a trial rather than a model","route":"/ideas/idea-crc-screening-uptake-and-age-extension/","tldr":"The only randomised trial of screening colonoscopy cut bowel cancer by 18 percent because only 42 percent of the people invited turned up. A test that is 20 percent more sensitive but is taken by the same people buys far less than an invitation that 20 percent more people accept."},{"id":"idea-crc-uk-colonoscopy-capacity-and-fit-threshold","kind":"idea","name":"UK gap: match endoscopy capacity and quality to the faecal immunochemical test thresholds the NHS has already set","route":"/ideas/idea-crc-uk-colonoscopy-capacity-and-fit-threshold/","tldr":"Every positive stool test in England, from the screening programme and from the symptomatic pathway, ends in a colonoscopy. The thresholds have been lowered faster than the capacity to act on them, and who performs the test decides whether it prevents anything."},{"id":"idea-crc-uk-young-patient-referral-and-diagnostic-interval","kind":"idea","name":"UK gap: shorten the route to diagnosis for patients below the screening age, where the rise in incidence is","route":"/ideas/idea-crc-uk-young-patient-referral-and-diagnostic-interval/","tldr":"The fastest rise in bowel cancer is in people two decades younger than any screening programme, who reach diagnosis through symptoms, often after several visits. Screening cannot help them; the referral pathway can."}],"trials":[],"papers":[{"id":"paper-bretthauer-nordicc-colonoscopy-screening-nejm-2022","name":"Effect of colonoscopy screening on risks of colorectal cancer and related death (NordICC)","route":"/key-papers/paper-bretthauer-nordicc-colonoscopy-screening-nejm-2022/","journal":"New England Journal of Medicine","year":2022,"whatItMeans":"Colonoscopy screening works, but the effect a health system gets is the effect of the invitation, not of the procedure; uptake, not test performance, is the binding constraint, and this is the trial that made that argument unavoidable."},{"id":"paper-kaminski-adenoma-detection-rate-interval-cancer-nejm-2010","name":"Quality indicators for colonoscopy and the risk of interval cancer","route":"/key-papers/paper-kaminski-adenoma-detection-rate-interval-cancer-nejm-2010/","journal":"New England Journal of Medicine","year":2010,"whatItMeans":"The paper that made the adenoma detection rate the central quality measure of every screening endoscopy service, and the reason endoscopist-level auditing is a condition of accreditation."},{"id":"paper-bullock-botensilimab-balstilimab-mss-colorectal-nat-med-2024","name":"Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial","route":"/key-papers/paper-bullock-botensilimab-balstilimab-mss-colorectal-nat-med-2024/","journal":"Nature Medicine","year":2024,"whatItMeans":"The first credible response signal in microsatellite stable colorectal cancer, and the reason the field's attention has moved to Fc engineering and to excluding patients with active liver metastases, in whom responses are rare."},{"id":"paper-quenet-prodige-7-hipec-peritoneal-colorectal-lancet-oncol-2021","name":"Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7)","route":"/key-papers/paper-quenet-prodige-7-hipec-peritoneal-colorectal-lancet-oncol-2021/","journal":"The Lancet Oncology","year":2021,"whatItMeans":"Complete cytoreductive surgery with modern systemic chemotherapy gives a median survival over 40 months in selected patients with peritoneal metastases, and the heated intraperitoneal oxaliplatin adds only late complications."}]}],"watch":[{"item":"NordICC primary completion on the registry (colonoscopy screening, 95,000 participants, actual; active, not recruiting); study completion is listed as July 2036, when the 15-year mortality answer is due","expected":"2026-06","source":"https://clinicaltrials.gov/study/NCT00883792","refs":[{"id":"nordicc","kind":"trial","name":"NordICC (Nordic-European Initiative on Colorectal Cancer)","route":"/trials/nordicc/","status":"mixed","tldr":"The first randomised trial of colonoscopy screening: being invited cut the risk of bowel cancer by about a fifth, but fewer than half of those invited attended, so the effect on deaths was small."},{"id":"colorectal-screening","kind":"technology","name":"Colorectal cancer screening (colonoscopy, FIT, stool DNA, blood)","route":"/technologies/colorectal-screening/","status":"standard-of-care","tldr":"Finding and removing polyps before they become cancer. Colonoscopy prevents cancer; stool and blood tests catch it early and get more people screened."},{"id":"idea-crc-screening-uptake-and-age-extension","kind":"idea","name":"Treat screening uptake, not test sensitivity, as the thing to optimise, and settle the age extension with a trial rather than a model","route":"/ideas/idea-crc-screening-uptake-and-age-extension/","tldr":"The only randomised trial of screening colonoscopy cut bowel cancer by 18 percent because only 42 percent of the people invited turned up. A test that is 20 percent more sensitive but is taken by the same people buys far less than an invitation that 20 percent more people accept."}]},{"item":"COBRA (NRG-GI005) study completion: circulating tumour DNA testing to direct treatment in stage IIA colon cancer (635 participants, actual; active, not recruiting)","expected":"2026-06-21","source":"https://clinicaltrials.gov/study/NCT04068103","refs":[{"id":"mrd-testing","kind":"technology","name":"MRD / molecular residual disease testing","route":"/technologies/mrd-testing/","status":"established","tldr":"An ultra-sensitive blood test after surgery that detects leftover cancer months before a scan would."},{"id":"ctdna","kind":"term","name":"Circulating tumour DNA (ctDNA)","route":"/terms/ctdna/","tldr":"Circulating tumour DNA (ctDNA) consists of fragments of DNA shed by tumour cells into the blood, detectable with sensitive sequencing."},{"id":"idea-crc-ctdna-de-escalation-beyond-stage-ii","kind":"idea","name":"Take ctDNA-guided de-escalation beyond stage II, and stop escalating on a positive result until a trial says it helps","route":"/ideas/idea-crc-ctdna-de-escalation-beyond-stage-ii/","tldr":"A blood test after surgery already lets stage II colon cancer patients skip chemotherapy safely. The same test in stage III would spare far more people, and the unproven half, giving more chemotherapy to those who test positive, has so far changed nothing."}]},{"item":"JANUS primary completion: adding irinotecan to FOLFOX after long-course radiotherapy in locally advanced rectal cancer (760 participants, actual; active, not recruiting)","expected":"2026-09-30","source":"https://clinicaltrials.gov/study/NCT05610163","refs":[{"id":"rectal-cancer","kind":"cancer","name":"Rectal cancer","route":"/cancers/rectal-cancer/","tldr":"Rectal cancer is bowel cancer in the last part of the large intestine, where surgery can mean a permanent stoma. Treatment now usually gives all the chemotherapy and radiotherapy first, and about half of people whose tumour disappears completely can keep their rectum and avoid surgery altogether."},{"id":"irinotecan","kind":"drug","name":"Irinotecan (and liposomal irinotecan)","route":"/drugs/irinotecan/","status":"approved","tldr":"Irinotecan is a topoisomerase-blocking chemotherapy central to bowel and pancreatic cancer regimens (FOLFIRI, FOLFIRINOX, NALIRIFOX) and to salvage therapy in childhood sarcomas; it carries the same warhead as the deruxtecan ADC payloads."},{"id":"total-neoadjuvant-therapy","kind":"term","name":"Total neoadjuvant therapy (TNT, rectal cancer)","route":"/terms/total-neoadjuvant-therapy/","tldr":"Giving all the chemotherapy and radiotherapy for rectal cancer before surgery rather than splitting it around the operation. It improves completion of chemotherapy, shrinks more tumours completely, and makes avoiding surgery possible for some patients."},{"id":"idea-crc-organ-preservation-randomised-in-pmmr-rectal","kind":"idea","name":"Randomise organ preservation against surgery in mismatch repair-proficient rectal cancer, with bowel function as a co-primary endpoint","route":"/ideas/idea-crc-organ-preservation-randomised-in-pmmr-rectal/","tldr":"Half of rectal cancer patients given all their chemotherapy and radiotherapy first can keep their rectum. Nobody has ever randomised that against having the operation, so the trade-off between avoiding a stoma and the risk of the cancer regrowing is still guesswork."}]},{"item":"AZUR-1 primary completion: dostarlimab monotherapy in untreated mismatch repair-deficient locally advanced rectal cancer (154 participants, actual; active, not recruiting)","expected":"2026-11-02","source":"https://clinicaltrials.gov/study/NCT05723562","refs":[{"id":"azur-1","kind":"trial","name":"AZUR-1","route":"/trials/azur-1/","status":"positive","tldr":"AZUR-1 is the registrational trial of the 'no surgery, no radiation, no chemo' approach for mismatch-repair-deficient rectal cancer, built on the MSK study where every patient had a complete response."},{"id":"dostarlimab","kind":"drug","name":"Dostarlimab","route":"/drugs/dostarlimab/","status":"approved","tldr":"Dostarlimab is a PD-1 blocker famous for making rectal cancer disappear without surgery in every patient with a mismatch-repair-deficient tumour."},{"id":"organ-preservation","kind":"term","name":"Organ preservation (watch-and-wait, bladder-sparing, larynx preservation)","route":"/terms/organ-preservation/","tldr":"Curing a cancer with drugs and radiotherapy so that the organ (rectum, bladder, larynx, limb) does not have to be removed, keeping surgery in reserve for the minority whose cancer regrows."},{"id":"msi-high-colorectal","kind":"cancer","name":"Mismatch-repair deficient (MSI-high) colorectal cancer","route":"/cancers/msi-high-colorectal/","tldr":"Mismatch-repair deficient bowel cancer has lost its DNA spell-checker, so it carries thousands of mutations that the immune system can recognise. Immunotherapy alone controls most metastatic cases for years and makes most localised tumours disappear before surgery, sometimes so completely that no surgery is needed."}]},{"item":"ATOMIC (Alliance A021502) study completion: adjuvant FOLFOX with or without atezolizumab in stage III mismatch repair-deficient colon cancer (712 participants, actual; active, not recruiting)","expected":"2026-12-18","source":"https://clinicaltrials.gov/study/NCT02912559","refs":[{"id":"atomic","kind":"trial","name":"ATOMIC (Alliance A021502)","route":"/trials/atomic/","status":"positive","tldr":"Adding a year of immunotherapy to chemotherapy after surgery halved recurrences in stage III colon cancers with a broken DNA spell-checker."},{"id":"atezolizumab","kind":"drug","name":"Atezolizumab","route":"/drugs/atezolizumab/","status":"approved","tldr":"A PD-L1 blocker used in lung, liver, and bladder cancer. In 2026 it became the first drug approved based on a blood test showing leftover cancer after bladder surgery."},{"id":"msi-high-colorectal","kind":"cancer","name":"Mismatch-repair deficient (MSI-high) colorectal cancer","route":"/cancers/msi-high-colorectal/","tldr":"Mismatch-repair deficient bowel cancer has lost its DNA spell-checker, so it carries thousands of mutations that the immune system can recognise. Immunotherapy alone controls most metastatic cases for years and makes most localised tumours disappear before surgery, sometimes so completely that no surgery is needed."}]},{"item":"Botensilimab and balstilimab in colorectal cancer, primary completion (234 participants, actual; active, not recruiting): the first randomised read on Fc-enhanced CTLA-4 blockade in microsatellite stable disease","expected":"2027-09","source":"https://clinicaltrials.gov/study/NCT05608044","refs":[{"id":"botensilimab","kind":"drug","name":"Botensilimab","route":"/drugs/botensilimab/","status":"phase-2","tldr":"Botensilimab is an experimental monoclonal antibody from Agenus in phase 2 trials for colorectal cancer, aimed at CTLA-4."},{"id":"balstilimab","kind":"drug","name":"Balstilimab","route":"/drugs/balstilimab/","status":"phase-2","tldr":"Balstilimab is a monoclonal antibody from Agenus Inc., in registered phase 2 trials for colorectal cancer."},{"id":"idea-immunotherapy-mss-crc","kind":"idea","name":"Making microsatellite-stable colorectal cancer immunotherapy-responsive","route":"/ideas/idea-immunotherapy-mss-crc/","tldr":"Ninety-five percent of bowel cancers ignore immunotherapy. Combinations that heat the tumour up (targeted drugs, radiation, new checkpoints) are the main hope."},{"id":"idea-crc-mss-immunotherapy-by-biomarker-not-by-line","kind":"idea","name":"Select microsatellite stable patients for immunotherapy by a measured immune biomarker, not by how many treatments they have already failed","route":"/ideas/idea-crc-mss-immunotherapy-by-biomarker-not-by-line/","tldr":"Ninety-five percent of advanced bowel cancers ignore immunotherapy, and the only real signal so far came in patients without active liver secondaries. Trials keep enrolling by treatment line rather than by immune biology, which guarantees the responders are diluted away."}]},{"item":"MOUNTAINEER-03 primary completion: tucatinib with trastuzumab and mFOLFOX6 against standard of care in first-line HER2-positive metastatic colorectal cancer (400 estimated participants; recruiting)","expected":"2027-12-31","source":"https://clinicaltrials.gov/study/NCT05253651","refs":[{"id":"mountaineer","kind":"trial","name":"MOUNTAINEER","route":"/trials/mountaineer/","status":"completed","tldr":"A HER2 pill plus antibody gave durable responses in the 3-5% of bowel cancers driven by HER2, and is now being tested as first-line treatment."},{"id":"tucatinib","kind":"drug","name":"Tucatinib","route":"/drugs/tucatinib/","status":"approved","tldr":"A HER2-selective pill that works in the brain, for HER2-positive breast cancer with brain metastases."},{"id":"trastuzumab","kind":"drug","name":"Trastuzumab","route":"/drugs/trastuzumab/","status":"approved","tldr":"The first targeted antibody for a solid tumour (1998), which turned HER2-positive breast cancer from the worst subtype into one of the most treatable."},{"id":"her2-amplified-colorectal","kind":"cancer","name":"HER2-amplified colorectal cancer","route":"/cancers/her2-amplified-colorectal/","tldr":"A few bowel cancers make too much of the HER2 protein, the same target as in HER2-positive breast cancer. Two HER2 drugs together, tucatinib and trastuzumab, shrink about four in ten of these tumours after chemotherapy has failed, and the antibody-drug conjugate trastuzumab deruxtecan works even when other HER2 drugs have stopped."}]},{"item":"BREAKWATER study completion: encorafenib and cetuximab with or without chemotherapy in previously untreated BRAF V600E metastatic disease (841 participants, actual; active, not recruiting)","expected":"2027-12-28","source":"https://clinicaltrials.gov/study/NCT04607421","refs":[{"id":"breakwater","kind":"trial","name":"BREAKWATER","route":"/trials/breakwater/","status":"positive","tldr":"Doubled survival, from about 15 to about 30 months, in the worst-prognosis genetic subtype of bowel cancer by adding two targeted drugs to first-line chemotherapy."},{"id":"encorafenib","kind":"drug","name":"Encorafenib","route":"/drugs/encorafenib/","status":"approved","tldr":"Encorafenib is a BRAF inhibitor that, with cetuximab and chemotherapy, became first-line standard for BRAF-mutant colorectal cancer in 2026."},{"id":"cetuximab","kind":"drug","name":"Cetuximab","route":"/drugs/cetuximab/","status":"approved","tldr":"Cetuximab is a chimeric antibody that blocks the EGFR growth receptor. It is used with FOLFIRI or FOLFOX in RAS wild-type, left-sided bowel cancer, with encorafenib in BRAF V600E disease, with KRAS G12C inhibitors, and with radiation or chemotherapy in head and neck cancer; RAS-mutant tumours gain nothing and may be harmed, so RAS testing comes first."},{"id":"braf-v600e-colorectal","kind":"cancer","name":"BRAF V600E-mutant colorectal cancer","route":"/cancers/braf-v600e-colorectal/","tldr":"BRAF V600E bowel cancer carries the same mutation as many melanomas, but BRAF drugs alone did nothing here because the tumour re-routes its growth signal through EGFR. Blocking both with encorafenib and cetuximab, now given with chemotherapy from the start, has doubled survival in a subtype that used to be the worst."}]},{"item":"CIRCULATE-US (NRG-GI008) primary completion: adjuvant chemotherapy directed by residual disease on circulating tumour DNA (1,912 estimated participants; recruiting)","expected":"2029-03-10","source":"https://clinicaltrials.gov/study/NCT05174169","refs":[{"id":"mrd-testing","kind":"technology","name":"MRD / molecular residual disease testing","route":"/technologies/mrd-testing/","status":"established","tldr":"An ultra-sensitive blood test after surgery that detects leftover cancer months before a scan would."},{"id":"signatera","kind":"drug","name":"Signatera","route":"/drugs/signatera/","status":"established","tldr":"Signatera is Natera's tumour-informed blood test that tracks 16 mutations from each patient's own tumour to detect residual or returning cancer after surgery. Medicare covers it in colorectal, breast, bladder, lung and ovarian cancer and for immunotherapy monitoring, and in 2026 it selected the bladder cancer patients for the first approval based on circulating tumour DNA."},{"id":"ctdna","kind":"term","name":"Circulating tumour DNA (ctDNA)","route":"/terms/ctdna/","tldr":"Circulating tumour DNA (ctDNA) consists of fragments of DNA shed by tumour cells into the blood, detectable with sensitive sequencing."},{"id":"idea-crc-ctdna-de-escalation-beyond-stage-ii","kind":"idea","name":"Take ctDNA-guided de-escalation beyond stage II, and stop escalating on a positive result until a trial says it helps","route":"/ideas/idea-crc-ctdna-de-escalation-beyond-stage-ii/","tldr":"A blood test after surgery already lets stage II colon cancer patients skip chemotherapy safely. The same test in stage III would spare far more people, and the unproven half, giving more chemotherapy to those who test positive, has so far changed nothing."}]},{"item":"Perioperative dostarlimab in untreated T4N0 or stage III mismatch repair-deficient resectable colon cancer, primary completion (892 estimated participants; phase 3; recruiting)","expected":"2029-03-19","source":"https://clinicaltrials.gov/study/NCT05855200","refs":[{"id":"dostarlimab","kind":"drug","name":"Dostarlimab","route":"/drugs/dostarlimab/","status":"approved","tldr":"Dostarlimab is a PD-1 blocker famous for making rectal cancer disappear without surgery in every patient with a mismatch-repair-deficient tumour."},{"id":"niche-2","kind":"trial","name":"NICHE-2","route":"/trials/niche-2/","status":"positive","tldr":"In NICHE-2, four weeks of immunotherapy before surgery wiped out most mismatch-repair-deficient colon cancers, and nobody had relapsed three years later."},{"id":"msi-high-colorectal","kind":"cancer","name":"Mismatch-repair deficient (MSI-high) colorectal cancer","route":"/cancers/msi-high-colorectal/","tldr":"Mismatch-repair deficient bowel cancer has lost its DNA spell-checker, so it carries thousands of mutations that the immune system can recognise. Immunotherapy alone controls most metastatic cases for years and makes most localised tumours disappear before surgery, sometimes so completely that no surgery is needed."},{"id":"organ-preservation","kind":"term","name":"Organ preservation (watch-and-wait, bladder-sparing, larynx preservation)","route":"/terms/organ-preservation/","tldr":"Curing a cancer with drugs and radiotherapy so that the organ (rectum, bladder, larynx, limb) does not have to be removed, keeping surgery in reserve for the minority whose cancer regrows."}]},{"item":"CIRCULATE (PRODIGE 70) primary completion: circulating tumour DNA-based adjuvant decision in stage II colon cancer (1,980 estimated participants; recruiting)","expected":"2032-03","source":"https://clinicaltrials.gov/study/NCT04120701","refs":[{"id":"mrd-testing","kind":"technology","name":"MRD / molecular residual disease testing","route":"/technologies/mrd-testing/","status":"established","tldr":"An ultra-sensitive blood test after surgery that detects leftover cancer months before a scan would."},{"id":"ctdna","kind":"term","name":"Circulating tumour DNA (ctDNA)","route":"/terms/ctdna/","tldr":"Circulating tumour DNA (ctDNA) consists of fragments of DNA shed by tumour cells into the blood, detectable with sensitive sequencing."},{"id":"unicancer","kind":"company","name":"UNICANCER","route":"/companies/unicancer/","tldr":"UNICANCER is the network of France's comprehensive cancer centres and its academic trials sponsor."},{"id":"idea-crc-ctdna-de-escalation-beyond-stage-ii","kind":"idea","name":"Take ctDNA-guided de-escalation beyond stage II, and stop escalating on a positive result until a trial says it helps","route":"/ideas/idea-crc-ctdna-de-escalation-beyond-stage-ii/","tldr":"A blood test after surgery already lets stage II colon cancer patients skip chemotherapy safely. The same test in stage III would spare far more people, and the unproven half, giving more chemotherapy to those who test positive, has so far changed nothing."}]},{"item":"NICHE platform primary completion: neoadjuvant checkpoint inhibition and novel combinations in early-stage colon cancer (353 estimated participants; recruiting)","expected":"2032-03-01","source":"https://clinicaltrials.gov/study/NCT03026140","refs":[{"id":"niche-2","kind":"trial","name":"NICHE-2","route":"/trials/niche-2/","status":"positive","tldr":"In NICHE-2, four weeks of immunotherapy before surgery wiped out most mismatch-repair-deficient colon cancers, and nobody had relapsed three years later."},{"id":"nivolumab","kind":"drug","name":"Nivolumab","route":"/drugs/nivolumab/","status":"approved","tldr":"Nivolumab was the second PD-1 blocker and is often combined with ipilimumab. Long-term data show about half of advanced melanoma patients alive at 10 years on the combination."},{"id":"ipilimumab","kind":"drug","name":"Ipilimumab","route":"/drugs/ipilimumab/","status":"approved","tldr":"Ipilimumab was the first checkpoint inhibitor (2011), and proved the immune system could be unleashed against cancer."},{"id":"nki","kind":"institution","name":"Netherlands Cancer Institute (NKI-AvL)","route":"/institutions/nki/","tldr":"Dutch national cancer centre that pioneered neoadjuvant immunotherapy (NADINA, NICHE) and TIL therapy in Europe."},{"id":"myriam-chalabi","kind":"person","name":"Myriam Chalabi","route":"/people/myriam-chalabi/","tldr":"Led NICHE-2, in which almost every mismatch-repair-deficient colon cancer responded to short pre-surgery immunotherapy."}]}]}