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Bending the Curve Trial by Trial
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Rectum (digestive system)

Rectal cancer

Rectal cancer, from the Miles operation to total mesorectal excision, chemoradiotherapy, total neoadjuvant therapy and organ preservation.

Colon and rectum combined · 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

27 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.
  • In 1982 R. J. Heald described five cases in which small foci of adenocarcinoma lay in the mesorectum several centimetres below the visible lower edge of a rectal cancer, and reported that total excision of the mesorectum had been part of more than 100 consecutive anterior resections. In his 1986 single-hospital series of 115 patients in whom curative resection was attempted, three pelvic recurrences had developed at an average of 4.2 years; neither report was a randomised comparison. In the Dutch randomised trial published in 2001, all 1,861 patients were to have standardised total mesorectal excision, and among the 1,748 who had a macroscopically complete local resection the two-year local recurrence rate was 2.4% with five days of preoperative radiotherapy and 8.2% without (P<0.001), while two-year survival among the 1,805 eligible patients was 82.0% and 81.8% (P=0.84).
  • On 19 October 2026 the FDA granted accelerated approval to dostarlimab, used alone, for adults with stage II or III locally advanced rectal cancer that is MSI-H or dMMR, as determined by an FDA-authorized test. The approval rests on AZUR-1, a single-arm phase 2 trial of 154 previously untreated patients. At an interim analysis (data cut-off 20 April 2026, median follow-up 26 months) sustained clinical complete response for 12 months by independent central review was 47% (54 of 116 evaluable patients; 95% CI 37 to 56), and 110 of the 154 patients (71%) had received no further treatment and had not progressed or relapsed. The prescribing information states that the long-term risk of relapse is unknown and that continued approval may be contingent on a confirmatory trial. The FDA news release says published estimates suggest that about 3% of locally advanced rectal cancers are dMMR or MSI-H.

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 27
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.

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. 1983 · Treatment · SurgeryTransanal endoscopic microsurgery described (Buess group, 1983-1987)From 1983 a German surgical group described a way to operate in the rectum through the anus, using a rectoscope with a stereoscopic view and fine instruments. Reports moved from animal experiments to a series of 75 patients with adenomas or early cancers and few complications. Who first described the technique is not settled here.Technique descriptions and case series, not a trial. 1983: 47 excisions of mucosa in animals, closed by suture. 1985 Endoscopy: 12 cases without postoperative complications. 1985 German report: 33 patients operated from July 1983 to April 1985, one relapse. 1987: 75 patients with sessile adenomas or early carcinomas of the rectum or rectosigmoid; complications in three, no deaths, one adenomatous recurrence needing operation. The 1984 Chirurg report is cited by title only.
  3. 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. 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.
  2. 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).
  3. 2004 · Treatment · Radiation⚑ needs reviewShort-course radiotherapy vs long-course chemoradiation trialsFour randomised trials compared a week of radiotherapy before rectal cancer surgery with a longer chemoradiation course, or with delayed surgery after the short course. Each reported its own main measure, such as sphincter preservation or local recurrence. None reported a statistically significant difference on it, which is not the same as showing the schedules are equal.Four trials, each on its own endpoint; no pooling. Polish I (316): sphincter preservation 61% short-course vs 58% chemoradiation (P=0.57). TROG 01.04 (326): 3-year local recurrence 7.5% short-course vs 4.4% long-course (difference 3.1%, 95% CI -2.1 to 8.3). Polish II (515 eligible): R0 resection 77% vs 71% (P=0.07). Stockholm III (840): local recurrence HR vs 5 x 5 Gy with immediate surgery 1.44 and 2.24; both deemed non-inferior in the 2017 report.
  4. 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.
  5. 2006 · Treatment · RadiationFluorouracil added to preoperative RT: EORTC 22921, FFCD 9203Two randomised trials asked whether adding fluorouracil chemotherapy to radiotherapy before rectal cancer surgery helps. In both, cancer returned locally less often with chemotherapy; in the French trial about 8 in 100 versus 17 in 100 at five years. Neither trial showed a survival benefit, and severe side effects were more common with chemoradiotherapy in the French trial.EORTC 22921 (1011; cT3-4; primary endpoint OS): 45 Gy with or without fluorouracil/leucovorin before and/or after surgery; 5-year local recurrence 17.1% without chemotherapy vs 8.7% (preoperative), 9.6% (postoperative), 7.6% (both), P=0.002; no significant OS difference. FFCD 9203 (733 eligible; primary endpoint OS): 5-year local recurrence 8.1% with chemoradiotherapy vs 16.5%; grade 3-4 acute toxicity 14.6% vs 2.7%.
  6. 2006 · Detection · UnderstandingMERCURY: MRI predicts the surgical circumferential marginIn a European study of 408 people with rectal cancer, MRI before surgery predicted whether the cut edge of the removed tissue would be clear of tumour. When MRI predicted a clear edge, more than nine in ten had one. Follow-up linked an MRI-involved edge to lower survival and more local recurrence.MERCURY (prospective observational, 11 units in four European countries, 408 patients): 354 (87%, 95% CI 83-90) had a clear circumferential margin on histopathology. MRI predicted a clear margin in 349; 327 of them (94%, 91-96) were clear at surgery; specificity 92% (90-95). In a 374-patient follow-up, 5-year DFS was 67.2% with an MRI-clear versus 47.3% with an MRI-involved margin (HR 1.65, 95% CI 1.01-2.69).
  7. 2009 · Treatment · RadiationMRC CR07: short-course radiotherapy vs selective chemoradiotherapyIn this trial of 1,350 people with operable rectal cancer, a week of radiotherapy before surgery was compared with surgery first, adding chemoradiotherapy afterwards only if the surgical margin was involved. At three years, local recurrence was estimated at about 4 in 100 people treated with radiotherapy first and about 11 in 100 treated with surgery first.CR07/C016: 1350 randomised, intention to treat; 5 x 5 Gy preoperative radiotherapy vs initial surgery with chemoradiotherapy only for an involved circumferential resection margin. Primary outcome local recurrence: HR 0.39 (95% CI 0.27-0.58, P<0.0001); 3-year rates 4.4% vs 10.6%. Disease-free survival HR 0.76 (0.62-0.94), 3-year 77.5% vs 71.5%. Overall survival HR 0.91 (0.73-1.13, P=0.40). Hazard ratios are for preoperative radiotherapy; median follow-up of survivors 4 years.
  8. 2010 · Treatment · ChemotherapyOxaliplatin with preoperative chemoradiation: four phase 3 trialsFour trials tested adding oxaliplatin to fluorouracil-type chemoradiation before rectal cancer surgery. Three reported no significant gain on their main results, and side effects rose. The German trial, which also added oxaliplatin after surgery, reported better three-year disease-free survival: 76 in 100 versus 71 in 100. A combined analysis found a small gain in disease-free survival, not in overall survival.Oxaliplatin vs none. STAR-01 (747): pCR 16% vs 16%; grade 3-4 toxicity 24% vs 8%. ACCORD 12 (598): ypCR (primary) 19.2% vs 13.9% (P=0.09). NSABP R-04 (1608; primary local-regional control): no significant difference in local-regional events, DFS or OS. CAO/ARO/AIO-04 (1236; oxaliplatin also adjuvant): 3-year DFS 75.9% vs 71.2%, HR 0.79 (0.64-0.98). Pooled published data, seven trials: DFS HR 0.90, OS HR 0.94.

Immunotherapy

  1. 2014 · Treatment · ChemotherapyAdjuvant chemotherapy after preoperative (chemo)radiotherapyStudies asked whether chemotherapy after surgery helps people who had radiotherapy or chemoradiotherapy first. Against observation, a long-term trial and a combined analysis of four trials found no clear survival gain. A phase 2 trial found better disease-free survival when oxaliplatin was added to fluorouracil. The questions differ, and the evidence is mixed.EORTC 22921 (1011; OS primary): adjuvant fluorouracil/leucovorin vs surveillance, 10-year OS 51.8% vs 48.4% (HR 0.91, 95% CI 0.77-1.09). Chronicle (113, closed early; DFS primary): 3-year DFS 78% XELOX vs 71% observation (HR 0.80, 0.38-1.69). IPD meta-analysis (four trials, 1196): OS HR 0.97 (0.81-1.17). ADORE (phase 2, 321; no observation arm): 6-year DFS 68.2% FOLFOX vs 56.8% fluorouracil/leucovorin (HR 0.63, 0.43-0.93).
  2. 2014 · Treatment · Surgery⚑ needs reviewLaparoscopic vs open rectal cancer surgery: five randomised trialsSeveral trials compared keyhole (laparoscopic) with open surgery for rectal cancer. Some followed cancer recurrence or survival for three years; two judged the quality of the removed tissue, where keyhole surgery was not shown to be as good as open surgery. The trials differ in design and patients, so their results are not directly comparable.Randomised trials of laparoscopic versus open rectal resection used different primary endpoints. COLOR II: 3-year locoregional recurrence 5.0% in both arms. COREAN (after chemoradiotherapy): 3-year DFS 79.2% laparoscopic vs 72.5% open. LASRE (low rectum): 81.4% vs 79.8%. ALaCaRT and ACOSOG Z6051 did not establish non-inferiority for a pathological composite (successful resection 82% vs 89%; 81.7% vs 86.9%). Their authors' pooled analysis: 3-year locoregional recurrence 5.4% laparoscopic vs 2.0% open.
  3. 2015 · De-escalation · Radiation⚑ needs reviewLocal excision after chemoradiotherapy: Z6041, GRECCAR 2, TAU-TEMAfter chemoradiotherapy, some small rectal tumours can be cut out through the anus, keeping the rectum. A French trial did not show this was better than removing the rectum. In a Spanish trial, about seven in a hundred had local recurrence at five years after excision, against six in a hundred after rectal surgery, with fewer early complications.Z6041 (phase 2, single-arm, cT2N0, 79 patients): 3-year DFS 88.2% (95% CI 81.3-95.8). GRECCAR 2 (phase 3, 145 analysed): 2-year composite event rate 56% vs 48% with local excision vs TME (OR 1.33, 95% CI 0.62-2.86; p=0.43); 5-year local recurrence 7% vs 7%. TAU-TEM (phase 3, noninferiority, mITT 81 per group): 5-year locoregional recurrence 7.4% vs 6.2% with CRT-TEM vs TME (difference -1.23%, interval -8.98% to 6.51%; margin 10%); morbidity 20.7% vs 50.6%.
  4. 2017 · Treatment · SurgeryLateral lymph node dissection: JCOG0212 and later nodal studiesIn Japan, removing lymph nodes at the side of the pelvis is standard in lower rectal cancer surgery; internationally it is not. A Japanese trial of 701 people tested leaving them out. It could not confirm that leaving them out was as good for staying free of relapse, and local recurrence was lower with the dissection.JCOG0212 (701 randomised; clinical stage II/III lower rectal cancer without lateral node enlargement): 5-year RFS 73.4% with mesorectal excision plus lateral lymph node dissection vs 73.3% with mesorectal excision alone (HR 1.07, 90.9% CI 0.84-1.36; 1-sided P for non-inferiority 0.0547; margin HR 1.34): non-inferiority not confirmed. Local recurrence 7.4% vs 12.6% (P=0.024). 7-year RFS 71.1% vs 70.7%.
  5. 2017 · Treatment · SurgeryRobotic vs laparoscopic rectal cancer surgery: ROLARR and REALTwo randomised trials compared robot-assisted with conventional keyhole surgery for rectal cancer. The first, across 10 countries, found no significant reduction in the need to switch to open surgery. The second, in China, reported fewer local recurrences and higher three-year disease-free survival with the robot. They asked different questions.ROLARR (471 randomised; 29 sites in 10 countries): conversion to open laparotomy, the primary outcome, 8.1% robotic vs 12.2% laparoscopic (adjusted OR 0.61, 95% CI 0.31-1.21; P=0.16). REAL (1240 randomised; 11 Chinese centres; superiority design): primary 3-year locoregional recurrence 1.6% robotic vs 4.0% laparoscopic (HR 0.45, 95% CI 0.22-0.92); 3-year DFS 87.2% vs 83.4% (HR 0.74, 95% CI 0.56-0.98).
  6. 2019 · Treatment · ChemotherapyCAO/ARO/AIO-12: induction vs consolidation chemotherapy in TNTGerman researchers gave the same chemotherapy and chemoradiotherapy in two orders before rectal cancer surgery: chemotherapy first, or chemoradiotherapy first with chemotherapy after. No cancer was left in the removed specimen in 17 in 100 people with chemotherapy first and 25 in 100 with chemotherapy last. Survival and recurrence at three and five years were similar.Randomised phase 2, pick-the-winner design (306 evaluable; hypothesis pCR 25% vs 15% with standard chemoradiotherapy): induction FOLFOX before chemoradiotherapy (A) vs chemoradiotherapy then consolidation chemotherapy (B). pCR 17% vs 25%; only B met the hypothesis (P<.001; A P=.210). 3-year DFS 73% in both groups (HR 0.95, 95% CI 0.63-1.45). 5-year OS 85.8% vs 84.2%. No concurrent control.
  7. 2019 · Treatment · Surgery⚑ needs reviewTransanal TME: Norwegian recurrence signal, then randomised trialsA national registry study from Norway reported more local recurrence after transanal TME than in a national comparison cohort, and the technique was suspended there. A later randomised trial (TaLaR) met its three-year non-inferiority margin for disease-free survival, and another (COLOR III) reported similar short-term safety; its main cancer-control result is pending.Norwegian registry cohort (157 TaTME patients, 2014-2018): estimated local recurrence at 2.4 years 11.6% (95% CI 6.6-19.9) vs 2.4% (1.4-4.3) in the national colorectal cancer registry cohort (P<0.001); the report's title states TaTME was suspended in Norway. TaLaR (randomised, 1115 patients): 3-year DFS 82.1% transanal vs 79.4% laparoscopic TME (non-inferiority margin -10 percentage points). COLOR III short-term: conversion 1% vs 17%; 3-year local recurrence not yet reported.

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 · De-escalation · RadiationTREC and STAR-TREC: organ preservation after radiotherapyTREC and STAR-TREC tested organ preservation for early rectal cancer: radiotherapy first, then removing any remaining tumour through the anus or watching it, with rectal surgery only if needed. At twelve months in STAR-TREC, among people aiming to keep the rectum, about eight in ten given chemoradiotherapy had avoided rectal surgery, against about six in ten given short-course radiotherapy.TREC (feasibility study, 55 randomised: short-course radiotherapy then TEM vs TME): serious adverse events 15% vs 39% (p=0.04); organ preservation 70% (19 of 27). STAR-TREC (phase 2/3, 409 in the 12-month analysis): among those allocated to or choosing organ preservation, 12-month TME-free survival 78.5% (95% CI 72.4-85.1) with long-course chemoradiotherapy vs 60.6% (53.6-68.4) with short-course radiotherapy (HR 1.90, 1.29-2.81; posterior probability of long-course superiority above 99.5%). The 30-month endpoint is not reported.
  3. 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.
  4. 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).
  5. 2023 · Treatment · Radiation⚑ needs reviewOPERA: contact X-ray brachytherapy boost for organ preservationOPERA tested a higher radiation dose for early rectal cancers, given as a contact X-ray boost applied to the tumour instead of an external beam boost. Among 148 people randomised, about eight in ten kept their rectum at three years with the contact boost, against about six in ten with the external boost. The tumours were small, under 5 cm.Phase 3, open-label, 148 patients, operable cT2-cT3b low-mid rectal adenocarcinoma under 5 cm. Chemoradiotherapy (45 Gy, capecitabine), then a 9 Gy external beam boost or contact X-ray brachytherapy boost (90 Gy in 3 fractions). Modified intention-to-treat (141): 3-year organ preservation 59% vs 81% (HR 0.36, 95% CI 0.19-0.70; p=0.0026). Tumours under 3 cm: 63% vs 97%. 5-year: 56% vs 79% (p=0.004); local regrowth 39% vs 17% (p=0.1; denominator not stated in the abstract).
  6. 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.
  7. 2024 · Treatment · Immunotherapy⚑ needs reviewPD-1 inhibitors with short-course TNT: UNION and STELLAR IITwo randomised trials in China added a PD-1 antibody to short-course radiotherapy and chemotherapy before rectal cancer surgery. In UNION, no cancer remained in the removed tissue in about 40 in 100 people versus 15 in 100 with chemoradiotherapy. In STELLAR II, complete response was about 45 in 100 versus 25 in 100. Neither paper reports survival.UNION (phase 3, early outcomes, 231; pCR primary): short-course radiotherapy, camrelizumab and CAPOX vs long-course chemoradiotherapy and CAPOX; ypT0N0 pCR 39.8% vs 15.3% (OR 3.7, 95% CI 2.0-6.9); grade 3 or worse treatment-related events 29.2% vs 27.2%; EFS and OS immature; MMR status not stated in the abstract. STELLAR II (phase 2, 218, pMMR/MSS): short-course TNT with or without sintilimab; CR rate 45.5% vs 25.0% (P=0.003); grade 3-4 events 34.5% vs 19.4%.

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.

    Not rectum-only: SEER Cancer Stat Facts has no page for the rectum alone (its list of cancer sites has 'Colon and Rectum' and, separately, 'Anus'), so no rectal-specific SEER value is available here. 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 caption 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. 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

    • 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.

    Not rectum-only: SEER Cancer Stat Facts has no page for the rectum alone (its list of cancer sites has 'Colon and Rectum' and, separately, 'Anus'), so no rectal-specific SEER value is available here. 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 caption 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 (the observed cell is '-'). 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.

    Not rectum-only; the page gives no colon-versus-rectum or biomarker breakdown. 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. Stage mix on the same page: localized 34% of cases (5-year relative survival 91.3%), regional 37% (75.2%), distant 23% (16.9%), unstaged 6% (49.7%).

    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.

    Not rectum-only. 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.

    Not rectum-only. 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.

    Not rectum-only. Same caveats as the 1975 value. The page headline gives 12.7 per 100,000 for 2020-2024 deaths and a fall of 1.3% a year on average over 2015-2024; use one figure or the other, not both.

    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.

Rectal cancer, treatment around surgery: local recurrence

Rectal adenocarcinoma treated with radiotherapy or chemoradiotherapy and surgery. Entry criteria differ by trial: resectable disease without distant spread (Dutch TME trial), clinical stage T3 or T4 or node-positive disease (CAO/ARO/AIO-94), resectable clinical stage T3 or T4 disease (EORTC 22921, FFCD 9203) and MRI-defined high-risk disease (RAPIDO). · Neoadjuvant · endpoint: Local recurrence

Results are not comparable across trials.

Lower is better. The plotted values are 5-year local recurrence as each trial defined it (for example cumulative incidence in CAO/ARO/AIO-94 and EORTC 22921), but the control arms differ: standardised TME alone (Dutch trial), postoperative chemoradiotherapy (CAO/ARO/AIO-94) and preoperative radiotherapy without fluorouracil (EORTC 22921, FFCD 9203; all FFCD 9203 patients were to receive adjuvant fluorouracil and leucovorin). For EORTC 22921 the pair shown is radiotherapy alone against preoperative chemoradiotherapy; its other two chemotherapy groups are not drawn. RAPIDO reports locoregional recurrence after R0 or R1 resection, a differently defined endpoint, as a rate at a median of 5.6 years, so it is listed apart and not drawn on the 5-year axis. Not drawn: the Swedish trial (its five-year figure is recorded as a rate rather than a time-point estimate, its abstract does not state the analysis population, and its record is still marked for review); MRC CR07 (a 3-year landmark, and its surgery-first value was calculated by applying the hazard ratio, not read from the curve); and the short-course versus long-course trials (Polish I, TROG 01.04, Polish II, Stockholm III), where the control arm is the short-course arm in TROG 01.04 and Polish I but the long-course arm in Polish II, endpoints and time points differ, and the Stockholm III record is still marked for review. Surgical technique, imaging, staging and follow-up changed over three decades. 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 (%)2001200420062006dutch-tme-trialCAO/ARO/AIO-94EORTC 22921FFCD 9203
  • experimental arm
  • control arm
  • different endpoint from the lane's
  • step line through experimental values
Local recurrence at 60 months, rate, across 4 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 %; EORTC 22921 (2006): experimental 8.7 % vs control 17.1 %; FFCD 9203 (2006): experimental 8.1 % vs control 16.5 %.
Data table
TrialYearEndpointControl (%)Experimental (%)
dutch-tme-trial2001Local recurrence10.9 %5.6 %
CAO/ARO/AIO-942004Local recurrence13 %6 %
EORTC 229212006Local recurrence17.1 %8.7 %
FFCD 92032006Local recurrence16.5 %8.1 %
RAPIDO2020Locoregional recurrence after R0/R1 resection (differs from lane) (not plotted: different measure or time point)6 %10 %

Rectal cancer, intensified and selective preoperative treatment: disease-free survival

Locally advanced rectal adenocarcinoma treated before surgery. Entry criteria differ by trial: T3 or T4 disease, or distal T2 (ACCORD 12), clinical stage T3 or T4 or node-positive disease (CAO/ARO/AIO-04), clinical stage II or III disease (NSABP R-04), biopsy-proven cT3 or cT4 M0 disease (PRODIGE 23), and cT2 node-positive, cT3 node-negative or cT3 node-positive disease in candidates for sphincter-sparing surgery (PROSPECT). · Neoadjuvant · endpoint: DFS

Results are not comparable across trials.

The plotted pairs test different questions against different control arms, so the lane does not show one treatment effect over time: oxaliplatin added to fluoropyrimidine chemoradiotherapy (ACCORD 12, CAO/ARO/AIO-04) and FOLFIRINOX added before chemoradiotherapy (PRODIGE 23), each against chemoradiotherapy. The plotted values are 3-year DFS. DFS was the primary endpoint in CAO/ARO/AIO-04 and PRODIGE 23 and a long-term follow-up analysis in ACCORD 12. CAO/ARO/AIO-04 also gave oxaliplatin after surgery and used a different fluorouracil schedule in its control group, and ACCORD 12 raised the radiotherapy dose in the oxaliplatin arm (45 Gy against 50 Gy). NSABP R-04 (5-year DFS) and PROSPECT (5-year DFS) are listed rather than drawn because their time point differs. PROSPECT tested omitting radiotherapy in most patients and aimed to show non-inferiority; its value is from the per-protocol population (all patients who received any dose), while its other analyses use all randomised patients. RAPIDO used a different primary endpoint (disease-related treatment failure), and OPRA and CAO/ARO/AIO-12 compared two sequences with no concurrent control arm, so those three have no entry. 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.

020406080100DFS at 36 months (%)201020102020ACCORD 12/0405-Prodige 2CAO/ARO/AIO-04UNICANCER-PRODIGE 23
  • experimental arm
  • control arm
  • different endpoint from the lane's
  • step line through experimental values
DFS at 36 months, rate, across 3 trials in this lane. ACCORD 12/0405-Prodige 2 (2010): experimental 72.7 % vs control 67.9 %; CAO/ARO/AIO-04 (2010): experimental 75.9 % vs control 71.2 %; UNICANCER-PRODIGE 23 (2020): experimental 76 % vs control 69 %.
Data table
TrialYearEndpointControl (%)Experimental (%)
ACCORD 12/0405-Prodige 22010DFS67.9 %72.7 %
CAO/ARO/AIO-042010DFS71.2 %75.9 %
UNICANCER-PRODIGE 232020DFS69 %76 %
NSABP R-042010DFS (not plotted: different measure or time point)64.2 %69.2 %
PROSPECT2023DFS (not plotted: different measure or time point)78.6 %80.8 %

Rectal cancer, intensified preoperative treatment: pathological complete response

Locally advanced rectal adenocarcinoma treated before surgery. Entry criteria differ by trial: resectable cT3-4 and/or node-positive mid-low rectal cancer (STAR-01), T3 or T4 disease or distal T2 (ACCORD 12), clinical stage T3 or T4 or node-positive disease (CAO/ARO/AIO-04), T3 or T4 or node-positive disease with mismatch repair status not stated in the abstract (UNION) and proficient mismatch repair or microsatellite-stable disease (STELLAR II). · Neoadjuvant · endpoint: pCR

Results are not comparable across trials.

A higher value means a larger proportion of people with a complete response in the operative specimen. Pathological complete response is not a survival endpoint, and the lane does not show that it predicts survival. Definitions differ: ACCORD 12 reports complete sterilisation of the operative specimen (ypCR), UNION ypT0N0 by blinded independent review, and STAR-01 and CAO/ARO/AIO-04 pCR; CAO/ARO/AIO-04's value is from its initial report of secondary endpoints, in patients who underwent surgery. STAR-01, ACCORD 12 and CAO/ARO/AIO-04 add oxaliplatin to fluoropyrimidine chemoradiotherapy (ACCORD 12 also raised the radiotherapy dose in the oxaliplatin arm). UNION changes two things at once, short-course radiotherapy instead of long-course chemoradiotherapy and the addition of camrelizumab, and its record is still marked for review because mismatch repair status is unconfirmed. STELLAR II reports a complete response rate (clinical or pathological), not pCR, with sintilimab added to short-course radiotherapy-based chemotherapy in proficient mismatch repair disease; it is drawn with a distinct marker. CAO/ARO/AIO-12 compared two sequences with no concurrent control arm and has no entry. NSABP R-04 has no pathological complete response value in its record, and Polish II reports pCR in a different comparison (short-course radiotherapy with FOLFOX4 against long-course chemoradiotherapy), so neither is drawn. The oxaliplatin trials and the PD-1 inhibitor trials answer different questions; 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.

020406080100pCR (%)20102010201020242024STAR-01ACCORD 12/0405-Prodige 2CAO/ARO/AIO-04UNIONSTELLAR II
  • experimental arm
  • control arm
  • different endpoint from the lane's
  • step line through experimental values
pCR, rate, across 5 trials in this lane. STAR-01 (2010): experimental 16 % vs control 16 %; ACCORD 12/0405-Prodige 2 (2010): experimental 19.2 % vs control 13.9 %; CAO/ARO/AIO-04 (2010): experimental 17 % vs control 13 %; UNION (2024): experimental 39.8 % vs control 15.3 %; STELLAR II (2024): experimental 45.5 % vs control 25 %.
Data table
TrialYearEndpointControl (%)Experimental (%)
STAR-012010pCR16 %16 %
ACCORD 12/0405-Prodige 22010pCR13.9 %19.2 %
CAO/ARO/AIO-042010pCR13 %17 %
UNION2024pCR15.3 %39.8 %
STELLAR II2024Complete response rate (clinical or pathological) (differs from lane)25 %45.5 %

Rectal cancer surgery: approach and 3-year disease-free survival

Rectal adenocarcinoma treated with curative-intent surgery by different approaches. COLOR II: solitary adenocarcinoma within 15 cm of the anal verge without distant metastases. COREAN: cT3N0-2 mid or low rectal cancer after preoperative chemoradiotherapy. LASRE: adenocarcinoma within 5 cm of the dentate line. REAL: middle or low rectal adenocarcinoma. TaLaR: clinical stage I to III mid-low rectal cancer. ALaCaRT: T1-T3 adenocarcinoma less than 15 cm from the anal verge. ACOSOG Z6051: clinical stage II or III disease within 12 cm of the anal verge, randomised after neoadjuvant therapy. · Localised · endpoint: DFS

Results are not comparable across trials.

This lane mixes three different comparisons: laparoscopic against open surgery (COLOR II, COREAN, LASRE), robotic against laparoscopic surgery (REAL) and transanal against laparoscopic TME (TaLaR), so the control arm changes along the lane from open to laparoscopic. It also mixes endpoint rank: 3-year DFS was the primary endpoint in COREAN, LASRE and TaLaR but a secondary endpoint in COLOR II and REAL, whose primary endpoint was 3-year locoregional recurrence. Populations differ (after preoperative chemoradiotherapy in COREAN, within 5 cm of the dentate line in LASRE, mid and low rectum in REAL and TaLaR, up to 15 cm from the anal verge in COLOR II), as do designs: non-inferiority in COLOR II, COREAN, LASRE and TaLaR, superiority in REAL, with different margins, surgeon experience and regions. The COREAN record is still marked for review because published errata to its 2014 and 10-year reports could not be read. COLOR III (transanal against laparoscopic TME) is also still marked for review and has no DFS result in its record, so it has no entry. ALaCaRT and ACOSOG Z6051 were designed on a pathological composite and report DFS at 2 years only; they are listed but not drawn on the 36-month axis. ROLARR has no DFS result. The pooled ALaCaRT and Z6051 analysis is described in the milestone and not drawn because it combines two trials already listed. 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.

020406080100DFS at 36 months (%)20142014201420172019COLOR IICOREANLASREREALTaLaR
  • experimental arm
  • control arm
  • different endpoint from the lane's
  • step line through experimental values
DFS at 36 months, rate, across 5 trials in this lane. COLOR II (2014): experimental 74.8 % vs control 70.8 %; COREAN (2014): experimental 79.2 % vs control 72.5 %; LASRE (2014): experimental 81.4 % vs control 79.8 %; REAL (2017): experimental 87.2 % vs control 83.4 %; TaLaR (2019): experimental 82.1 % vs control 79.4 %.
Data table
TrialYearEndpointControl (%)Experimental (%)
COLOR II2014DFS70.8 %74.8 %
COREAN2014DFS72.5 %79.2 %
LASRE2014DFS79.8 %81.4 %
REAL2017DFS83.4 %87.2 %
TaLaR2019DFS79.4 %82.1 %
ALaCaRT2014DFS (not plotted: different measure or time point)82 %80 %
ACOSOG Z60512014DFS (not plotted: different measure or time point)83.2 %79.5 %

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.

Rectal cancer: treatment before surgery

Rectal adenocarcinoma considered for treatment before surgery. Entry criteria differ by trial, and some steps apply only to selected groups (for example mismatch repair-deficient tumours, or small tumours with a good response). · 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)
  7. Surgery7Local excision after chemoradiotherapyLocal excision after chemoradiotherapy: Z6041, GRECCAR 2, TAU-TEM (2015)
  8. Immunotherapy8Dostarlimab, dMMR (accelerated approval)Dostarlimab alone for mismatch repair-deficient rectal cancer (2022)
Today. Based only on the trials cited in each step. The FDA granted dostarlimab accelerated approval on 19 October 2026 for MSI-H/dMMR disease. Local excision records, including the 2025 TAU-TEM results, are still marked for review.
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
  • 2023: 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
  • 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 → Local excision after chemoradiotherapy → Dostarlimab, dMMR (accelerated approval)

Today and tomorrow

Standard of care today

Localised

Operable and early-stage rectal cancer, from guideline abstracts (full texts not read):

  • the abstract of NCCN Guidelines Insights: Rectal Cancer, Version 3.2024 lists, among recent updates to the NCCN rectal cancer guideline, the addition of endoscopic submucosal dissection as an option for early-stage rectal cancer
  • the same abstract says treatment planning weighs the intent of surgery (curative or palliative) and the likely effect on bowel function, anal continence and genitourinary function, and that the risk of pelvic recurrence is higher with rectal than with colon cancer
  • the ESMO guideline on localised rectal cancer (2025) is cited by identifier only because PubMed carries no abstract
  • randomised comparisons of laparoscopic, robotic and transanal approaches and of lateral lymph node dissection are on the timeline
Guideline: Benson AB, Venook AP, Adam M, Chang G, Chen YJ, Ciombor KK, et al 2024Guideline: Hofheinz RD, Fokas E, Benhaim L, Price TJ, Arnold D, Beets-Tan R, et al 2025
Neoadjuvant

Locally advanced rectal cancer that is mismatch repair-proficient, from guideline abstracts (full texts not read):

  • the abstract of the ASCO guideline (2024
  • evidence searched from 2013 to 2023) recommends that, after MRI assessment, total neoadjuvant therapy be offered as initial treatment to patients with microsatellite stable or mismatch repair-proficient tumours located in the lower rectum and/or at higher risk of local and/or distant metastases
  • for patients without higher-risk factors the same abstract says chemotherapy with selective chemoradiotherapy depending on extent of response, total neoadjuvant therapy, or neoadjuvant long-course chemoradiotherapy or short-course radiotherapy may be discussed
  • for candidates for total neoadjuvant therapy it gives chemotherapy after radiation as the preferred timing and long-course chemoradiotherapy as preferred over short-course radiotherapy, with short-course radiotherapy also a viable option depending on circumstances
  • that abstract also states that the guidance is not intended as a statement of the standard of care
  • the abstract of NCCN Guidelines Insights: Rectal Cancer, Version 3.2024 lists updates to the total neoadjuvant therapy approach based on the results of recent trials, without giving details
  • the ESMO localised rectal cancer guideline (2025) is cited by identifier only because PubMed carries no abstract
  • randomised trials of short-course radiotherapy, chemoradiotherapy, total neoadjuvant therapy and selective radiotherapy are on the timeline
Guideline: Scott AJ, Kennedy EB, Berlin J, Brown G, Chalabi M, Cho MT, et al 2024Guideline: Benson AB, Venook AP, Adam M, Chang G, Chen YJ, Ciombor KK, et al 2024Guideline: Hofheinz RD, Fokas E, Benhaim L, Price TJ, Arnold D, Beets-Tan R, et al 2025
Locally advanced

Locally advanced rectal cancer that is MSI-H or dMMR, from FDA documents read in full and the EMA product page:

  • on 19 October 2026 the FDA granted accelerated approval (21 CFR 601.41) to dostarlimab (Jemperli
  • BLA 761174/S-015) as a single agent for adults with stage II or III disease, as determined by an FDA-authorized test, based on sustained clinical complete response for 12 months
  • the prescribing information states that the long-term risk of relapse is unknown and that continued approval may be contingent on verification of clinical benefit in a confirmatory trial, and the approval letter's postmarketing requirement is completion of AZUR-1 (NCT05723562), with trial completion given as October 2029
  • the prescribing information reports efficacy from an interim analysis of 154 treated patients (data cut-off 20 April 2026, median follow-up 26 months), in which sustained clinical complete response for 12 months by independent central review was 47% (54 of 116 evaluable patients, 95% CI 37 to 56) and 110 patients (71%) had no further treatment and had not progressed or relapsed
  • the FDA news release says longer follow-up is needed to understand the duration of response and how often the cancer returns, and that published estimates suggest about 3% of locally advanced rectal cancers are dMMR or MSI-H
  • the Jemperli page of the European Medicines Agency (updated 13 October 2026) lists endometrial cancer indications and does not mention rectal cancer
  • the 2024 ASCO guideline abstract, which predates this approval and names no drug, states that immunotherapy is recommended for MSI-H or dMMR locally advanced rectal cancer (full text not read)
FDA 2026FDA 2026FDA 2026FDA 2026EMA 2021Guideline: Scott AJ, Kennedy EB, Berlin J, Brown G, Chalabi M, Cho MT, et al 2024
Neoadjuvant

Organ preservation after neoadjuvant treatment, from guideline abstracts and FDA documents (full guideline texts not read):

  • the abstract of the 2024 ASCO guideline says nonoperative management may be discussed as an alternative to total mesorectal excision for patients who have a clinical complete response to neoadjuvant therapy
  • the abstract of NCCN Guidelines Insights: Rectal Cancer, Version 3.2024 lists the addition of a watch-and-wait nonoperative management approach for clinical complete responders to neoadjuvant therapy among its recent updates
  • in AZUR-1, as described in the FDA notice, patients with a clinical complete response at either of the first two post-treatment assessments entered a non-operative management period with scheduled monitoring, and the approval letter asks for organ preservation at 3 years to be characterised
  • studies of watch-and-wait, contact X-ray brachytherapy, local excision and response-adapted organ preservation are on the timeline
Guideline: Scott AJ, Kennedy EB, Berlin J, Brown G, Chalabi M, Cho MT, et al 2024Guideline: Benson AB, Venook AP, Adam M, Chang G, Chen YJ, Ciombor KK, et al 2024FDA 2026FDA 2026
Metastatic
Metastatic rectal cancer is not covered by a separate list on this page. The trials, regulatory actions and guideline for metastatic disease are written for colorectal cancer as a whole and are collected on the Colon cancer page: the ESMO guideline on metastatic colorectal cancer (2023 edition, and a 2026 edition with the same title) is cited by identifier only because PubMed carries no abstract and the texts were not read.
Guideline: 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

  • ACO/ARO/AIO-18.1 NCT04246684

    In MRI-defined intermediate- and high-risk rectal cancer, does fluoropyrimidine- and oxaliplatin-based chemoradiotherapy followed by consolidation chemotherapy differ from short-course radiotherapy followed by consolidation chemotherapy in organ preservation (survival with the rectum intact, no major surgery and no stoma; the registry's primary outcome at 3 years), with watch-and-wait offered after a clinical complete response and surgery otherwise? Registry record: randomised phase 3, 702 enrolled (actual), active, not recruiting; the primary completion date listed (September 2026) has passed; no results posted.

  • Janus Rectal Cancer Trial (A022104/NRG-GI010) NCT05610163

    In stage II or III mismatch repair-proficient rectal adenocarcinoma, does FOLFIRINOX after long-course chemoradiotherapy differ from FOLFOX or CAPOX after long-course chemoradiotherapy in clinical complete response (phase 2 primary outcome) and disease-free survival (phase 3 primary outcome)? Registry record: randomised phase 2/3, 760 enrolled (actual), active, not recruiting; no results posted.

  • GRECCAR 14 NCT04749108

    In locally advanced rectal cancer with a very good response to induction chemotherapy (modified FOLFIRINOX, six cycles), does immediate proctectomy differ from capecitabine-based chemoradiotherapy (50 Gy) followed by proctectomy in R0 resection rate (phase 2 primary outcome) and 3-year disease-free survival (phase 3 primary outcome)? Registry record: randomised phase 2/3, 1,075 planned (estimated), recruiting; no results posted.

  • ENSEMBLE NCT05646511

    In locally advanced rectal cancer, does short-course radiotherapy followed by six cycles of CAPOXIRI differ from short-course radiotherapy followed by six cycles of CAPOX in organ-preservation-adapted disease-free survival at up to 3 years (the registry's primary outcome)? Registry record: randomised phase 3, 608 planned (estimated), recruiting; no results posted.

  • TNTi NCT06229041

    In high-risk locally advanced rectal cancer, does adding the PD-1 antibody camrelizumab (the agent named in the registry) to total neoadjuvant treatment change the pathological complete response rate (the registry's primary outcome)? The registry lists MSI-H or dMMR tumours as an exclusion. Registry record: randomised phase 3, 472 planned (estimated), recruiting; no results posted.

  • NORAD01 NCT03875781

    In primary resectable locally advanced rectal cancer, is preoperative modified FOLFIRINOX alone non-inferior to modified FOLFIRINOX followed by chemoradiotherapy for 3-year progression-free survival (the endpoint stated in the registry summary)? Registry record: randomised phase 3, 540 planned (estimated), recruiting; no results posted.

Pioneers

  • Gerhard Buess

    First author of the 1983 to 1987 reports on transanal endoscopic microsurgery cited in this timeline, Credited in 2015 and 2022 reviews with developing or first introducing transanal endoscopic microsurgery

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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Links open the primary source. A flag marked ⚑ needs review means a value or claim has not yet been independently confirmed.

2004De-escalationSurgery

majorNeoadjuvantLocally advanced

Watch-and-wait after chemoradiotherapy for complete clinical response

In 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.

Standard before

In the series, patients with incomplete clinical response after chemoradiation were referred for radical resection, and the authors compared resected pT0N0 specimens with observation after complete clinical response.

What changed

The authors concluded that surgical resection may not improve outcome in stage 0 rectal cancer and may add stoma construction and morbidity; later registry data (IWWD) describe the outcomes of watch-and-wait in larger numbers.

Why it mattered

This series raised the possibility that patients with a complete clinical response after chemoradiotherapy could be observed instead of operated on, with similar reported survival. The International Watch & Wait Database later described 880 clinical complete responders managed this way, with a 2-year cumulative incidence of local regrowth of 25.2%.

Caveats

  • Non-randomised, with groups defined by response; selection and the difficulty of defining clinical complete response limit what the comparison can show. According to the full text, patients were treated at one institution (University of São Paulo, 1991 to 2002), and patients with sustained complete regression for at least 12 months were considered stage 0.
  • Follow-up was shorter in the resection group (mean 48 months) than in the observation group (mean 57.3 months).
  • In the International Watch & Wait Database (Lancet 2018), 2-year cumulative local regrowth was 25.2% (95% CI 22.2-28.5) and 88% of regrowth was diagnosed in the first 2 years; follow-up was a median of 3.3 years, and the registry pools data from 47 institutes in 15 countries, about half from earlier cohort series and half unpublished.
  • This entry is not placed on a progress chart with randomised hazard ratios; organ-preservation percentages from series and from the OPRA randomised phase 2 trial are not comparable.