Five cases are described where minute foci of adenocarcinoma have been demonstrated in the mesorectum several centimetres distal to the apparent lower edge of a rectal cancer. In 2 of these there was no other evidence of lymphatic spread of the tumour. In orthodox anterior resection much of this tissue remains in the pelvis, and it is suggested that these foci might lead to suture-line or pelvic recurrence. Total excision of the mesorectum has, therefore, been carried out as a part of over 100 consecutive anterior resections. Fifty of these, which were classified as ‘curative’ or ‘conceivably curative’ operations, have now been followed for over 2 years with no pelvic or staple-line recurrence.

Pembrolizumab has shown improved progression-free survival versus chemotherapy in patients with newly diagnosed microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. However, the treatment's effect on overall survival in this cohort of patients was unknown. Here, we present the final overall survival analysis of the KEYNOTE-177 study.This randomised, open-label, phase 3 study was done in 193 academic medical centres and hospitals in 23 countries. We recruited patients aged at least 18 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously untreated microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. Patients were randomly assigned (1:1) in blocks of four using an interactive voice response system or integrated web response system to intravenous pembrolizumab 200 mg every 3 weeks or to the investigator's choice of intravenous mFOLFOX6 (oxaliplatin 85 mg/m on day 1, leucovorin 400 mg/m on day 1, and fluorouracil 400 mg/m bolus on day 1 followed by a continuous infusion of 1200 mg/m per day for 2 days on days 1-2) or intravenous FOLFIRI (irinotecan 180 mg/m on day 1, leucovorin 400 mg/m on day 1, and fluorouracil 400 mg/m bolus on day 1 followed by a continuous infusion of 1200 mg/m per day for 2 days on days 1-2), every 2 weeks with or without intravenous bevacizumab 5 mg/kg every 2 weeks or intravenous weekly cetuximab (first dose 400 mg/m, then 250 mg/m for every subsequent dose). Patients receiving chemotherapy could cross over to pembrolizumab for up to 35 treatment cycles after progression. The co-primary endpoints were overall survival and progression-free survival in the intention-to-treat population. KEYNOTE-177 is registered at ClinicalTrials.gov, NCT02563002, and is no longer enrolling patients.Between Feb 11, 2016, and Feb 19, 2018, 852 patients were screened, of whom 307 (36%) were randomly assigned to pembrolizumab (n=153) or chemotherapy (n=154). 93 (60%) patients crossed over from chemotherapy to anti-PD-1 or anti-PD-L1 therapy (56 patients to on-study pembrolizumab and 37 patients to off-study therapy). At final analysis (median follow-up of 44·5 months [IQR 39·7-49·8]), median overall survival was not reached (NR; 95% CI 49·2-NR) with pembrolizumab vs 36·7 months (27·6-NR) with chemotherapy (hazard ratio [HR] 0·74; 95% CI 0·53-1·03; p=0·036). Superiority of pembrolizumab versus chemotherapy for overall survival was not demonstrated because the prespecified α of 0·025 needed for statistical significance was not achieved. At this updated analysis, median progression-free survival was 16·5 months (95% CI 5·4-38·1) with pembrolizumab versus 8·2 months (6·1-10·2) with chemotherapy (HR 0·59, 95% CI 0·45-0·79). Treatment-related adverse events of grade 3 or worse occurred in 33 (22%) of 153 patients in the pembrolizumab group versus 95 (66%) of 143 patients in the chemotherapy group. Common adverse events of grade 3 or worse that were attributed to pembrolizumab were increased alanine aminotransferase, colitis, diarrhoea, and fatigue in three (2%) patients each, and those attributed to chemotherapy were decreased neutrophil count (in 24 [17%] patients), neutropenia (22 [15%]), diarrhoea (14 [10%]), and fatigue (13 [9%]). Serious adverse events attributed to study treatment occurred in 25 (16%) patients in the pembrolizumab group and in 41 (29%) patients in the chemotherapy group. No deaths attributed to pembrolizumab occurred; one death due to intestinal perforation was attributed to chemotherapy.In this updated analysis, although pembrolizumab continued to show durable antitumour activity and fewer treatment-related adverse events compared with chemotherapy, there was no significant difference in overall survival between the two treatment groups. These findings support pembrolizumab as an efficacious first-line therapy in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer.MSD.Copyright © 2022 Elsevier Ltd. All rights reserved.

Neoadjuvant short-course radiotherapy combined with chemotherapy as total neoadjuvant therapy increases the pathological complete response rate for patients with locally advanced rectal cancer. The potential synergistic effects of combining radiotherapy and immunotherapy might benefit patients with locally advanced rectal cancer. We aimed to compare the efficacy and safety of short-course radiotherapy followed by capecitabine-oxaliplatin chemotherapy with or without immunotherapy as total neoadjuvant therapy in patients with locally advanced rectal cancer.SPRING-01 was a single-centre, open-label, phase 2, randomised controlled trial done at the Shandong Provincial Hospital, China. Patients were aged 18-85 years with an Eastern Cooperative Oncology Group performance status of 0-1 and had biopsy-confirmed, newly diagnosed, treatment-naive, primary, locally advanced rectal adenocarcinoma with at least one of the following features: clinical tumour stage T3-4 or greater, clinical nodal stage N1 or higher, extramural vascular invasion, mesorectal fascia involvement, or lateral lymph node metastasis. Participants were randomly assigned (1:1) to receive either sintilimab plus capecitabine-oxaliplatin or capecitabine-oxaliplatin alone. The randomisation sequence was generated using computer-generated random numbers with SAS software version 9.4, using a simple randomisation method without stratification or blocking, and allocation was concealed using opaque, sealed envelopes. Neither patients nor clinical staff were masked to treatment allocation; however, pathological assessments and data analyses were conducted in a blinded manner. Patients received short-course radiotherapy (5 × 5 Gy over 5 days) followed by six cycles of intravenous capecitabine-oxaliplatin chemotherapy (intravenous oxaliplatin 130 mg/m over 2 h on day 1, and oral capecitabine 1000 mg/m twice daily on days 1-14 of each 3-week cycle) with or without intravenous sintilimab (200 mg/m on day 1 of each 3-week cycle), starting 1 week after completion of radiotherapy. Total mesorectal excision surgery, was done 2-3 weeks after the completion of total neoadjuvant therapy. The primary endpoint was the pathological complete response rate in the intention-to-treat population. The trial was registered with the Chinese Clinical Trial Registry (ChiCTR2100052288).Between Oct 8, 2021, and Sept 26, 2023, 116 patients with locally advanced rectal cancer were screened, of whom 98 eligible patients were randomly assigned to the sintilimab plus capecitabine-oxaliplatin group (n=49) or the capecitabine-oxaliplatin group (n=49). 68 (69%) of 98 patients were male and 30 (31%) were female; all patients were Asian. Median follow-up was 25 months (IQR 20-32). The pathological complete response rate was significantly higher in the sintilimab plus capecitabine-oxaliplatin group than in the capecitabine-oxaliplatin group (29 [59·2%, 95% CI 45·4-72·9] vs 16 [32·7%, 19·5-45·8]; p=0·015). Postoperative complications occurred in 11 (24% [95% CI 12-37]) of 45 patients in the sintilimab plus capecitabine-oxaliplatin group and in five (11% [2-21]) of 44 in the capecitabine-oxaliplatin group. Treatment-related adverse events during neoadjuvant therapy occurred in 45 (92%) of 49 patients in the sintilimab plus capecitabine-oxaliplatin group and in 44 (90%) of 49 patients in the capecitabine-oxaliplatin group. The most common treatment-related adverse events in the sintilimab plus capecitabine-oxaliplatin group and the capecitabine-oxaliplatin group were thrombocytopenia (18 [37%] vs 26 [53%]), leukopenia (19 [39%] vs 26 [53%]), anaemia (27 [55%] vs 33 [67%]), nausea or vomiting (25 [51%] vs 27 [55%]), and diarrhoea (21 [43%] vs 24 [49%]). Grade 3-4 treatment-related adverse events were observed in 16 (33%) patients in the sintilimab plus capecitabine-oxaliplatin group and 17 (35%) patients in the capecitabine-oxaliplatin group. The most common grade 3-4 adverse event was thrombocytopenia, reported in six (12%) patients in the sintilimab plus capecitabine-oxaliplatin group and in 11 (22%) patients in the capecitabine-oxaliplatin group. Serious adverse events occurred in 15 (31%) of 49 patients in the sintilimab plus capecitabine-oxaliplatin group and in nine (18%) of 49 patients in the capecitabine-oxaliplatin group. The most common serious adverse event in both treatment groups was thrombocytopenia. One (2%) patient in the capecitabine-oxaliplatin group died from septic shock due to acute ileus. No treatment-related deaths occurred in the sintilimab plus capecitabine-oxaliplatin group.In patients with locally advanced rectal cancer, short-course radiotherapy combined with sintilimab and capecitabine-oxaliplatin as a total neoadjuvant treatment significantly increased the pathological complete response rate while maintaining manageable safety profile. These findings suggest that this regimen might be a promising neoadjuvant treatment approach for locally advanced rectal cancer.The National Natural Science Foundation of China; The Special Foundation for Taishan Scholars Program of Shandong Province; The Key Research and Development Program of Shandong Province; The Natural Science Foundation of Shandong Province; The China Postdoctoral Science Foundation; and Innovent Biologics.For the Chinese translation of the abstract see Supplementary Materials section.Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

Neoadjuvant short-course radiotherapy (SCRT) followed by CAPOX and camrelizumab (a programmed cell death protein 1 monoclonal antibody) has shown potential clinical activity for locally advanced rectal cancer (LARC) in a phase II trial. This study aimed to further confirm the efficacy and safety of SCRT followed by CAPOX and camrelizumab compared to long-course chemoradiotherapy (LCRT) followed by CAPOX alone as neoadjuvant treatment for LARC.In this randomized, phase III trial, patients with T3-4/N+ rectal adenocarcinoma were randomly assigned (1 : 1) to receive SCRT or long-course chemoradiotherapy (LCRT), followed by two cycles of camrelizumab and CAPOX or CAPOX alone, respectively. After surgery, each arm underwent either six cycles of camrelizumab and CAPOX, followed by up to 17 doses of camrelizumab, or six cycles of CAPOX. The primary endpoint was pathological complete response (pCR) rate (ypT0N0) assessed by a blinded independent review committee. Key secondary endpoints tested hierarchically were 3-year event-free survival (EFS) rate and overall survival (OS).Between July 2021 and March 2023, the intention-to-treat population comprised 113 patients in the experimental arm and 118 patients in the control arm, with surgery carried out in 92% and 83.9%, respectively. At data cut-off (11 July 2023), the pCR rates were 39.8% [95% confidence interval (CI) 30.7% to 49.5%] in the experimental arm compared to 15.3% (95% CI 9.3% to 23.0%) in the control arm (difference, 24.6%; odds ratio, 3.7; 95% CI 2.0-6.9; P < 0.001). In each arm, surgical complication rates were 40.0% and 40.8%, and grade ≥3 treatment-related adverse events were 29.2% and 27.2%. Three-year EFS rate and OS continue to mature.In LARC patients, neoadjuvant SCRT followed by camrelizumab plus CAPOX demonstrated a significantly higher pCR rate than LCRT followed by CAPOX, with a well-tolerated safety profile. SCRT followed by camrelizumab and chemotherapy can be recommended as a neoadjuvant treatment modality for these patients.Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.

To assess whether the integration of PD-1 inhibitor with total neoadjuvant therapy (iTNT) can lead to an improvement in complete responses (CRs) and favors a watch-and-wait (WW) strategy in patients with proficient mismatch repair or microsatellite stable (pMMR/MSS) locally advanced rectal cancer (LARC).

The benefit of radiotherapy for rectal cancer is largely based on a balance between decrease in local recurrence and increase in bowel dysfunction. Predicting postoperative disability is helpful for recovery plans and early intervention. We aimed to develop and validate a risk model to improve the prediction of major bowel dysfunction after restorative rectal cancer resection with neoadjuvant radiotherapy using perioperative features.Eligible patients more than one year after restorative resection following radiotherapy were invited to complete the low anterior resection syndrome (LARS) score in three national hospitals of China. Clinical characteristics and imaging parameters were assessed with machine learning algorithms. The post-radiotherapy LARS prediction model (PORTLARS) was constructed by logistic regression on the basis of key factors with proportional weighs. The accuracy of model for major LARS prediction was internally and externally validated.A total of 868 patients reported mean LARS score of 28.4 after average time of 4.7 years since surgery. Key predictors for major LARS included the length of distal rectum, anastomotic leakage, proximal colon of neorectum, and pathological nodal-stage. PORTLARS had a favorable area under the curve for predicting major LARS in the internal dataset (0.835, 95% confidence interval (CI) 0.800-0.870, n=521) and external dataset (0.884, 95% CI 0.848-0.921, n=347). The model achieved both sensitivity and specificity over 0.83 in the external validation. Additionally, PORTLARS outperformed the pre-operative LARS score for prediction of major events.PORTLARS could predict major bowel dysfunction after rectal cancer resection following radiotherapy with high accuracy and robustness. It may serve as a useful tool to highlight patients who need additional support for long-term dysfunction in the early stage.Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.

Total mesorectal excision (TME) for rectal cancer (RC) often results in significant bowel symptoms, commonly known as Low Anterior Resection Syndrome (LARS). Although pelvic floor muscle training (PFMT) is recommended in non-cancer populations for treating bowel symptoms, this has been scarcely investigated in RC-patients. The objective was to investigate PFMT-effectiveness on LARS in patients after TME for RC.A multicenter single-blind prospective randomized controlled trial (RCT) comparing PFMT (intervention; n=50) versus no PFMT (control; n=54) one month following TME/stoma closure was performed. Primary endpoint was the proportion of participants with an improvement in LARS category at four months. Secondary outcomes were: continuous LARS-scores, COREFO-scores, NRS-scores, stool diary items and SF-12 scores; all assessed at 1, 4, 6 and 12 months.The proportion of participants with an improvement in LARS-category was statistically higher after PFMT compared to controls at four (38.3% vs. 19.6%; P=0.0415) and six (47.8% vs. 21.3%; P=0.0091) months, but no longer at 12 months (40.0% vs. 34.9%; P=0.3897). Following secondary outcomes were significantly lower at four months: LARS-scores (continuous, P=0.0496), COREFO-scores (P=0.0369) and frequency of bowel movements (P=0.0277), solid stool leakage (day, P=0.0241; night, P=0.0496) and the number of clusters (P=0.0369), derived from the stool diary. No significant differences were found for NRS- /QoL-scores.PFMT for bowel symptoms after TME resulted in lower proportions and faster recovery of bowel symptoms up to six months after surgery/stoma closure, justifying PFMT as an early, first-line treatment option for bowel symptoms after RC.Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.

Systemic relapses remain a major problem in locally advanced rectal cancer. Using short-course radiotherapy followed by chemotherapy and delayed surgery, the Rectal cancer And Preoperative Induction therapy followed by Dedicated Operation (RAPIDO) trial aimed to reduce distant metastases without compromising locoregional control.In this multicentre, open-label, randomised, controlled, phase 3 trial, participants were recruited from 54 centres in the Netherlands, Sweden, Spain, Slovenia, Denmark, Norway, and the USA. Patients were eligible if they were aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, had a biopsy-proven, newly diagnosed, primary, locally advanced rectal adenocarcinoma, which was classified as high risk on pelvic MRI (with at least one of the following criteria: clinical tumour [cT] stage cT4a or cT4b, extramural vascular invasion, clinical nodal [cN] stage cN2, involved mesorectal fascia, or enlarged lateral lymph nodes), were mentally and physically fit for chemotherapy, and could be assessed for staging within 5 weeks before randomisation. Eligible participants were randomly assigned (1:1), using a management system with a randomly varying block design (each block size randomly chosen to contain two to four allocations), stratified by centre, ECOG performance status, cT stage, and cN stage, to either the experimental or standard of care group. All investigators remained masked for the primary endpoint until a prespecified number of events was reached. Patients allocated to the experimental treatment group received short-course radiotherapy (5 × 5 Gy over a maximum of 8 days) followed by six cycles of CAPOX chemotherapy (capecitabine 1000 mg/m orally twice daily on days 1-14, oxaliplatin 130 mg/m intravenously on day 1, and a chemotherapy-free interval between days 15-21) or nine cycles of FOLFOX4 (oxaliplatin 85 mg/m intravenously on day 1, leucovorin [folinic acid] 200 mg/m intravenously on days 1 and 2, followed by bolus fluorouracil 400 mg/m intravenously and fluorouracil 600 mg/m intravenously for 22 h on days 1 and 2, and a chemotherapy-free interval between days 3-14) followed by total mesorectal excision. Choice of CAPOX or FOLFOX4 was per physician discretion or hospital policy. Patients allocated to the standard of care group received 28 daily fractions of 1·8 Gy up to 50·4 Gy or 25 fractions of 2·0 Gy up to 50·0 Gy (per physician discretion or hospital policy), with concomitant twice-daily oral capecitabine 825 mg/m followed by total mesorectal excision and, if stipulated by hospital policy, adjuvant chemotherapy with eight cycles of CAPOX or 12 cycles of FOLFOX4. The primary endpoint was 3-year disease-related treatment failure, defined as the first occurrence of locoregional failure, distant metastasis, new primary colorectal tumour, or treatment-related death, assessed in the intention-to-treat population. Safety was assessed by intention to treat. This study is registered with the EudraCT, 2010-023957-12, and ClinicalTrials.gov, NCT01558921, and is now complete.Between June 21, 2011, and June 2, 2016, 920 patients were enrolled and randomly assigned to a treatment, of whom 912 were eligible (462 in the experimental group; 450 in the standard of care group). Median follow-up was 4·6 years (IQR 3·5-5·5). At 3 years after randomisation, the cumulative probability of disease-related treatment failure was 23·7% (95% CI 19·8-27·6) in the experimental group versus 30·4% (26·1-34·6) in the standard of care group (hazard ratio 0·75, 95% CI 0·60-0·95; p=0·019). The most common grade 3 or higher adverse event during preoperative therapy in both groups was diarrhoea (81 [18%] of 460 patients in the experimental group and 41 [9%] of 441 in the standard of care group) and neurological toxicity during adjuvant chemotherapy in the standard of care group (16 [9%] of 187 patients). Serious adverse events occurred in 177 (38%) of 460 participants in the experimental group and, in the standard of care group, in 87 (34%) of 254 patients without adjuvant chemotherapy and in 64 (34%) of 187 with adjuvant chemotherapy. Treatment-related deaths occurred in four participants in the experimental group (one cardiac arrest, one pulmonary embolism, two infectious complications) and in four participants in the standard of care group (one pulmonary embolism, one neutropenic sepsis, one aspiration, one suicide due to severe depression).The observed decreased probability of disease-related treatment failure in the experimental group is probably indicative of the increased efficacy of preoperative chemotherapy as opposed to adjuvant chemotherapy in this setting. Therefore, the experimental treatment can be considered as a new standard of care in high-risk locally advanced rectal cancer.Dutch Cancer Foundation, Swedish Cancer Society, Spanish Ministry of Economy and Competitiveness, and Spanish Clinical Research Network.Copyright © 2021 Elsevier Ltd. All rights reserved.

Prospective data comparing watch-and-wait (WW) to mandatory total mesorectal excision (TME) in patients with locally advanced rectal cancer (LARC) remains limited, as randomized control trials assessing these two treatment approaches are considered impractical. This pooled analysis of the CAO/ARO/AIO-12 and OPRA trials analyzes survival outcomes among LARC patients managed with either a selective WW or mandatory TME strategy following total neoadjuvant therapy (TNT).The CAO/ARO/AIO-12 and OPRA trials were multicenter, phase II trials that randomized patients with stage II/III rectal cancer to receive either induction or consolidation chemotherapy as part of TNT. All patients in the CAO/ARO/AIO-12 trial underwent TME within six weeks of completing TNT. The OPRA trial allowed patients with a complete or near-complete response to enter WW while those with an incomplete response proceeded to TME. The primary endpoint of the present pooled analysis was disease-free survival (DFS). Secondary endpoints included distant recurrence-free survival (DRFS), local recurrence-free survival (LRFS) and overall survival (OS).This pooled analysis included 628 patients (n=304 CAO/ARO/AIO-12; n=324 OPRA). Median follow-up was 3.6 (IQR 1.13) and 5.1 (IQR 2.2) years, respectively. Patients in the CAO/ARO/AIO-12 trial were more likely to have cT3/4 and cN positive disease while patients in the OPRA trial had tumors closer to the anal verge. Compliance to TNT and rates of grade 3+ adverse events were similar between studies. There were no differences in DFS, DRFS, LRFS or OS based on treatment strategy or TNT treatment arm.This pooled analysis demonstrated equivalent oncologic outcomes between patients treated with mandatory TME and selective WW strategies following TNT. These results strengthen available evidence indicating that WW is a safe treatment option for patients with an excellent response to neoadjuvant therapy.Copyright © 2025 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.

Radiotherapy displays unique antitumor synergism with immune checkpoint inhibitors, which is indicated by high pathological complete response (pCR) rates from single-arm trials of locally advanced rectal cancer (LARC). Here we test the efficacy and safety of the radiation-immune checkpoint inhibitor combination in patients with LARC in a phase 2, randomized trial conducted in eight major colorectal cancer centers in Beijing. In total, 186 eligible all-comer (proficient mismatch repair and deficient mismatch repair) participants were enrolled. The patients were randomly assigned to receive neoadjuvant chemoradiation + concurrent/sequential PD-1 blockade (experiment groups A/B) or neoadjuvant chemoradiation alone (control group). Radical surgeries were scheduled after neoadjuvant treatments. The primary endpoint was the pCR rate. The pCR rates were 27.1%, 32.7% and 14.0% for experiment groups A and B and the control group, respectively. The difference in pCR rates between experiment group B and the control group reached statistical significance (risk ratio 2.332, 95% confidence interval 1.106-4.916; P = 0.019). No substantial differences between either one of the experiment groups and the control group were observed regarding adverse reaction, surgical complication and disease progression. Our results show that adding PD-1 blockade after neoadjuvant chemoradiation increases the pCR rate for patients with LARC and raises no substantial safety concerns. Phase 3 trials with larger sample sizes are warranted (ClinicalTrials.gov identifier NCT05245474 ).© 2025. The Author(s), under exclusive licence to Springer Nature America, Inc.

An increasing number of patients with rectal cancer who respond well to neoadjuvant chemoradiotherapy (nCRT) are being considered for organ preservation programs. However, due to the lack of high-level evidence, the survival outcomes of the organ preservation programs are still full of controversy and uncertainty.To assess the effects of total mesorectal excision surgery (TME), watch-and-wait (W&W) and local excision (LE) on long-term outcomes after nCRT, we searched PubMed, Embase, and Web of Science for articles published between 1 January 2010, and 1 December 2023.We found 7029 pieces of literature, of which 26 studies met the inclusion criteria, and recruited 2778 participants in the network meta-analysis. Risk of bias assessment showed that most included studies had a low risk of bias. Low-certainty evidence suggests that the TME group was significantly superior to all other interventions for the 2-year local regrowth rate. (W&W group [OR, 0.20; 95% CI, 0.12-0.35], LE group compared with TME group [3.00; 1.60 to 5.80]). There was no significant difference in the 2-year local regrowth rate between W&W and LE group (OR, 0.60; 95% CI, 0.32 to 1.20). There was high to moderate certainty evidence that at three years, the W&W group had a significant advantage in overall survival compared with the TME group (OR, 0.37; 95% CI, 0.09 to 0.95). After five years, no significant difference in overall survival was found between the three treatment modalities.We concluded that TME achieved the most significant reduction in 2-year local regrowth rates. However, the W&W strategy and LE demonstrated non-inferiority to TME in long-term survival outcomes.Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc. on Behalf of JBI.

..PURPOSETo provide evidence-based guidance for clinicians who treat patients with locally advanced rectal cancer.METHODSA systematic review of the literature published from 2013 to 2023 was conducted to identify relevant systematic reviews, phase II and III randomized controlled trials (RCTs), and observational studies where applicable.RESULTSTwelve RCTs, two systematic reviews, and one nonrandomized study met the inclusion criteria for this systematic review. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations.RECOMMENDATIONSFollowing assessment with magnetic resonance imaging, for patients with microsatellite stable or proficient mismatch repair locally advanced rectal cancer, total neoadjuvant therapy (TNT; ie chemoradiation [CRT] and chemotherapy) should be offered as initial treatment for patients with tumors located in the lower rectum and/or patients who are at higher risk for local and/or distant metastases. Patients without higher-risk factors may discuss chemotherapy with selective CRT depending on extent of response, TNT, or neoadjuvant long-course CRT or short-course radiation. For patients who are candidates for TNT, the preferred timing for chemotherapy is after radiation, and neoadjuvant long-course CRT is preferred over short-course radiation therapy (RT), however short-course RT may also be a viable treatment option depending on circumstances. Nonoperative management may be discussed as an alternative to total mesorectal excision for patients who have a clinical complete response to neoadjuvant therapy. For patients whose tumors are microsatellite instability-high or mismatch repair deficient, immunotherapy is recommended.Additional information is available at http://www.asco.org/gastrointestinal-cancer-guidelines.

This study aimed to assess whether clinical complete response (cCR) criteria developed for neoadjuvant chemoradiotherapy (NACRT) are applicable to patients with proficient mismatch repair locally advanced rectal cancer (LARC) who are treated with NACRT combined with immunotherapy (NAICRT).

Organ preservation as a successful management for rectal cancer is an evolving field. Refinement of neoadjuvant therapies and extended interval to response assessment has improved tumour downstaging and cCR rates.

Despite therapeutic advancements, disease-free survival and overall survival of patients with locally advanced rectal cancer have not improved in most trials as a result of distant metastases. For treatment decision-making, both long-term oncologic outcomes and impact on quality-of-life indices should be considered (for example, bowel function). Total neoadjuvant therapy (TNT), comprised of chemotherapy and radiotherapy or chemoradiotherapy, is now a standard treatment approach in patients with features of high-risk disease to prevent local recurrence and distant metastases. In selected patients who have a clinical complete response, subsequent surgery might be avoided through non-operative management, but patients who do not respond to TNT have a poor prognosis. Refined molecular characterization might help to predict which patients would benefit from TNT and non-operative management. Specifically, integrated analysis of spatiotemporal multi-omics using artificial intelligence and machine learning is promising. Three prospective trials of TNT and non-operative management in Japan, the USA and Germany are collaborating to better understand drivers of response to TNT. Here, we address the future direction for TNT.© 2024. Springer Nature Limited.

Although it has long been known that the immune cell composition has a strong prognostic and predictive value in colorectal cancer (CRC), scoring systems such as the immunoscore (IS) or quantification of intraepithelial lymphocytes are only slowly being adopted into clinical routine use and have their limitations. To address this we established and evaluated a multistain deep learning model (MSDLM) utilizing artificial intelligence (AI) to determine the AImmunoscore (AIS) in more than 1,000 patients with CRC. Our model had high prognostic capabilities and outperformed other clinical, molecular and immune cell-based parameters. It could also be used to predict the response to neoadjuvant therapy in patients with rectal cancer. Using an explainable AI approach, we confirmed that the MSDLM's decisions were based on established cellular patterns of anti-tumor immunity. Hence, the AIS could provide clinicians with a valuable decision-making tool based on the tumor immune microenvironment.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.