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Colon and rectum (digestive system)

Colorectal cancer

How surgery, screening, chemotherapy and biomarker-directed drugs developed in the care of colon and rectal cancer.

5-year relative survival · United States, SEER 8 registries

49.41%→67.73%

1975 (observed value) to 2018 (observed value; last observed year in the table). Read these with the caveats under “Then and now”.Source

42 milestones, by decade

  • Sir Ernest Miles first performed his radical abdomino-perineal excision for rectal carcinoma in 1907, after almost a decade of audit in which he studied the outcomes of patients with rectal carcinoma, according to a 2003 history paper. A 2025 history paper adds that Miles was credited with formalising the procedure in 1908, but that the Japanese surgeons Ito and Torikata independently developed a similar approach in 1904 and introduced a two-team approach in 1906. Both statements are taken from the papers' abstracts, so the question of priority is the authors' account and not a settled fact.
  • NordICC randomised presumptively healthy people aged 55 to 64, drawn from population registries in Poland, Norway, Sweden and the Netherlands, to an invitation to one screening colonoscopy or to no invitation. In the three countries with follow-up data (84,585 participants), 11,843 of 28,220 people in the invited group (42.0%) were screened. After a median of 10 years, the risk of colorectal cancer was 0.98% in the invited group and 1.20% in the usual-care group (risk ratio 0.82; 95% CI 0.70 to 0.93) and the risk of death from colorectal cancer was 0.28% versus 0.31% (risk ratio 0.90; 95% CI 0.64 to 1.16). These are intention-to-screen results for an invitation, with fewer than half of invitees screened, and the confidence interval for cancer death (0.64 to 1.16) spans a risk 36% lower to 16% higher.
  • In a prospective phase 2 study reported in 2022, 12 people with mismatch repair-deficient stage II or III rectal adenocarcinoma who completed six months of single-agent dostarlimab and had at least six months of follow-up all had a clinical complete response (100%; 95% CI 74 to 100) on MRI, PET, endoscopy, digital rectal examination and biopsy. At the time of the report none had received chemoradiotherapy or surgery, no progression or recurrence had been reported over 6 to 25 months of follow-up, and no adverse events of grade 3 or higher had been reported; the authors state that longer follow-up is needed. A supplemental application for this use, based on a larger single-arm phase 2 trial, was announced by the company on 24 August 2026 as accepted for FDA priority review; it is not an approval.

Evidence current to October 2026 · Checked against primary sources to the extent possible

A guided tour of 12 milestones. You can pause or step through it yourself.

Filter milestonesshowing all 42
Treatment type
Setting

The age of rays

  1. 1908 · Treatment · Surgery⚑ needs reviewMiles' abdominoperineal excision formalised for rectal cancerIn 1908 the surgeon W. Ernest Miles published a method of abdomino-perineal excision for rectal cancer in The Lancet. A history paper says he first performed the operation in 1907; another says Japanese surgeons developed a similar approach independently from 1904. The operation became a long-standing standard for rectal cancer.Miles WE, Lancet 1908: a method of abdomino-perineal excision for carcinoma of the rectum and terminal pelvic colon (text not read). Wiley 2003: first performed in 1907, after almost a decade of audit. Sakai 2025: Miles is credited with formalising the procedure in 1908; Ito and Torikata independently developed a similar approach in 1904. Lirici 2016: the operation became a gold standard for many years. No outcome figures extracted.
  2. 1932 · Understanding · Understanding⚑ needs reviewDukes classification of rectal cancerIn 1932 the pathologist Cuthbert Dukes published a classification of rectal cancer in the Journal of Pathology and Bacteriology. A modern summary describes stages A, B and C, from minimal disease to spread into surrounding tissue. It was later modified and has largely been replaced by TNM staging.Dukes CE, J Pathol Bacteriol 1932, 'The classification of cancer of the rectum' (article text not read). A secondary summary (EBSCO Research Starters, 2024) describes stage A as minimal disease with high five-year survival and stages B and C as spread into surrounding tissue with lower survival; later subdivided (B1, B2, C1, C2), with stage D for distant spread. No case numbers or survival figures are extracted. Jass 1987 proposed a score-based alternative derived from 379 patients.

Chemotherapy

  1. 1957 · Treatment · Chemotherapy⚑ needs reviewHeidelberger 1957: fluorinated pyrimidines as tumour inhibitorsIn 1957 Heidelberger and colleagues published a short paper in Nature titled 'Fluorinated pyrimidines, a new class of tumour-inhibitory compounds'. This record rests on the title only, because no abstract or text was read. Fluorouracil is now widely used in cancer treatment, and it is the backbone of the colon cancer adjuvant regimens later in this timeline.Heidelberger C, Chaudhuri NK, Danneberg P et al., Nature 1957, 'Fluorinated pyrimidines, a new class of tumour-inhibitory compounds'. PubMed holds the title and bibliographic record only (no abstract) and the text was not read, so no experimental design or results are recorded. A 2003 review describes 5-fluorouracil as widely used in cancer treatment.

Molecular origins

  1. 1982 · Treatment · SurgeryHeald reports total excision of the mesorectum (1982)In 1982 R. J. Heald reported five patients with small deposits of cancer in the fatty tissue around the rectum, several centimetres below the visible tumour. He removed that tissue, the mesorectum, as part of over a hundred consecutive operations. A later historical review describes total mesorectal excision, developed by Heald in 1982, as the present gold standard.Heald, Br J Surg 1982 (case series, no control group): five cases had tumour foci in the mesorectum distal to the primary; total excision of the mesorectum was part of over 100 consecutive anterior resections, and 50 curative or conceivably curative operations followed for over 2 years had no pelvic or staple-line recurrence. Heald and Ryall, Lancet 1986 (consecutive series): 115 patients with curative resection attempted, three pelvic recurrences at an average of 4.2 years; corrected cumulative 5-year survival 87%.
  2. 1990 · Understanding · Understanding⚑ needs reviewAdenoma-carcinoma sequence and a genetic model of colorectal cancerA 1988 study of 172 bowel tumour samples by Vogelstein and colleagues found that DNA changes accumulated as polyps progressed towards cancer: some were common in large polyps and cancers but rare in small polyps. In 1990 Fearon and Vogelstein published a Cell paper presenting a genetic model of colorectal tumour development.Vogelstein 1988 (172 specimens): ras mutations in 58% of adenomas over 1 cm, 47% of carcinomas and 9% of smaller adenomas; chromosome 18 deletions in 73% of carcinomas, 47% of advanced adenomas; 17p loss in 75% of carcinomas; alterations accumulated in parallel with clinical progression. The 1990 Cell paper (Fearon, Vogelstein), titled as a genetic model for colorectal tumorigenesis, has no PubMed abstract and was not read, so its content is not summarised.
  3. 1990 · Treatment · Chemotherapy⚑ needs reviewAdjuvant fluorouracil plus levamisole for stage III colon cancerIn a large randomised trial of people with resected colon cancer, one year of fluorouracil plus levamisole lowered the risk of recurrence by about forty percent in cancer that had reached the lymph nodes, compared with observation, and reduced deaths by about a third. The authors concluded this should be standard treatment for that stage.Moertel 1990: 1296 patients with resected stage B2 or C colon cancer randomised to observation or 1 year of levamisole plus fluorouracil (stage C also to levamisole alone). Median follow-up 3 years. In stage C, levamisole plus fluorouracil reduced recurrence risk by 41% (P<0.0001) and the death rate by 33% (P approx. 0.006); levamisole alone had no detectable effect; stage B2 results were equivocal. Final report 1995: 929 eligible stage III patients, 40% and 33% reductions.
  4. 1993 · Detection · Detection & preventionFaecal occult blood screening trials and mortalityIn a Minnesota trial, people offered a yearly stool test for hidden blood had fewer deaths from bowel cancer over 13 years than people not offered it; testing every two years did not differ significantly. Trials in England and Denmark also reported fewer deaths. The tests, intervals and uptake differed, so each trial is read against its own control group.Randomised faecal occult blood test (FOBT) trials versus unscreened controls. Minnesota (46,551 aged 50-80): 13-year cumulative colorectal cancer mortality per 1,000 was 5.88 annual (about 83% of slides rehydrated), 8.33 biennial, 8.83 control; only annual was significantly lower. At 30 years, relative risk 0.68 annual, 0.78 biennial; all-cause mortality unchanged (1.00). Nottingham (biennial, not rehydrated): 360 vs 420 deaths, odds ratio 0.85 (95% CI 0.74-0.98). Funen: mortality ratio 0.82 (0.68-0.99).
  5. 1993 · Understanding · UnderstandingLynch syndrome and DNA mismatch repair genesFamilies with many bowel, stomach and womb cancers had been recorded since 1895. In 1993 and 1994, studies linked such families to a region of chromosome 2, to errors in short repeated stretches of tumour DNA, and to genes that normally repair DNA copying mistakes. The condition is now called Lynch syndrome.Papers from 1993 and 1994: familial colorectal cancer linked to chromosome 2 (lod scores 6.39 and 1.45 in two kindreds); widespread microsatellite instability in familial tumours (13% of sporadic cancers shared it); instability in 25 of 90 tumours (28%), more often proximal colon; hMSH2 and hMLH1 proposed as HNPCC genes. Hampel 2008: 44 of 1,566 patients with colorectal cancer (2.8%, 95% CI 2.1-3.8) had Lynch syndrome.
  6. 1993 · Detection · Detection & preventionPolypectomy and colorectal cancer prevention (National Polyp Study)The National Polyp Study followed people who had adenomas removed at colonoscopy. Fewer colorectal cancers appeared than expected from comparison groups, and a later report found fewer deaths from the disease than expected in the general population. The comparison was with expected rates, not a randomised control group.National Polyp Study (cohort, not randomised). 1993: 1,418 people with adenomas removed, average follow-up 5.9 years (8,401 person-years); 5 asymptomatic early-stage cancers vs 48.3, 43.4 and 20.7 expected from three reference groups (reductions 90, 88 and 76 percent, P<0.001). 2012: 2,602 people, median follow-up 15.8 years; 12 colorectal cancer deaths vs 25.4 expected, standardized incidence-based mortality ratio 0.47 (95% CI 0.26-0.80).
  7. 1997 · Treatment · Radiation⚑ needs reviewSwedish Rectal Cancer Trial: short-course preoperative radiotherapyBetween 1987 and 1990, 1168 people in Sweden with rectal cancer that could be removed were assigned to five days of radiotherapy before surgery or to surgery alone. Five years on, cancer had come back locally in eleven in every hundred who had radiotherapy and twenty-seven in every hundred who did not. Survival was also higher with radiotherapy.Randomised, 1168 patients younger than 80 with resectable rectal cancer: preoperative radiotherapy (25 Gy in five fractions, surgery within one week) vs surgery alone. Five years: local recurrence 11% vs 27% (P<0.001); overall survival 58% vs 48% (P=0.004). Median follow-up 13 years, 908 patients with curative surgery: local recurrence 9% vs 26% (P<0.001); overall survival 38% vs 30% (P=0.008); cancer-specific survival 72% vs 62% (P=0.03).

Targeted therapy

  1. 2000 · Treatment · ChemotherapyIrinotecan with fluorouracil as first-line therapy for metastatic CRCTwo randomised trials in 2000 added irinotecan to fluorouracil and leucovorin as the first treatment for bowel cancer that had spread. In both, median survival was longer than with fluorouracil and leucovorin alone: 17.4 versus 14.1 months in one trial and 14.8 versus 12.6 months in the other.Douillard (Lancet, 25 March 2000; n=387): irinotecan plus infusional fluorouracil/folinate vs fluorouracil/folinate alone; median OS 17.4 vs 14.1 months (p=0.031); TTP 6.7 vs 4.4 months. FDA approved first-line use 20 April 2000. Saltz (NEJM, 28 September 2000; n=683, ITT): IFL vs bolus fluorouracil/leucovorin; median OS 14.8 vs 12.6 months (P=0.04), PFS 7.0 vs 4.3 months (P=0.004), response 39% vs 21%.
  2. 2000 · Treatment · ChemotherapyOxaliplatin added to infusional fluorouracil in advanced CRCTwo randomised trials in 2000 added oxaliplatin to fluorouracil and leucovorin as the first treatment for advanced bowel cancer. Tumours responded more than twice as often with oxaliplatin and took longer to progress, but overall survival was not significantly better in the larger trial and was similar in the other, and nerve damage and diarrhoea were more frequent.Giacchetti (n=200; chronomodulated fluorouracil-leucovorin): response 53% vs 16% (P<.001); median PFS 8.7 vs 6.1 months (P=.048); median OS 19.4 vs 19.9 months. de Gramont (n=420; LV5FU2): median PFS 9.0 vs 6.2 months (P=.0003); response 50.7% vs 22.3%; median OS 16.2 vs 14.7 months (P=.12). FDA accelerated approval 9 August 2002; first-line indication 9 January 2004.
  3. 2001 · Treatment · RadiationDutch TME trial: preoperative radiotherapy plus standardised TMEIn the Netherlands, 1861 people with rectal cancer that could be removed had careful, standardised surgery with or without five days of radiotherapy beforehand. Two years on, cancer had come back locally in about two in every hundred with radiotherapy and about eight in every hundred without. Survival was the same, and was still equal at five years.Randomised, 1861 patients: 5 x 5 Gy radiotherapy then TME vs TME alone, with standardised surgery. Two-year local recurrence 2.4% vs 8.2% (P<0.001); two-year survival 82.0% vs 81.8% (P=0.84). At median 6.1 years, five-year local recurrence 5.6% vs 10.9%, overall survival 64.2% vs 63.5%. At median 12 years, ten-year local recurrence 5% vs 11% (P<0.0001); overall survival did not differ.
  4. 2004 · Treatment · RadiationCAO/ARO/AIO-94: preoperative vs postoperative chemoradiotherapyGerman researchers assigned 823 people with advanced rectal cancer to chemoradiotherapy before or after surgery. Five-year survival was about the same, three in four. Cancer returned locally in six in every hundred treated before surgery and thirteen in every hundred treated after, and severe side effects were less common with treatment before surgery.Randomised, 823 patients with cT3/T4 or node-positive rectal cancer: preoperative vs postoperative fluorouracil-based chemoradiotherapy; primary endpoint overall survival. Five years: overall survival 76% vs 74% (P=0.80); cumulative incidence of local relapse 6% vs 13% (P=0.006); grade 3-4 acute toxicity 27% vs 40%. At median 134 months: 10-year overall survival 59.6% vs 59.9% (P=0.85); local relapse 7.1% vs 10.1% (P=0.048).
  5. 2004 · Treatment · ChemotherapyMOSAIC: oxaliplatin added to adjuvant fluorouracil for colon cancerIn MOSAIC, people who had surgery for stage II or III colon cancer were randomly given six months of fluorouracil with leucovorin, with or without oxaliplatin. At three years about seventy-eight in a hundred were alive without recurrence with oxaliplatin, against about seventy-three without. At ten years, survival was higher with oxaliplatin in stage III but not stage II.MOSAIC (André 2004): 2246 patients with resected stage II or III colon cancer randomised to LV5FU2 or FOLFOX4 for 6 months. Median follow-up 37.9 months: 3-year DFS 78.2% (95% CI 75.6-80.7) vs 72.9% (70.2-75.7); HR for recurrence 0.77, P=0.002. At 10 years, stage III OS 67.1% vs 59.0% (HR 0.80, P=0.016); stage II OS HR 1.00 (P=0.980).
  6. 2004 · De-escalation · SurgeryWatch-and-wait after chemoradiotherapy for complete clinical responseIn 2004 a research group in São Paulo reported 265 people with distal rectal cancer treated with chemoradiotherapy. About one in four had no detectable tumour afterwards and were observed rather than operated on. Estimated five-year survival in the observed group was 100%, and 92% were free of disease. The groups were not randomised.Non-randomised comparison: 265 patients with distal rectal adenocarcinoma received chemoradiation (5-fluorouracil, leucovorin, 5040 cGy). Complete clinical response in 71 (26.8%), observed without surgery; 22 (8.3%) with incomplete response had pT0N0 specimens. Five-year overall and disease-free survival: 100% and 92% (observation) vs 88% and 83% (resection). Mean follow-up 57.3 vs 48 months; 2 endorectal recurrences in the observation group.
  7. 2004 · Treatment · TargetedCetuximab and panitumumab: anti-EGFR antibodies in refractory CRCCetuximab and panitumumab are antibodies that block EGFR, a growth-signal receptor on tumour cells. In bowel cancer that had stopped responding to chemotherapy, cetuximab was active alone and with irinotecan, and both drugs delayed progression compared with supportive care alone. The FDA approved them in 2004 and 2006 under its accelerated pathway.BOND (n=329, irinotecan-refractory): response 22.9% with cetuximab plus irinotecan vs 10.8% with cetuximab alone; median TTP 4.1 vs 1.5 months; median survival 8.6 vs 6.9 months (P=0.48). CO.17 (n=572): cetuximab plus BSC vs BSC, OS HR 0.77 (95% CI 0.64 to 0.92), median 6.1 vs 4.6 months. Panitumumab plus BSC vs BSC (n=463): PFS HR 0.54 (0.44 to 0.66); OS HR 1.00 (0.82 to 1.22). FDA accelerated approvals 12 February 2004 and 27 September 2006.
  8. 2004 · Treatment · TargetedBevacizumab added to first-line irinotecan-based chemotherapyIn 813 people with untreated bowel cancer that had spread, adding bevacizumab, a drug that targets the growth of blood vessels, to a chemotherapy regimen containing irinotecan lengthened median survival from 15.6 to 20.3 months. The FDA approved it for first-line use in February 2004.813 patients with previously untreated metastatic CRC randomised to IFL plus bevacizumab 5 mg/kg every 2 weeks (n=402) or IFL plus placebo (n=411). Primary endpoint OS: median 20.3 vs 15.6 months, HR 0.66, P<0.001. PFS 10.6 vs 6.2 months (HR 0.54, P<0.001); response rate 44.8% vs 34.8% (P=0.004). Grade 3 hypertension 11.0% vs 2.3%. FDA approval 26 February 2004.
  9. 2008 · Reversal · TargetedKRAS mutation predicts no benefit: anti-EGFR limited to wild-typeCetuximab and panitumumab were first approved for bowel cancers carrying the EGFR receptor. In 2008, two analyses of randomised trials showed that people whose tumours had a KRAS mutation gained no benefit, while those without it did. The FDA later revised the cetuximab label and then limited its use to tumours without the mutation.Biomarker analyses of two randomised trials of anti-EGFR antibody plus best supportive care versus best supportive care alone. Panitumumab (KRAS known in 427 of 463): PFS HR 0.45 (95% CI 0.34 to 0.59) in wild-type vs 0.99 (0.73 to 1.36) in mutant tumours. Cetuximab, CO.17 (K-ras tested in 394 of 572): wild-type OS median 9.5 vs 4.8 months, HR 0.55 (0.41 to 0.74); mutant OS HR 0.98 (P=0.89). FDA limited cetuximab to K-ras wild-type disease on 6 July 2012.
  10. 2010 · Reversal · TargetedAdjuvant bevacizumab and cetuximab trials in colon cancerFour large randomised trials added a targeted drug, bevacizumab or cetuximab, to oxaliplatin-based chemotherapy after surgery for colon cancer. None improved disease-free survival. In one trial the authors noted overall survival data suggesting a possible harm with bevacizumab, and cetuximab added side effects. Both drugs had shown benefit in advanced disease, which is a different setting.Adjuvant colon cancer, DFS primary endpoint. NSABP C-08 (bevacizumab + mFOLFOX6; 2672 analysed): HR 0.89 (95% CI 0.76-1.04), P=0.15. AVANT (3451 randomised; stage III primary analysis): HR 1.17 (0.98-1.39) bevacizumab-FOLFOX4 and 1.07 (0.90-1.28) bevacizumab-XELOX vs FOLFOX4; OS HR 1.27 (1.03-1.57) for bevacizumab-FOLFOX4. N0147 (KRAS wild-type, mFOLFOX6 with or without cetuximab): 3-year DFS 71.5% with vs 74.6% without, HR 1.21 (0.98-1.49). PETACC-8 (KRAS exon 2 wild-type, 1602): HR 1.05 (0.85-1.29).
  11. 2010 · Detection · Detection & preventionFlexible sigmoidoscopy screening trialsFour randomised trials, in the UK, Italy, the US and Norway, offered flexible sigmoidoscopy (an examination of the lower bowel) or no screening. All four reported fewer bowel cancers in the invited group. Bowel cancer deaths were significantly lower in three; the Italian difference was not significant. Later Norwegian data showed reductions in men, little or no effect in women.Colorectal cancer mortality by randomised group in four sigmoidoscopy trials: UK once-only, HR 0.69 (95% CI 0.59-0.82), median 11.2 years; NORCCAP, HR 0.73 (0.56-0.94); PLCO (repeat screening), RR 0.74 (0.63-0.87); SCORE, RR 0.78 (0.56-1.08, not significant). PLCO distal cancer death RR 0.50, proximal 0.97. NORCCAP at 14.8 years: men HR 0.63 (0.47-0.83), women 1.01 (0.77-1.33).

Immunotherapy

  1. 2012 · Treatment · TargetedRegorafenib for previously treated metastatic CRC (CORRECT)For people whose bowel cancer had kept growing after all standard treatments, a placebo-controlled trial tested regorafenib, a tablet that blocks several growth signals. Survival was longer than with placebo, by a little over a month, at the cost of frequent side effects such as hand-foot skin reaction.Double-blind phase 3 trial, 760 patients with metastatic colorectal cancer progressing during or within 3 months after the last standard therapy, randomised 2:1 to regorafenib (n=505) or placebo (n=255), both with best supportive care. Median OS 6.4 vs 5.0 months (HR 0.77, 95% CI 0.64-0.94; one-sided P=0.0052; preplanned interim analysis). Hand-foot skin reaction of grade 3 or higher: 17% with regorafenib.
  2. 2015 · Treatment · ImmunotherapyPD-1 blockade in mismatch repair-deficient colorectal cancerTumours that cannot repair DNA copying errors carry many mutations. In a small 2015 study, pembrolizumab produced responses in 4 of 10 such bowel cancers and in none of 18 without the repair defect. Later nivolumab studies, with and without ipilimumab, reported responses in about a third to over half of previously treated patients, all without a comparison group.Non-randomised phase 2 studies. Le 2015 (n=41 across cohorts): immune-related ORR 40% (4 of 10) in dMMR colorectal vs 0% (0 of 18) in pMMR. CheckMate 142, previously treated: nivolumab ORR 31.1% (95% CI 20.8 to 42.9; n=74); nivolumab plus ipilimumab 55% (45.2 to 63.8; n=119). First line, nivolumab plus low-dose ipilimumab: 69% (53 to 82; n=45). FDA accelerated approvals 31 July 2017 and 10 July 2018.
  3. 2015 · Treatment · ChemotherapyTrifluridine-tipiracil (TAS-102): RECOURSE and SUNLIGHTTrifluridine-tipiracil is an oral chemotherapy tablet. In a placebo-controlled trial of refractory metastatic bowel cancer it lengthened survival by under two months. A later trial in a similar setting found that adding bevacizumab to it lengthened survival by about three months compared with the tablet alone.RECOURSE (double-blind phase 3, n=800, 2:1): median OS 7.1 months with trifluridine-tipiracil vs 5.3 with placebo (HR 0.68, 95% CI 0.58-0.81; P<0.001). SUNLIGHT (open-label phase 3, 246 per arm, at most two prior regimens): trifluridine-tipiracil plus bevacizumab vs trifluridine-tipiracil alone, median OS 10.8 vs 7.5 months (HR 0.61, 95% CI 0.49-0.77); median PFS 5.6 vs 2.4 months (HR 0.44, 95% CI 0.36-0.54).
  4. 2016 · Treatment · TargetedHER2-targeted therapy for HER2-positive metastatic CRCA small share of bowel cancers carry extra HER2, the target of breast-cancer drugs. Four separate studies without a comparison group gave HER2-directed drugs to people whose cancer had stopped responding to standard treatment; each reported tumour responses in roughly 30 to 45 of every 100 people treated. The US provisionally approved tucatinib with trastuzumab in 2023.Four single-arm phase 2 studies in HER2-positive or HER2-amplified metastatic colorectal cancer, each reporting its own objective response rate (not comparable across studies): HERACLES trastuzumab + lapatinib 30% (8 of 27; 95% CI 14-50); MyPathway pertuzumab + trastuzumab 32% (18 of 57; 95% CI 20-45); DESTINY-CRC01 trastuzumab deruxtecan 45.3% (cohort A, n=53; 95% CI 31.6-59.6); MOUNTAINEER tucatinib + trastuzumab 38.1% (n=84; 95% CI 27.7-49.3).
  5. 2018 · Treatment · TargetedFruquintinib for refractory metastatic CRC (FRESCO and FRESCO-2)Fruquintinib is a capsule that blocks the receptors for a blood-vessel growth signal. A trial in China and a larger international trial each compared it with placebo in people whose bowel cancer had progressed after standard treatments, and each found longer survival with fruquintinib.FRESCO (double-blind phase 3, China, n=416, 2:1): median OS 9.3 vs 6.6 months, fruquintinib vs placebo (HR 0.65, 95% CI 0.51-0.83; P<0.001). FRESCO-2 (double-blind phase 3, 14 countries, n=691, 2:1, progressed on or intolerant to trifluridine-tipiracil or regorafenib or both): median OS 7.4 vs 4.8 months (HR 0.66, 95% CI 0.55-0.80; P<0.0001). Grade 3 or worse adverse events 63% vs 50% in FRESCO-2.
  6. 2018 · De-escalation · ChemotherapyIDEA: 3 versus 6 months of adjuvant oxaliplatin chemotherapySix randomised trials were pooled to ask whether three months of oxaliplatin chemotherapy after surgery for stage III colon cancer works as well as six months, with less nerve damage. Overall, the pooled analysis could not confirm that three months was as good. For the CAPOX regimen it met the standard set in advance, but for FOLFOX it did not.IDEA pooled analysis (Grothey 2018): six phase 3 trials, 12,834 patients with stage III colon cancer, 3 vs 6 months of FOLFOX or CAPOX. Noninferiority (upper CI limit 1.12) was not confirmed overall (HR 1.07, 95% CI 1.00-1.15); seen for CAPOX (HR 0.95, 0.85-1.06), not FOLFOX (HR 1.16, 1.06-1.26). Final 5-year OS 82.4% vs 82.8% (HR 1.02, 0.95-1.11; noninferiority p=0.058).
  7. 2019 · Treatment · TargetedBEACON: encorafenib plus cetuximab for BRAF V600E mCRCSome bowel cancers carry a change called BRAF V600E and do poorly on standard chemotherapy. In a randomised trial of people whose cancer had progressed after one or two earlier treatments, adding encorafenib to cetuximab lengthened survival by several months. The US regulator approved the two-drug version, not the three-drug one tested alongside it.Open-label phase 3 trial, 665 patients with BRAF V600E-mutated metastatic colorectal cancer after one or two prior regimens, randomised 1:1:1 to triplet (encorafenib, binimetinib, cetuximab), doublet (encorafenib, cetuximab) or control (cetuximab with irinotecan or FOLFIRI). Interim median OS 9.0 vs 5.4 months, triplet vs control (HR 0.52, 95% CI 0.39-0.70); doublet 8.4 months (HR 0.60, 95% CI 0.45-0.79). Confirmed ORR 26% vs 2%.

Precision & engineered

  1. 2020 · Treatment · ChemotherapyTotal neoadjuvant therapy: RAPIDO and PRODIGE 23Two randomised trials gave chemotherapy before surgery for locally advanced rectal cancer, rather than only after it. In RAPIDO, a week of radiotherapy then chemotherapy lowered treatment failure at three years; in PRODIGE 23, chemotherapy before chemoradiotherapy improved disease-free survival. In RAPIDO, cancer returned locally more often at five years after complete surgery.RAPIDO (920 randomised): short-course radiotherapy then chemotherapy vs chemoradiotherapy; 3-year disease-related treatment failure 23.7% vs 30.4% (HR 0.75, 95% CI 0.60-0.95); at 5.6 years locoregional recurrence after R0/R1 resection 10% vs 6% (P=0.027). PRODIGE 23 (n=461): FOLFIRINOX before chemoradiotherapy; 3-year DFS 76% vs 69% (HR 0.69, 0.49-0.97); 7-year overall survival 81.9% vs 76.1% (RMST P=0.033). Endpoints, populations and controls differ.
  2. 2020 · Treatment · ImmunotherapyKEYNOTE-177: pembrolizumab first-line for MSI-H/dMMR metastatic CRCIn untreated advanced MSI-H/dMMR bowel cancer (tumours that cannot repair DNA copying errors), pembrolizumab was compared with chemotherapy. Cancer progressed after a median of 16.5 versus 8.2 months, with fewer severe side effects. At over five years median survival was 77.5 versus 36.7 months, but the final survival analysis was not statistically significant and many chemotherapy patients later received immunotherapy.Open-label phase 3: 307 patients with untreated MSI-H/dMMR metastatic CRC randomised 1:1 to pembrolizumab (n=153) or investigator-choice chemotherapy (n=154), crossover allowed. PFS median 16.5 vs 8.2 months (HR 0.60, 95% CI 0.45 to 0.80; P=0.0002; second interim analysis). Final OS HR 0.74 (95% CI 0.53 to 1.03; p=0.036), prespecified significance not met. At over 5 years, OS HR 0.73 (95% CI 0.53 to 0.99); effective crossover 62%. FDA approval 29 June 2020.
  3. 2021 · Reversal · SurgeryPRODIGE 7: HIPEC added to cytoreductive surgery (peritoneal CRC)PRODIGE 7 randomly assigned 265 people with colorectal cancer that had spread to the lining of the abdomen to surgery that removes all visible tumour, with or without heated chemotherapy washed through the abdomen. Median survival was about forty-one to forty-two months in both groups, and later complications were more frequent with the heated chemotherapy.PRODIGE 7 (Quénet 2021): phase 3, 265 patients with colorectal peritoneal metastases (PCI 25 or less) after complete cytoreduction, randomised to surgery plus oxaliplatin HIPEC (n=133) or surgery alone (n=132). Median OS 41.7 months (95% CI 36.2-53.8) vs 41.2 (35.1-49.7); HR 1.00 (95.37% CI 0.63-1.58), P=0.99; median follow-up 63.8 months. Grade 3 or worse adverse events at 60 days: 26% vs 15% (P=0.035).
  4. 2022 · Treatment · ChemotherapyDYNAMIC: ctDNA-guided adjuvant therapy in stage II colon cancerIn DYNAMIC, people with stage II colon cancer were randomly assigned to have chemotherapy decisions guided by a blood test for circulating tumour DNA or by standard features of the tumour. Fewer people in the test-guided group had chemotherapy, about fifteen in a hundred against twenty-eight, and two-year recurrence-free survival was about the same, near ninety-three percent.DYNAMIC (Tie 2022): 455 patients with stage II colon cancer randomised 2:1 to ctDNA-guided (n=302) or standard management (n=153). Adjuvant chemotherapy 15% vs 28%. 2-year RFS 93.5% vs 92.4% (difference 1.1 points, 95% CI -4.1 to 6.2; noninferiority margin -8.5), median follow-up 37 months. 5-year RFS 88% vs 87%; 5-year OS 93.8% vs 93.3% (HR 1.05, P=0.887). DYNAMIC-III (stage III): de-escalation did not meet its noninferiority margin.
  5. 2022 · Treatment · ImmunotherapyDostarlimab alone for mismatch repair-deficient rectal cancerIn a small phase 2 study, people with rectal cancer caused by faulty DNA mismatch repair received the immunotherapy drug dostarlimab for six months. In the first twelve to complete treatment and be followed for at least six months, no tumour could be detected afterwards, and none had had radiation or surgery. Follow-up was short.Phase 2, single-arm rectal cohort (NCT04165772), stage II or III dMMR rectal adenocarcinoma, dostarlimab every 3 weeks for 6 months, then chemoradiotherapy and surgery unless clinical complete response. 12 of 12 patients with at least 6 months of follow-up (range 6-25 months) had a clinical complete response (100%; 95% CI 74-100); no grade 3 or higher adverse events. 2025 update: all 49 patients who completed treatment had a clinical complete response; 37 sustained it at 12 months.
  6. 2022 · Treatment · Targeted⚑ needs reviewKRAS G12C inhibitors with anti-EGFR antibodiesA small share of bowel cancers carry a KRAS G12C change. Used alone, drugs aimed at it worked modestly. Paired with an anti-EGFR antibody, one drug shrank tumours in nearly half of 28 evaluable people in a non-randomised study; its US approval was withdrawn in 2026. Another delayed progression against standard treatment in a randomised trial.KRYSTAL-1 (phase 1-2, nonrandomised, KRAS G12C colorectal cancer): adagrasib + cetuximab, ORR 46% (95% CI 28-66; 28 evaluable patients), median PFS 6.9 months (32 patients). CodeBreaK 300 (phase 3, n=160): sotorasib 960 mg + panitumumab vs investigator's choice, median PFS 5.6 vs 2.2 months (HR 0.49, 95% CI 0.30-0.80; P=0.006); ORR 26.4% vs 0%. OS HR 0.70 (95% CI 0.41-1.18; P=0.20).
  7. 2022 · Detection · Detection & preventionNordICC: invitation to screening colonoscopyIn a trial in four European countries (follow-up data from three), people aged 55 to 64 were randomly invited to one screening colonoscopy or not invited. Fewer than half of those invited had the examination. After about ten years, fewer colorectal cancers were found in the invited group; deaths from colorectal cancer were not clearly different, with an imprecise estimate.Pragmatic randomised trial of invitation to one screening colonoscopy vs usual care (ages 55-64; 84,585 with follow-up in Poland, Norway, Sweden); 42.0% of the invited group were screened. Intention-to-screen at 10 years: colorectal cancer risk 0.98% vs 1.20% (risk ratio 0.82, 95% CI 0.70-0.93); colorectal cancer death 0.28% vs 0.31% (risk ratio 0.90, 0.64-1.16); all-cause death risk ratio 0.99 (0.96-1.04). Separate instrumental-variable per-protocol analysis: incidence reduction 35 to 41%; mortality intervals include 1.
  8. 2022 · De-escalation · ChemotherapyOPRA: total neoadjuvant therapy and selective watch-and-waitIn OPRA, 324 people with stage II or III rectal cancer had chemotherapy and chemoradiotherapy in one of two orders; those whose tumour disappeared or nearly did could watch and wait. After about five years, roughly seven in ten were free of disease in both groups. Survival without total mesorectal excision (organ preservation) was higher when chemotherapy came last.Randomised phase 2, 324 patients with stage II/III rectal adenocarcinoma: induction chemotherapy then chemoradiotherapy (INCT-CRT) vs chemoradiotherapy then consolidation chemotherapy (CRT-CNCT); TME or watch-and-wait by response. Two stand-alone studies against a historical 3-year DFS of 75%, not head to head. 3-year DFS 76% in each; 5-year DFS 71% vs 69% (P=0.68); 5-year TME-free survival 39% vs 54% (P=0.012).
  9. 2023 · Treatment · ChemotherapyFOxTROT: neoadjuvant chemotherapy for locally advanced colon cancerIn FOxTROT, people with colon cancer growing into or beyond the bowel wall were randomly given six weeks of chemotherapy before surgery and eighteen weeks after, or twenty-four weeks after surgery alone. Fewer in the before-surgery group had residual or returned disease within two years, about seventeen in a hundred against twenty-two. Benefit looked small with mismatch repair deficiency.FOxTROT (Morton 2023): 1053 patients (699 NAC, 354 control) with radiologically staged T3-4 N0-2 M0 colon cancer randomised 2:1 to 6 weeks of preoperative oxaliplatin-fluoropyrimidine plus 18 weeks postoperatively, or 24 weeks postoperatively. Residual disease or recurrence within 2 years: 16.9% vs 21.5% (rate ratio 0.72, 95% CI 0.54-0.98, P=0.037); complete resection 94% vs 89%. Panitumumab added no benefit.
  10. 2023 · De-escalation · ChemotherapyPROSPECT: neoadjuvant FOLFOX with selective chemoradiotherapyPROSPECT compared chemotherapy first, adding chemoradiotherapy only if the tumour shrank little or chemotherapy had to stop, with standard chemoradiotherapy before surgery, in people with rectal cancer suitable for sphincter-sparing surgery. After about five years, disease-free survival was similar, roughly eight in ten in both groups. Fewer than one in ten given chemotherapy first had radiation before surgery.Noninferiority phase 2/3, 1194 randomised (1128 started treatment): neoadjuvant FOLFOX with selective chemoradiotherapy vs chemoradiotherapy, cT2N+/cT3N0/cT3N+ rectal cancer. At median 58 months, DFS hazard ratio 0.92 (90.2% CI 0.74-1.14; P=0.005 for noninferiority, margin 1.29); 5-year DFS 80.8% vs 78.6%; overall survival HR 1.04 (0.74-1.44). Preoperative chemoradiotherapy was given to 9.1% of the FOLFOX group.
  11. 2024 · Treatment · ImmunotherapyCheckMate 8HW: nivolumab plus ipilimumab in MSI-H/dMMR mCRCColorectal cancers with faulty DNA mismatch repair can respond to immune checkpoint drugs. In a randomised trial, people given nivolumab plus ipilimumab as their first treatment stayed free of progression longer than those given chemotherapy. A second report found they also stayed free of progression longer than with nivolumab alone. In 2025 the US approvals became full approvals.Open-label phase 3 trial, 2:2:1 randomisation (nivolumab + ipilimumab, nivolumab, chemotherapy) in MSI-H/dMMR metastatic colorectal cancer. First line (NEJM 2024): 24-month PFS 72% vs 14% for nivolumab + ipilimumab vs chemotherapy (P<0.001; centrally confirmed, n=255). All lines (Lancet 2025): nivolumab + ipilimumab vs nivolumab, PFS HR 0.62 (95% CI 0.48-0.81; P=0.0003).
  12. 2024 · Treatment · ImmunotherapyNICHE-2: neoadjuvant nivolumab plus ipilimumab for dMMR colon cancerIn NICHE-2, 115 people with locally advanced colon cancer with mismatch repair deficiency had nivolumab and ipilimumab before surgery. Nearly all had surgery on time. Among 111 assessed, about two in three had no viable tumour left, and none had recurrence by a median of 26 months. It was a single-group study without a comparison arm.NICHE-2 (Chalabi 2024): phase 2, single-arm, 115 patients with untreated locally advanced dMMR colon cancer given neoadjuvant nivolumab plus ipilimumab. Timely surgery in 113 (98%; 97.5% CI 93-100). In 111 patients in the efficacy analysis, pathological response in 109 (98%; 95% CI 94-100), major pathological response in 105 (95%), pCR in 75 (68%). Grade 3-4 immune-related adverse events in 5 (4%). Median follow-up 26 months: no recurrence; 3-year DFS not reported in the abstract.
  13. 2024 · Treatment · TargetedBREAKWATER: first-line encorafenib, cetuximab and chemotherapyBowel cancers with a BRAF V600E change have had limited benefit from standard first-line chemotherapy. In a randomised trial, adding encorafenib and cetuximab to the chemotherapy mFOLFOX6 shrank more tumours, delayed progression and lengthened survival compared with standard care. US approval was provisional (accelerated) in 2024; in 2026 the regulator recorded its follow-up requirement as fulfilled.Open-label phase 3 trial, previously untreated BRAF V600E-mutant metastatic colorectal cancer: encorafenib + cetuximab + mFOLFOX6 vs standard care (chemotherapy with or without bevacizumab). ORR by blinded central review 60.9% vs 40.0% (odds ratio 2.443, one-sided P=0.0008). PFS median 12.8 vs 7.1 months (HR 0.53, 95% CI 0.41-0.68). Interim OS median 30.3 vs 15.1 months (HR 0.49, 95% CI 0.38-0.63).
  14. 2026 · Treatment · ImmunotherapyATOMIC: atezolizumab plus adjuvant FOLFOX in dMMR stage III colonIn ATOMIC, people with stage III colon cancer with mismatch repair deficiency were randomly given FOLFOX alone or with atezolizumab, an immunotherapy continued for a year. At three years about eighty-six in a hundred were alive without recurrence with atezolizumab, against about seventy-six. Severe side effects were more common with it. The FDA approved the combination on 8 October 2026.ATOMIC (Sinicrope 2026): phase 3, 712 patients with resected stage III dMMR colon cancer randomised 1:1 to atezolizumab plus mFOLFOX6 for 6 months then atezolizumab (12 months in total; n=355) or mFOLFOX6 alone (n=357). Median follow-up 40.9 months: 3-year DFS 86.3% (95% CI 81.8-89.8) vs 76.2% (70.9-80.6); HR 0.50 (0.35-0.73), P<0.001. Grade 3-4 adverse events 84.1% vs 71.9%. 5-year OS 89.7% vs 87.9% (HR 0.90, 0.55-1.47), immature.

Then and now

  • 5-year relative survival · United States, SEER 8 registries

    • 49.41%

      1975 (observed value)

    Colon and rectum combined, all races, both sexes; the SEER 8 five-year relative survival series (1975-2018) on the SEER Cancer Stat Facts colorectal page. The page states no age range or stage mix for this series.

    Relative survival excludes deaths from other causes. 'Observed' is the table's label for the yearly value, as opposed to the Joinpoint modeled-trend value in the adjacent column. The column is headed 'Year' and the chart note says only '1975-2018'; the page does not say the year is the year of diagnosis. Survival measured from diagnosis can rise through earlier detection (lead-time bias) as well as through treatment, and the page does not say how much of the change in this series is due to screening, stage at diagnosis, treatment or other factors, so read it beside the mortality values. Observed values are used because the 2019-2023 entries in the table are modeled-trend values only. Compare only with other values from this same SEER 8 series. The modeled-trend value for 1975 is 48.63%.

    Source

  • 5-year relative survival · United States, SEER 8 registries

    • 62.3%

      1990 (observed value)

    Colon and rectum combined, all races, both sexes; the SEER 8 five-year relative survival series (1975-2018) on the SEER Cancer Stat Facts colorectal page. The page states no age range or stage mix for this series.

    Relative survival excludes deaths from other causes. 'Observed' is the table's label for the yearly value, as opposed to the Joinpoint modeled-trend value in the adjacent column. The column is headed 'Year' and the chart note says only '1975-2018'; the page does not say the year is the year of diagnosis. Survival measured from diagnosis can rise through earlier detection (lead-time bias) as well as through treatment, and the page does not say how much of the change in this series is due to screening, stage at diagnosis, treatment or other factors, so read it beside the mortality values. Observed values are used because the 2019-2023 entries in the table are modeled-trend values only. Compare only with other values from this same SEER 8 series. Included so that the pace of change is visible: the observed value rose from 49.41% (1975) to 62.30% (1990) and was 67.73% in 2018, with the observed value highest in 2016 (69.04%); the modeled-trend value for 1990 is 62.59%.

    Source

  • 5-year relative survival · United States, SEER 8 registries

    • 67.73%

      2018 (observed value; last observed year in the table)

    Colon and rectum combined, all races, both sexes; the SEER 8 five-year relative survival series (1975-2018) on the SEER Cancer Stat Facts colorectal page. The page states no age range or stage mix for this series.

    Relative survival excludes deaths from other causes. 'Observed' is the table's label for the yearly value, as opposed to the Joinpoint modeled-trend value in the adjacent column. The column is headed 'Year' and the chart note says only '1975-2018'; the page does not say the year is the year of diagnosis. Survival measured from diagnosis can rise through earlier detection (lead-time bias) as well as through treatment, and the page does not say how much of the change in this series is due to screening, stage at diagnosis, treatment or other factors, so read it beside the mortality values. Observed values are used because the 2019-2023 entries in the table are modeled-trend values only. Compare only with other values from this same SEER 8 series. The observed value was 69.04% in 2016 and 68.73% in 2017; the modeled-trend value for 2018 is 68.04%.

    Source

  • 5-year relative survival · United States, SEER 21 (excluding IL)

    • 65.4%

      2016-2022

    Colon and rectum combined, all races, both sexes; the headline figure on the SEER Cancer Stat Facts colorectal page. The page states no age range beside it.

    A different registry set and time basis from the SEER 8 series, so it is not a continuation of the 1975-2018 values and must not be subtracted from them. The page labels the period '2016-2022' and does not say whether it is the diagnosis period. Relative survival excludes deaths from other causes; the page does not discuss lead-time bias or overdiagnosis.

    Source

  • 5-year relative survival · United States, SEER 21 (excluding IL)

    • 91.3%

      2016-2022; localized stage at diagnosis (34% of cases)

    Colon and rectum combined, all races, both sexes, localized (confined to the primary site) by SEER Combined Summary Stage.

    Stage-specific value from the same SEER 21 table as the 65.4% figure. The page gives the stage mix as 34% localized, 37% regional, 23% distant and 6% unstaged (its text separately says 33.8% are diagnosed at the local stage), and says stage at diagnosis has a strong influence on survival. Five-year figure only. Not comparable with SEER 8 values.

    Source

  • 5-year relative survival · United States, SEER 21 (excluding IL)

    • 75.2%

      2016-2022; regional stage at diagnosis (37% of cases)

    Colon and rectum combined, all races, both sexes, regional (spread to regional lymph nodes) by SEER Combined Summary Stage.

    Same SEER 21 table and caveats as the localized value. Not comparable with SEER 8 values.

    Source

  • 5-year relative survival · United States, SEER 21 (excluding IL)

    • 16.9%

      2016-2022; distant stage at diagnosis (23% of cases)

    Colon and rectum combined, all races, both sexes, distant (cancer has metastasized) by SEER Combined Summary Stage.

    Same SEER 21 table and caveats as the localized value. The page gives no breakdown by biomarker (for example mismatch repair status or BRAF V600E) or by colon versus rectum. Not comparable with SEER 8 values.

    Source

  • Age-standardised mortality · United States

    • 28.08per 100,000

      1975 (observed)

    Colon and rectum combined, all races, both sexes; age-adjusted death rate from US mortality data (not SEER registries), the 'Death Rate - U.S.' column.

    Death rates describe the whole US population and are not measured from the date of diagnosis, so they are not affected by lead time the way survival from diagnosis is; the page attributes the changes to no cause (incidence, screening, treatment and population ageing all act on this rate). Screened cancers are best read with mortality and survival side by side.

    Source

  • Age-standardised mortality · United States

    • 28.59per 100,000

      1976 (observed; highest value in the 1975-2024 table)

    Colon and rectum combined, all races, both sexes; age-adjusted death rate from US mortality data.

    Highest observed value in the 'Death Rate - U.S.' column; the 1978 value (28.56) is nearly the same. Same caveats as the 1975 value.

    Source

  • Age-standardised mortality · United States

    • 12.57per 100,000

      2024 (observed)

    Colon and rectum combined, all races, both sexes; age-adjusted death rate from US mortality data.

    The page headline gives 12.7 per 100,000 for 2020-2024 deaths; use one or the other, not both. The page says age-adjusted death rates fell on average 1.3% a year over 2015-2024. Same caveats as the 1975 value.

    Source

  • 10-year relative survival · United Kingdom

    • 22.4%

      Diagnosed in the 1970s

    People diagnosed with colon cancer in the UK; no age range stated for this figure (the page gives age-specific ten-year values for 2018 separately). Colon and rectal cancer are reported separately on the page.

    The sentence giving the 1970s figure does not itself name the UK (it sits on a UK statistics page); Cancer Research UK words this as 'survived their disease beyond ten years' for the 1970s and as a predicted figure for 2018. The page does not say whether the figures are net or relative survival, which UK nations are included for the 1970s, or how the 2018 prediction was made. It says survival trends reflect a combination of changes in treatment and stage distribution. Different source, country and measure from the SEER series; do not compare directly with them. The schema's nearest metric label '10y-relative-survival' is used because the page does not name the measure.

    Source

  • 10-year relative survival · United Kingdom

    • 54.3%

      2018 (the page says 'predicted')

    People diagnosed with colon cancer in the UK; the page also gives 64.3% (females) and 60.5% (males) aged 15-44 and 48.0% (females) and 48.5% (males) aged 75-99 for 2018.

    Cancer Research UK words this as 'survived their disease beyond ten years' for the 1970s and as a predicted figure for 2018. The page does not say whether the figures are net or relative survival, which UK nations are included for the 1970s, or how the 2018 prediction was made. It says survival trends reflect a combination of changes in treatment and stage distribution. Different source, country and measure from the SEER series; do not compare directly with them. The schema's nearest metric label '10y-relative-survival' is used because the page does not name the measure.

    Source

  • 10-year relative survival · United Kingdom

    • 24.6%

      Diagnosed in the 1970s

    People diagnosed with rectal cancer in the UK; no age range stated for this figure. Colon and rectal cancer are reported separately on the page.

    The sentence giving the 1970s figure does not itself name the UK (it sits on a UK statistics page); Cancer Research UK words this as 'survived their disease beyond ten years' for the 1970s and as a predicted figure for 2018. The page does not say whether the figures are net or relative survival, which UK nations are included for the 1970s, or how the 2018 prediction was made. It says survival trends reflect a combination of changes in treatment and stage distribution. Different source, country and measure from the SEER series; do not compare directly with them. The schema's nearest metric label '10y-relative-survival' is used because the page does not name the measure.

    Source

  • 10-year relative survival · United Kingdom

    • 53.9%

      2018 (the page says 'predicted')

    People diagnosed with rectal cancer in the UK; the page also gives 66.8% (females) and 59.5% (males) aged 15-44 and 41.8% (females) and 42.8% (males) aged 75-99 for 2018.

    Cancer Research UK words this as 'survived their disease beyond ten years' for the 1970s and as a predicted figure for 2018. The page does not say whether the figures are net or relative survival, which UK nations are included for the 1970s, or how the 2018 prediction was made. It says survival trends reflect a combination of changes in treatment and stage distribution. Different source, country and measure from the SEER series; do not compare directly with them. The schema's nearest metric label '10y-relative-survival' is used because the page does not name the measure.

    Source

Survival figures are affected by earlier detection (lead time) and overdiagnosis, and by changes in who is diagnosed. For screened cancers, read them alongside mortality.

Evidence chains

A lane follows one defined population and setting, where each new trial tests against what was then standard. Compare only within a lane, and read every comparison as illustrative.

Colon cancer after resection: 3-year disease-free survival

Resected colon cancer given adjuvant treatment. MOSAIC and NSABP C-07 enrolled stage II and III, the bevacizumab and cetuximab trials stage II and III or stage III, IDEA stage III, and ATOMIC only stage III with mismatch repair deficiency. · Adjuvant · endpoint: DFS

Results are not comparable across trials.

Populations, eras, control regimens and what is being tested differ. The 1990 levamisole trial used older staging and reported no disease-free survival value here, so it is listed but not drawn. MOSAIC and NSABP C-07 tested adding oxaliplatin; the bevacizumab and cetuximab trials tested adding an antibody to oxaliplatin-based chemotherapy (the cetuximab figure is the KRAS wild-type primary analysis). IDEA is a pooled comparison of 3 against 6 months of treatment, so the 3-month arm is drawn as the experimental arm and its non-inferiority margin was not met overall; the component IDEA trials used other margins and endpoints and are not plotted. ATOMIC enrolled only dMMR tumours and its control is mFOLFOX6. Comparisons are only within each trial's own arms.

Each pair shows one trial: its control arm and its experimental arm. Yesterday's experimental arm is often today's control. Populations, definitions and follow-up differ.

020406080100DFS at 36 months (%)200420042010201020182026MOSAICNSABP C-07NSABP C-08N0147IDEAATOMIC
  • experimental arm
  • control arm
  • different endpoint from the lane's
  • step line through experimental values
DFS at 36 months, rate, across 6 trials in this lane. MOSAIC (2004): experimental 78.2 % vs control 72.9 %; NSABP C-07 (2004): experimental 76.1 % vs control 71.8 %; NSABP C-08 (2010): experimental 77.4 % vs control 75.5 %; N0147 (2010): experimental 71.5 % vs control 74.6 %; IDEA (2018): experimental 74.6 % vs control 75.5 %; ATOMIC (2026): experimental 86.3 % vs control 76.2 %.
Data table
TrialYearEndpointControl (%)Experimental (%)
MOSAIC2004DFS72.9 %78.2 %
NSABP C-072004DFS71.8 %76.1 %
NSABP C-082010DFS75.5 %77.4 %
N01472010DFS74.6 %71.5 %
IDEA2018DFS75.5 %74.6 %
ATOMIC2026DFS76.2 %86.3 %

Metastatic, first-line chemotherapy: overall survival

Previously untreated metastatic or advanced colorectal cancer, in trials reported between 2000 and 2004. · Metastatic · endpoint: OS

Results are not comparable across trials.

The control arms differ: bolus fluorouracil and leucovorin (Saltz), infusional fluorouracil and folinate (Douillard, de Gramont), chronomodulated fluorouracil and leucovorin (Giacchetti), and irinotecan-based IFL plus placebo (Hurwitz). The added drug differs as well (irinotecan, oxaliplatin or bevacizumab), as do fluorouracil schedules, follow-up and later treatments. The Hurwitz trial's control already contains irinotecan, so its median is not on the same footing as the fluorouracil-only controls. Medians are drawn as published; compare only each trial's own two arms.

Each pair shows one trial: its control arm and its experimental arm. Yesterday's experimental arm is often today's control. Populations, definitions and follow-up differ.

0510152025OS, median (months)20002000200020002004douillard-irinotecan-5fu-lvirinotecan-study-group-iflgiacchetti-oxaliplatin-chronomodulateddegramont-lv5fu2-oxaliplatinhurwitz-ifl-bevacizumab
  • experimental arm
  • control arm
  • different endpoint from the lane's
  • step line through experimental values
OS, median, across 5 trials in this lane. douillard-irinotecan-5fu-lv (2000): experimental 17.4 months vs control 14.1 months; irinotecan-study-group-ifl (2000): experimental 14.8 months vs control 12.6 months; giacchetti-oxaliplatin-chronomodulated (2000): experimental 19.4 months vs control 19.9 months; degramont-lv5fu2-oxaliplatin (2000): experimental 16.2 months vs control 14.7 months; hurwitz-ifl-bevacizumab (2004): experimental 20.3 months vs control 15.6 months.
Data table
TrialYearEndpointControl (months)Experimental (months)
douillard-irinotecan-5fu-lv2000OS14.1 months17.4 months
irinotecan-study-group-ifl2000OS12.6 months14.8 months
giacchetti-oxaliplatin-chronomodulated2000OS19.9 months19.4 months
degramont-lv5fu2-oxaliplatin2000OS14.7 months16.2 months
hurwitz-ifl-bevacizumab2004OS15.6 months20.3 months

Metastatic, after standard chemotherapy: overall survival

Metastatic colorectal cancer that progressed on standard treatment. The control arm in each plotted trial is best supportive care alone or with placebo. · Metastatic · endpoint: OS

Results are not comparable across trials.

Prior-therapy requirements, number of earlier lines, region, biomarker selection and crossover differ. CO.17 enrolled people with detectable EGFR before KRAS testing was used to select treatment, and its control was best supportive care alone; CORRECT, RECOURSE, FRESCO and FRESCO-2 used placebo. FRESCO was run in China and FRESCO-2 in a global population. SUNLIGHT compared trifluridine-tipiracil with and without bevacizumab, an active control that does not fit with the placebo-controlled trials, so it is not plotted. BEACON, in BRAF V600E-mutated disease with an active control, is a different population and is not in this lane. Compare only each trial's own two arms.

Each pair shows one trial: its control arm and its experimental arm. Yesterday's experimental arm is often today's control. Populations, definitions and follow-up differ.

02468101214OS, median (months)20042012201520182018CO.17CORRECTRECOURSEFRESCOFRESCO-2
  • experimental arm
  • control arm
  • different endpoint from the lane's
  • step line through experimental values
OS, median, across 5 trials in this lane. CO.17 (2004): experimental 6.1 months vs control 4.6 months; CORRECT (2012): experimental 6.4 months vs control 5 months; RECOURSE (2015): experimental 7.1 months vs control 5.3 months; FRESCO (2018): experimental 9.3 months vs control 6.6 months; FRESCO-2 (2018): experimental 7.4 months vs control 4.8 months.
Data table
TrialYearEndpointControl (months)Experimental (months)
CO.172004OS4.6 months6.1 months
CORRECT2012OS5 months6.4 months
RECOURSE2015OS5.3 months7.1 months
FRESCO2018OS6.6 months9.3 months
FRESCO-22018OS4.8 months7.4 months

MSI-H or dMMR metastatic, first line: progression-free survival

Previously untreated unresectable or metastatic colorectal cancer with MSI-H or dMMR status. · Metastatic · endpoint: PFS

Results are not comparable across trials.

Both trials compared an immunotherapy with investigator's-choice chemotherapy, but they are parallel experiments, not steps in a sequence. KEYNOTE-177 reports a median PFS; CheckMate 8HW reports a 24-month PFS rate for its first-line comparison, so it is listed but not drawn on the same axis. MSI-H or dMMR status was confirmed by different methods, follow-up and crossover differ, and CheckMate 8HW's first-line analysis covers part of its randomised population. The two regimens were not compared with each other; read each trial's own two arms.

Each pair shows one trial: its control arm and its experimental arm. Yesterday's experimental arm is often today's control. Populations, definitions and follow-up differ.

05101520PFS, median (months)2020KEYNOTE-177
  • experimental arm
  • control arm
  • different endpoint from the lane's
  • step line through experimental values
PFS, median, across 1 trial in this lane. KEYNOTE-177 (2020): experimental 16.5 months vs control 8.2 months.
Data table
TrialYearEndpointControl (months)Experimental (months)
KEYNOTE-1772020PFS8.2 months16.5 months
CheckMate 8HW2024PFS (not plotted: different measure or time point)14 %72 %

Rectal cancer, treatment around surgery: local recurrence

Rectal adenocarcinoma treated with radiotherapy or chemoradiotherapy and surgery. Entry criteria differ by trial: resectable disease (Swedish and Dutch trials), T3 or T4 or node-positive disease (CAO/ARO/AIO-94), and MRI-defined high-risk disease (RAPIDO). · Neoadjuvant · endpoint: Local recurrence

Results are not comparable across trials.

Control arms differ: surgery alone (Swedish trial), standardised TME alone (Dutch trial), postoperative chemoradiotherapy (CAO/ARO/AIO-94) and standard chemoradiotherapy (RAPIDO). Lower is better. The Dutch and CAO/ARO/AIO-94 values are 5-year cumulative local recurrence. RAPIDO reports locoregional recurrence after R0 or R1 resection, a differently defined endpoint, at a median of 5.6 years, so it is drawn with a distinct marker or listed apart. The Swedish trial is not drawn because its result is stored as a plain rate and its record is still marked for review. Surgical technique, imaging and follow-up differ; compare only each trial's own two arms.

Each pair shows one trial: its control arm and its experimental arm. Yesterday's experimental arm is often today's control. Populations, definitions and follow-up differ.

020406080100Local recurrence at 60 months (%)20012004dutch-tme-trialCAO/ARO/AIO-94
  • experimental arm
  • control arm
  • different endpoint from the lane's
  • step line through experimental values
Local recurrence at 60 months, rate, across 2 trials in this lane. dutch-tme-trial (2001): experimental 5.6 % vs control 10.9 %; CAO/ARO/AIO-94 (2004): experimental 6 % vs control 13 %.
Data table
TrialYearEndpointControl (%)Experimental (%)
dutch-tme-trial2001Local recurrence10.9 %5.6 %
CAO/ARO/AIO-942004Local recurrence13 %6 %
RAPIDO2020Locoregional recurrence after R0/R1 resection (differs from lane) (not plotted: different measure or time point)6 %10 %

Rectal cancer, total neoadjuvant and selective radiotherapy: disease-free survival

Rectal adenocarcinoma staged cT3 or cT4 (PRODIGE 23) or cT2 node-positive, cT3 node-negative or cT3 node-positive and suitable for sphincter-sparing surgery (PROSPECT). · Neoadjuvant · endpoint: DFS

Results are not comparable across trials.

PRODIGE 23 tested adding chemotherapy before standard chemoradiotherapy and showed superiority at 3 years; PROSPECT tested omitting radiotherapy in most patients and aimed to show non-inferiority at 5 years, so the time points differ and the PROSPECT value is listed rather than drawn. The PROSPECT figure is from the per-protocol population, while its other analyses use all randomised patients. RAPIDO used a different primary endpoint (disease-related treatment failure) and is not plotted. OPRA's two arms are both experimental with no concurrent control, so it is not a pair and has no entry. Compare only each trial's own arms.

Each pair shows one trial: its control arm and its experimental arm. Yesterday's experimental arm is often today's control. Populations, definitions and follow-up differ.

020406080100DFS at 36 months (%)2020UNICANCER-PRODIGE 23
  • experimental arm
  • control arm
  • different endpoint from the lane's
  • step line through experimental values
DFS at 36 months, rate, across 1 trial in this lane. UNICANCER-PRODIGE 23 (2020): experimental 76 % vs control 69 %.
Data table
TrialYearEndpointControl (%)Experimental (%)
UNICANCER-PRODIGE 232020DFS69 %76 %
PROSPECT2023DFS (not plotted: different measure or time point)78.6 %80.8 %

Screening trials: colorectal cancer mortality

Asymptomatic adults aged about 50 to 64 invited to screening (faecal occult blood testing, once-only flexible sigmoidoscopy, a single colonoscopy invitation) compared with no invitation or usual care. · Screening · endpoint: Colorectal cancer mortality

Results are not comparable across trials.

The tests, age ranges, uptake and follow-up differ, and these are intention-to-screen comparisons of an invitation, not of the test itself. The faecal occult blood trials and the sigmoidoscopy trials report hazard ratios or relative risks without a risk in each arm, so only NordICC's 10-year risk of death from colorectal cancer can be drawn here. NordICC's per-protocol result is not a two-arm comparison and is not used. Read each trial's own two arms; the values cannot be ranked across tests.

Each pair shows one trial: its control arm and its experimental arm. Yesterday's experimental arm is often today's control. Populations, definitions and follow-up differ.

020406080100Colorectal cancer mortality (%)2022NordICC
  • experimental arm
  • control arm
  • different endpoint from the lane's
  • step line through experimental values
Colorectal cancer mortality, rate, across 1 trial in this lane. NordICC (2022): experimental 0.28 % vs control 0.31 %.
Data table
TrialYearEndpointControl (%)Experimental (%)
NordICC2022Colorectal cancer mortality0.31 %0.28 %

Standard of care, then and now

How the usual sequence of treatment changed for one setting. Choose a point in time; each step links to the milestone behind it.

Metastatic colorectal cancer: first-line options

Previously untreated metastatic colorectal cancer; later options depend on biomarkers (MSI-H or dMMR, BRAF V600E) · Metastatic

  1. Chemotherapy1FU/LV + irinotecanIrinotecan with fluorouracil as first-line therapy for metastatic CRC (2000)
  2. Chemotherapy2FU/LV + oxaliplatinOxaliplatin added to infusional fluorouracil in advanced CRC (2000)
  3. Targeted3IFL + bevacizumabBevacizumab added to first-line irinotecan-based chemotherapy (2004)
  4. Immunotherapy4MSI-H/dMMR: pembrolizumabKEYNOTE-177: pembrolizumab first-line for MSI-H/dMMR metastatic CRC (2020)
  5. Immunotherapy5MSI-H/dMMR: nivolumab + ipilimumabCheckMate 8HW: nivolumab plus ipilimumab in MSI-H/dMMR mCRC (2024)
  6. Targeted6BRAF V600E: encorafenib, cetuximab, mFOLFOX6BREAKWATER: first-line encorafenib, cetuximab and chemotherapy (2024)
Today. Based only on the trials cited in each step. Two further first-line trials are listed: nivolumab with ipilimumab for MSI-H or dMMR tumours, and an encorafenib regimen for BRAF V600E-mutated tumours.
Text version
  • 2000: FU/LV + irinotecan → FU/LV + oxaliplatin
  • 2004: FU/LV + irinotecan → FU/LV + oxaliplatin → IFL + bevacizumab
  • 2020: FU/LV + irinotecan → FU/LV + oxaliplatin → IFL + bevacizumab → MSI-H/dMMR: pembrolizumab
  • Today: FU/LV + irinotecan → FU/LV + oxaliplatin → IFL + bevacizumab → MSI-H/dMMR: pembrolizumab → MSI-H/dMMR: nivolumab + ipilimumab → BRAF V600E: encorafenib, cetuximab, mFOLFOX6

Rectal cancer: treatment before surgery

Rectal adenocarcinoma considered for treatment before surgery; entry criteria differ by trial · Neoadjuvant

  1. Radiation1Short-course RT, then TMEDutch TME trial: preoperative radiotherapy plus standardised TME (2001)
  2. Radiation2Chemoradiotherapy before surgeryCAO/ARO/AIO-94: preoperative vs postoperative chemoradiotherapy (2004)
  3. Surgery3Watch-and-wait after complete responseWatch-and-wait after chemoradiotherapy for complete clinical response (2004)
  4. Chemotherapy4Total neoadjuvant therapyTotal neoadjuvant therapy: RAPIDO and PRODIGE 23 (2020)
  5. Chemotherapy5Selective watch-and-wait after TNTOPRA: total neoadjuvant therapy and selective watch-and-wait (2022)
  6. Chemotherapy6FOLFOX first, selective chemoradiotherapyPROSPECT: neoadjuvant FOLFOX with selective chemoradiotherapy (2023)
Today. Based only on the trials cited in each step. OPRA studied selective watch-and-wait after total neoadjuvant therapy, and PROSPECT limited radiotherapy to patients whose tumour responded little to FOLFOX.
Text version
  • 2001: Short-course RT, then TME
  • 2004: Short-course RT, then TME → Chemoradiotherapy before surgery → Watch-and-wait after complete response
  • 2020: Short-course RT, then TME → Chemoradiotherapy before surgery → Watch-and-wait after complete response → Total neoadjuvant therapy
  • Today: Short-course RT, then TME → Chemoradiotherapy before surgery → Watch-and-wait after complete response → Total neoadjuvant therapy → Selective watch-and-wait after TNT → FOLFOX first, selective chemoradiotherapy

Reversals and dead ends

Approaches that were abandoned or withdrawn, and trials whose results were later questioned, are part of the story.

  • 2008

    KRAS mutation predicts no benefit: anti-EGFR limited to wild-type

    Cetuximab and panitumumab were first approved for bowel cancers carrying the EGFR receptor. In 2008, two analyses of randomised trials showed that people whose tumours had a KRAS mutation gained no benefit, while those without it did. The FDA later revised the cetuximab label and then limited its use to tumours without the mutation.

    Biomarker analyses of two randomised trials of anti-EGFR antibody plus best supportive care versus best supportive care alone. Panitumumab (KRAS known in 427 of 463): PFS HR 0.45 (95% CI 0.34 to 0.59) in wild-type vs 0.99 (0.73 to 1.36) in mutant tumours. Cetuximab, CO.17 (K-ras tested in 394 of 572): wild-type OS median 9.5 vs 4.8 months, HR 0.55 (0.41 to 0.74); mutant OS HR 0.98 (P=0.89). FDA limited cetuximab to K-ras wild-type disease on 6 July 2012.

  • 2010

    Adjuvant bevacizumab and cetuximab trials in colon cancer

    Four large randomised trials added a targeted drug, bevacizumab or cetuximab, to oxaliplatin-based chemotherapy after surgery for colon cancer. None improved disease-free survival. In one trial the authors noted overall survival data suggesting a possible harm with bevacizumab, and cetuximab added side effects. Both drugs had shown benefit in advanced disease, which is a different setting.

    Adjuvant colon cancer, DFS primary endpoint. NSABP C-08 (bevacizumab + mFOLFOX6; 2672 analysed): HR 0.89 (95% CI 0.76-1.04), P=0.15. AVANT (3451 randomised; stage III primary analysis): HR 1.17 (0.98-1.39) bevacizumab-FOLFOX4 and 1.07 (0.90-1.28) bevacizumab-XELOX vs FOLFOX4; OS HR 1.27 (1.03-1.57) for bevacizumab-FOLFOX4. N0147 (KRAS wild-type, mFOLFOX6 with or without cetuximab): 3-year DFS 71.5% with vs 74.6% without, HR 1.21 (0.98-1.49). PETACC-8 (KRAS exon 2 wild-type, 1602): HR 1.05 (0.85-1.29).

  • 2021

    PRODIGE 7: HIPEC added to cytoreductive surgery (peritoneal CRC)

    PRODIGE 7 randomly assigned 265 people with colorectal cancer that had spread to the lining of the abdomen to surgery that removes all visible tumour, with or without heated chemotherapy washed through the abdomen. Median survival was about forty-one to forty-two months in both groups, and later complications were more frequent with the heated chemotherapy.

    PRODIGE 7 (Quénet 2021): phase 3, 265 patients with colorectal peritoneal metastases (PCI 25 or less) after complete cytoreduction, randomised to surgery plus oxaliplatin HIPEC (n=133) or surgery alone (n=132). Median OS 41.7 months (95% CI 36.2-53.8) vs 41.2 (35.1-49.7); HR 1.00 (95.37% CI 0.63-1.58), P=0.99; median follow-up 63.8 months. Grade 3 or worse adverse events at 60 days: 26% vs 15% (P=0.035).

Today and tomorrow

Standard of care today

Screening

Guideline abstracts were read; the guideline full texts were not. The ACS 2018 abstract recommends regular screening for average-risk adults from age 45 with a high-sensitivity stool-based test or a structural examination (a qualified recommendation for starting at 45; the recommendation for regular screening from 50 is strong). The ACS 2026 update abstract reaffirms starting at 45 and continuing to 75 for people with a life expectancy over 10 years; lists a next-generation multitarget stool DNA test and a multitarget stool RNA test alongside annual high-sensitivity FIT and guaiac-based FOBT as preferred stool-based options (the abstract's sentence ends 'at 3-year intervals', and which of these tests that interval applies to is not clear from the abstract); says blood-based tests, with lower sensitivity for advanced precancerous lesions and stage I cancers, should be recommended only to people who decline or do not complete preferred tests; and says a positive noncolonoscopy test needs timely colonoscopy, preferably within 6 months. The USPSTF 2021 abstract gives grade A for ages 50 to 75, grade B for 45 to 49 and grade C (selective offering) for 76 to 85. FDA device records (openFDA PMA database, original decisions):

  • Cologuard (P130017) approved 2014-08-11, with an approval-order statement covering adults 50 or older at average risk
  • Shield, a blood test (P230009), approved 2024-07-26 for average-risk adults 45 or older, with a positive result to be followed by colonoscopy and the test not a replacement for colonoscopy. The openFDA record also lists a later supplement (S029, 2019-09-20) described as approval to expand the indicated age range from 50 or older to 45 or older
  • that supplement and the other later ones were not read, so the current Cologuard indication is not described here. The randomised evidence for an invitation to colonoscopy is NordICC (see the hooks)
Guideline: Wolf AMD, Fontham ETH, Church TR, Flowers CR, Guerra CE, LaMonte SJ, et al 2018Wolf AMD, Hoffman RM, Walter LC, Zeigler-Johnson C, Church TR, Guerra CE, et al 2026Guideline: Davidson KW, Barry MJ, Mangione CM, Cabana M, Caughey AB, Davis EM, et al 2021US Food and Drug Administration 2026US Food and Drug Administration 2026Bretthauer M, Løberg M, Wieszczy P, Kalager M, Emilsson L, Garborg K, et al 2022
Adjuvant

Stage III colon cancer, from FDA approval letters read in full. Oxaliplatin (Eloxatin; NDA 21-492/S-004; letter signed 2004-11-04):

  • in combination with infusional 5-FU/leucovorin for adjuvant treatment of stage III colon cancer after complete resection of the primary tumour
  • the letter states the indication is based on an improvement in disease-free survival, with no demonstrated overall-survival benefit after a median follow-up of 4 years. Atezolizumab (Tecentriq
  • BLA 761034/S-065
  • letter e-signed 2026-10-08): in combination with a fluoropyrimidine and oxaliplatin for adjuvant treatment of adult and paediatric patients 2 years of age and older with stage III mismatch repair-deficient (dMMR) colon cancer. The letter contains no accelerated-approval wording, so this is recorded as a regular approval (an inference from the letter)
  • it lists a postmarketing commitment to validate a companion diagnostic for dMMR stage 3 colon cancer, with the final report due 09/2029. The EMA position for this indication was not checked. Guidelines are cited by identifier only and their text was not read: ESMO localised colon cancer 2020 (with a 2026 ESMO Clinical Practice Guideline Express Update on physical exercise in localised colon cancer, which is a separate document) and NCCN Colon Cancer v2.2021 and v3.2024 (the latest NCCN colon article found in PubMed
  • the current live NCCN version was not retrieved)
U 2004U 2026Guideline: Argilés G, Tabernero J, Labianca R, Hochhauser D, Salazar R, Iveson T, et al 2020Guideline: Benson AB, Venook AP, Al-Hawary MM, Arain MA, Chen YJ, Ciombor KK, et al 2021Guideline: Benson AB, Venook AP, Adam M, Chang G, Chen YJ, Ciombor KK, et al 2024Guideline: Pentheroudakis G, Argilés G, Arnold D, Smyth E, Ducreux M 2026
Locally advanced
Rectal cancer. No regulatory document or guideline text was read for chemoradiotherapy, total neoadjuvant therapy or organ preservation; those are covered by the rectal milestones. For mismatch repair-deficient or microsatellite instability-high disease, a company announcement dated 2026-08-24 states that the FDA accepted for priority review a supplemental BLA for dostarlimab in previously untreated stage II and III dMMR/MSI-H locally advanced rectal cancer, assigned a PDUFA action date of February 2027, and that the application is eligible for review under the Commissioner's National Priority Voucher programme, which could lead to an earlier decision. The announcement says the filing rests on AZUR-1, a single-arm phase 2 trial of 154 participants, and that its data will be submitted to a congress later in 2026; no efficacy figures are recorded here. This is an application under review and not an approval: a web search on 2026-10-20 found no approval. Guidelines are cited by identifier only (text not read): ESMO localised rectal cancer 2025 and NCCN Guidelines Insights: Rectal Cancer v3.2024; the current NCCN version was not retrieved.
GSK plc 2026Guideline: Hofheinz RD, Fokas E, Benhaim L, Price TJ, Arnold D, Beets-Tan R, et al 2025Guideline: Benson AB, Venook AP, Adam M, Chang G, Chen YJ, Ciombor KK, et al 2024
Metastatic

Biomarker-defined first-line treatment, from FDA approval letters read in full and EMA pages read. Pembrolizumab (Keytruda; BLA 125514/S-084; letter e-signed 2020-06-29):

  • first-line treatment of unresectable or metastatic MSI-H or dMMR colorectal cancer
  • no accelerated-approval wording, recorded as regular (an inference). Nivolumab (Opdivo
  • BLA 125554/S-132
  • letter e-signed 2025-04-08): updates the labelled indications to nivolumab with ipilimumab for adult and paediatric patients 12 years and older with unresectable or metastatic MSI-H or dMMR colorectal cancer, and single-agent nivolumab for MSI-H or dMMR metastatic disease that progressed after a fluoropyrimidine, oxaliplatin and irinotecan
  • the letter refers to the conversion from accelerated approval to full approval and states that the supplement fulfils the commitments made under 21 CFR 601.41 for the earlier supplements S-034 and S-063. Encorafenib (Braftovi
  • NDA 210496): with cetuximab and mFOLFOX6 for BRAF V600E-mutated metastatic colorectal cancer, accelerated approval (S-017, letter e-signed 2024-12-20)
  • a later letter (S-019, e-signed 2026-02-24) covers encorafenib with cetuximab and fluorouracil-based chemotherapy and states that the approval fulfils the commitments made under 21 CFR 314.510 ('Subpart H fulfilled'), so the accelerated approval is recorded as converted (the letter does not use the word 'converted'). EMA product pages (read 2026-10-20
  • the dates of indication extensions were not extracted): Keytruda monotherapy for MSI-H or dMMR colorectal cancer in the first-line metastatic setting and after previous fluoropyrimidine-based combination therapy
  • Opdivo with ipilimumab for dMMR or MSI-H colorectal cancer as first-line treatment of unresectable or metastatic disease and after prior fluoropyrimidine-based combination chemotherapy
  • Braftovi with cetuximab and FOLFOX as first-line treatment of BRAF V600E-mutated metastatic colorectal cancer. The ESMO metastatic colorectal cancer guideline is cited by identifier only (2023 edition and a 2026 edition, Ann Oncol 2026;37(6)
  • whether the 2026 text supersedes the 2023 one was not established) and neither text was read. Approvals for chemotherapy backbones and anti-EGFR or anti-VEGF antibodies are in the metastatic milestones and were not re-read for this page
US Food and Drug Administration 2020US Food and Drug Administration 2025US Food and Drug Administration 2024US Food and Drug Administration 2026European Medicines Agency 2026European Medicines Agency 2026European Medicines Agency 2026Guideline: Cervantes A, Adam R, Roselló S, Arnold D, Normanno N, Taïeb J, et al 2023Guideline: Cremolini C, Chalabi M, Elez E, Fassan M, Gelli M, Goéré D, et al 2026
Relapsed / refractory

Later-line metastatic disease, from FDA approval letters read in full. Regorafenib (NDA 203085; 2012-09-27):

  • metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy and, if KRAS wild type, an anti-EGFR therapy. Trifluridine/tipiracil (Lonsurf
  • NDA 207981): approved 2015-09-22 for the same prior-treatment description (anti-EGFR therapy if RAS wild type)
  • supplement S-012 (2023-08-02) adds use as a single agent or in combination with bevacizumab. Fruquintinib (Fruzaqla
  • NDA 217564
  • 2023-11-08): metastatic disease previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy and, if RAS wild type and medically appropriate, an anti-EGFR therapy. Biomarker-directed options: encorafenib with cetuximab for BRAF V600E-mutated disease after prior therapy (S-006, 2020-04-08
  • no accelerated-approval wording, recorded as regular, an inference)
  • tucatinib with trastuzumab for RAS wild-type, HER2-positive disease that progressed after fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy (S-004, 2023-01-19, accelerated approval)
  • adagrasib with cetuximab for KRAS G12C-mutated locally advanced or metastatic disease after the same chemotherapies (S-005, 2024-06-21, accelerated approval
  • withdrawn at the sponsor's request, see below)
  • sotorasib with panitumumab for KRAS G12C-mutated disease after the same chemotherapies (S-009, 2025-01-16
  • no accelerated-approval wording, recorded as regular, an inference)
  • trastuzumab deruxtecan for unresectable or metastatic HER2-positive (IHC 3+) solid tumours after prior systemic treatment with no satisfactory alternative (S-028, 2024-04-05, accelerated approval
  • not specific to colorectal cancer). Adagrasib with cetuximab: a later letter (NDA 216340/S-011, e-signed 2026-09-01) approves the sponsor's voluntary withdrawal of this accelerated-approval colorectal indication, states that the confirmatory study (Study 849-010) fulfilled the postmarketing requirement but 'did not confirm clinical benefit', and notes that an efficacy supplement would be needed to resume marketing for this indication
  • the adagrasib colorectal indication is therefore no longer an approved use. For tucatinib, the only later efficacy supplement in the openFDA Drugs@FDA list (queried 2026-10-20) is S-010 (2026-10-07), whose letter covers HER2-positive breast cancer
  • for trastuzumab deruxtecan, the later letters S-039 (lung) and S-041/S-043 (breast) were read and other later efficacy supplements were not. Whether the tucatinib and trastuzumab deruxtecan accelerated approvals have been converted was not established. EMA product pages (read 2026-10-20): Fruzaqla (authorised 20 June 2024) as monotherapy after standard therapies in people who progressed on or are intolerant to trifluridine-tipiracil or regorafenib
  • Lonsurf (authorised 25 April 2016) with bevacizumab after two prior regimens, and as monotherapy after available therapies. Zanzalintinib with atezolizumab: a Form 8-K filed by Exelixis dated 2026-09-10 (company filing) states that the FDA extended the review period for the NDA (zanzalintinib with atezolizumab, metastatic colorectal cancer) by three months after a submission the FDA deemed a major amendment, with a new action date of March 3, 2027
  • an OncLive report of 2026-09-11 (secondary source) gives the earlier date as December 3, 2026. This is an application under review, not an approval. The ESMO metastatic colorectal cancer guideline is cited by identifier only (2023 edition and a 2026 edition
  • neither text was read)
US Food and Drug Administration 2012US Food and Drug Administration 2015US Food and Drug Administration 2023US Food and Drug Administration 2023US Food and Drug Administration 2020US Food and Drug Administration 2023US Food and Drug Administration 2024US Food and Drug Administration 2025US Food and Drug Administration 2024European Medicines Agency 2026European Medicines Agency 2024OncLive 2026US Food and Drug Administration 2026Exelixis, Inc 2026Guideline: Cervantes A, Adam R, Roselló S, Arnold D, Normanno N, Taïeb J, et al 2023Guideline: Cremolini C, Chalabi M, Elez E, Fassan M, Gelli M, Goéré D, et al 2026

Trials to watch

  • AZUR-2 NCT05855200

    In untreated T4N0 or stage III dMMR/MSI-H resectable colon cancer, does perioperative dostarlimab monotherapy differ from standard of care (FOLFOX or CAPOX, or observation after surgery) in event-free survival assessed by blinded independent central review (the registry's primary outcome)? Registry record: randomised open-label phase 3, 892 estimated, GlaxoSmithKline sponsor. Registry status: recruiting; no results posted.

  • MOUNTAINEER-03 NCT05253651

    In previously untreated HER2-positive metastatic colorectal cancer, does tucatinib with trastuzumab and mFOLFOX6 differ from mFOLFOX6 with or without cetuximab or bevacizumab in progression-free survival by blinded independent central review (the registry's primary outcome)? Registry record: randomised open-label phase 3, 400 estimated, sponsor Seagen (a wholly owned subsidiary of Pfizer). Registry status: recruiting; no results posted.

  • COMMIT (NRG-GI004/S1610) NCT02997228

    In first-line dMMR/MSI-H metastatic colorectal cancer, how do mFOLFOX6 with bevacizumab, atezolizumab alone, and atezolizumab with mFOLFOX6 and bevacizumab compare in progression-free survival (the registry's primary outcome)? Registry record: randomised phase 3, 120 estimated, sponsor National Cancer Institute. Registry status: active, not recruiting; no results posted.

  • CIRCULATE (PRODIGE 70) NCT04120701

    In resected stage II colon cancer (the registry's eligibility also admits high rectal tumours; ages 18 to 75), does a circulating tumour DNA-based decision to give adjuvant chemotherapy change 3-year disease-free survival in people with detectable ctDNA (the registry's primary outcome)? Registry record: randomised phase 3, 1,980 estimated, sponsor Centre Hospitalier Universitaire Dijon; the registry lists one chemotherapy arm and two follow-up arms. Registry status: recruiting; no results posted.

  • ACO/ARO/AIO-18.1 NCT04246684

    In MRI-defined intermediate- and high-risk rectal cancer, does chemoradiotherapy followed by consolidation chemotherapy differ from short-course radiotherapy followed by consolidation chemotherapy in organ preservation (the registry's primary outcome), with surgery or watch-and-wait chosen after restaging? Registry record: randomised phase 3, 702 enrolled (actual), sponsor Prof. Dr. med. Claus Rödel. Registry status: active, not recruiting; no results posted.

  • KANDLELIT-012 (MK-1084-012) NCT06997497

    In first-line KRAS G12C-mutant, locally advanced unresectable or metastatic colorectal cancer, how does calderasib (MK-1084) with cetuximab and mFOLFOX6 compare with mFOLFOX6 with or without bevacizumab? The registry lists progression-free survival and, for Part 1, dose-limiting toxicity and adverse-event counts as primary outcomes. Registry record: randomised open-label phase 3, 477 estimated, sponsor Merck Sharp & Dohme LLC. Registry status: recruiting; no results posted.

References

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Every figure was checked against its primary source to the extent possible. Items that could not be fully confirmed are marked “needs review”. Educational history, not medical advice.

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2022TreatmentTargeted

majorMetastaticRelapsed / refractoryNeeds review

KRAS G12C inhibitors with anti-EGFR antibodies

A small share of bowel cancers carry a KRAS G12C change. Used alone, drugs aimed at it worked modestly. Paired with an anti-EGFR antibody, one drug shrank tumours in nearly half of 28 evaluable people in a non-randomised study; its US approval was withdrawn in 2026. Another delayed progression against standard treatment in a randomised trial.

KRYSTAL-1 (phase 1-2, nonrandomised, KRAS G12C colorectal cancer): adagrasib + cetuximab, ORR 46% (95% CI 28-66; 28 evaluable patients), median PFS 6.9 months (32 patients). CodeBreaK 300 (phase 3, n=160): sotorasib 960 mg + panitumumab vs investigator's choice, median PFS 5.6 vs 2.2 months (HR 0.49, 95% CI 0.30-0.80; P=0.006); ORR 26.4% vs 0%. OS HR 0.70 (95% CI 0.41-1.18; P=0.20).

Standard before

The CodeBreaK 300 abstract states that monotherapy with KRAS G12C inhibitors had yielded only modest efficacy in colorectal cancer; the randomised comparator in the chemorefractory setting was trifluridine-tipiracil or regorafenib.

What changed

FDA approvals for KRAS G12C-mutated colorectal cancer after fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy: adagrasib with cetuximab (accelerated, 21 June 2024; withdrawn at the sponsor's request on 1 September 2026) and sotorasib with panitumumab (16 January 2025).

Why it mattered

It defined a molecular subgroup of colorectal cancer with its own targeted regimens, in which combining a KRAS G12C inhibitor with an EGFR antibody was tested to overcome the limited activity of the inhibitors alone; for adagrasib with cetuximab the randomised confirmatory trial did not confirm benefit.

Caveats

  • The two approvals differ in type: the adagrasib approval was accelerated (the FDA letter required the randomised phase 3 Study 849-010 and does not name the study that supported the accelerated approval) and was withdrawn at the sponsor's request on 1 September 2026, while the sotorasib approval letter has no accelerated wording, so 'regular' is an inference.
  • KRYSTAL-10, the randomised phase 3 study of adagrasib plus cetuximab against chemotherapy, is registered as NCT04793958 (registry secondary id 849-010, the study named in the FDA letters) with no posted results. The FDA withdrawal letter of 1 September 2026 states that the postmarketing requirement (Study 849-010) was fulfilled but the trial did not confirm clinical benefit; a 2026 review states that it did not improve progression-free or overall survival versus chemotherapy despite a higher objective response rate. No primary peer-reviewed report was found, so no numbers are recorded here.
  • In CodeBreaK 300 the overall survival analysis was not adequately powered and was not statistically significant; crossover from investigator's choice was permitted after the primary analysis. The NEJM paper has a published erratum (PMID 39938112) whose content could not be accessed, so the figures are as given in the original abstract.
  • KRYSTAL-1 cohorts were not randomised, so response rates are not compared between the adagrasib alone and combination cohorts or with CodeBreaK 300. The 46% response rate is from 28 evaluable patients in the published report.