Abstract The treatment of patients with locally advanced rectal cancer (LARC) requires a multidisciplinary approach to achieve optimal outcomes. Both total mesorectal excision and neoadjuvant chemoradiotherapy have contributed to improved survival and reduced locoregional recurrence over the years. However, LARC is still associated with high levels of distant recurrence. Induction chemotherapy was introduced to further improve outcomes in LARC. It can deal with micrometastasis up front, reducing the risk of distant disease. Furthermore, it improves complete response rates for rectal cancer patients, improving the chances of patients undergoing organ preservation. The current chapter assess the theory behind induction chemotherapy and the role it has in rectal cancer.

BACKGROUND:Data are sparse on the value of perioperative systemic therapy in patients with resectable colorectal peritoneal-only metastases. This trial aimed to compare the efficacy of perioperative systemic therapy versus surgery alone in this population. METHODS:This randomised, open-label, phase 3 trial was done at all nine Dutch tertiary centres and one Belgian tertiary centre. Eligible patients were aged 18 years or older with a WHO performance status of 0 or 1 and pathologically proven resectable peritoneal-only metastases of a colorectal adenocarcinoma who did not receive systemic therapy for at least 6 months. Enrolled patients were randomly assigned (1:1) to perioperative systemic therapy and cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC; perioperative systemic therapy group) or upfront CRS-HIPEC alone (surgery alone group) using a web-based system with minimisation stratified by previous systemic therapy, synchronous or metachronous peritoneal metastases, peritoneal cancer index 0-10 or 11-20, and mitomycin C-based or oxaliplatin-based HIPEC. At investigator's choice, perioperative systemic therapy comprised either four 3-week neoadjuvant and adjuvant cycles of CAPOX (intravenous oxaliplatin 130 mg/m2 followed by oral capecitabine 1000 mg/m2 twice per day on days 1-14), six 2-week neoadjuvant and adjuvant cycles of FOLFOX (intravenous oxaliplatin 85 mg/m2 with intravenous leucovorin 400 mg/m2, followed by bolus intravenous 5-fluorouracil 400 mg/m2, and continuous intravenous 5-fluorouracil 2400 mg/m2 for 48 h), or six 2-week neoadjuvant cycles of FOLFIRI (intravenous irinotecan 180 mg/m2 with intravenous leucovorin 400 mg/m2, followed by bolus intravenous 5-fluorouracil 400 mg/m2, and continuous intravenous 5-fluorouracil 2400 mg/m2 for 48 h) followed by either four 3-week adjuvant cycles of oral capecitabine (1000 mg/m2 twice per day on days 1-14) or six 2-week adjuvant cycles of 5-fluorouracil and leucovorin (intravenous leucovorin 400 mg/m2, followed by bolus intravenous 5-fluorouracil 400 mg/m2, and continuous intravenous 5-fluorouracil 2400 mg/m2 for 48 h). Intravenous bevacizumab was added to the first three neoadjuvant cycles of CAPOX (7·5 mg/kg) or the first four neoadjuvant cycles of FOLFOX or FOLFIRI (5 mg/kg). The primary outcome was overall survival assessed in a prespecified modified intention-to-treat population, excluding patients who withdrew consent before treatment or violated major eligibility criteria. Major postoperative morbidity was defined as Clavien-Dindo grade 3-5 and assessed up to 90 days postoperatively. Major systemic therapy-related toxicity was defined as Common Terminology Criteria for Adverse Events (CTCAE) grade 3-5 and assessed up to 30 days after its last administration. The Dutch patient organisation for colorectal cancer was involved in the trial design. The trial is registered with Clinicaltrials.gov (NCT02758951) and is active but not recruiting. FINDINGS:Between June 15, 2017, and April 29, 2024, 1922 patients were screened for eligibility. Of these, 358 patients were enrolled and randomly assigned to perioperative systemic therapy (n=180) or surgery alone (n=178). 351 patients were included in the modified intention-to-treat population (173 patients randomly assigned to perioperative systemic therapy and 178 patients to surgery alone; 181 [52%] male and 170 [48%] female). After a median follow-up of 41 months (IQR 21-62), median overall survival was 44 months (95% CI 30-54) in the perioperative systemic therapy group versus 39 months (95% CI 31-46) in the surgery alone group (hazard ratio [HR] 0·85, 95% CI 0·62-1·15; p=0·28). In 292 patients who underwent macroscopic complete or near complete CRS-HIPEC, major 90-day postoperative morbidity occurred in 49 (36%) of 138 patients in the perioperative systemic therapy group and in 40 (26%) of 154 patients in the surgery alone group. The most common Clavien-Dindo grade 3-4 postoperative adverse events were intra-abdominal abscess (16 [12%] of 138 patients in the perioperative systemic therapy group vs 16 [10%] of 154 patients in the surgery alone group), anastomotic leakage (12 [9%] vs six [4%]), and fascia dehiscence (13 [9%] vs six [4%]). 90-day postoperative mortality occurred in two (1%) patients in the perioperative systemic therapy group (anastomotic leakage and cerebrovascular accident) and in one (1%) patient in the surgery alone group (anastomotic leakage). Major systemic therapy-related toxicity occurred in 92 (57%) of 161 patients who started perioperative systemic therapy. The most common CTCAE grade 3-4 systemic therapy-related adverse events were hypertension (13 [8%] patients), diarrhoea (12 [7%] patients), neutropenia (11 [7%] patients), and thromboembolic events (ten [6%] patients). Systemic therapy-related death occurred in one (1%) patient (hyperglycaemia). INTERPRETATION:Perioperative systemic therapy cannot be recommended in all patients with resectable colorectal peritoneal-only metastases. FUNDING:Dutch Cancer Society, F Hoffman-La Roche.

AIM:In rectal cancer, neo-adjuvant (chemo)radiotherapy (n(C)RT) should be used selectively, due to related toxicity. The decision to offer n(C)RT is mainly based on preoperative MRI staging. cN category has limited accuracy and its use when deciding on n(C)RT is controversial. This population-based study aimed to assess the association between cN category and local recurrence (LR) rate. METHOD:Data from a national cross-sectional cohort of patients who underwent curative resection of primary rectal cancer in the Netherlands in 2016 were used. Patients were subdivided by neo-adjuvant treatment strategy: no n(C)RT, short-course RT with short interval to surgery (SCRT-SI) or downstaging therapy (SCRT with long interval to surgery, CRT, total neoadjuvant therapy or chemotherapy only). The 4-year LR rate was calculated per (y)cN category and corrected for known pre-operative confounders in Cox-regression analysis. RESULTS:Of 2148 included patients, 1000 received no n(C)RT, 449 SCRT-SI and 699 downstaging therapy. Median follow-up was 50 months (interquartile range [IQR] 38-55). The 4-year LR rates for cN0, cN1 and cN2 were 6.3%, 5.0% and 6.2% without n(C)RT, and 0%, 2.4% and 0% after SCRT-SI. In patients treated with downstaging therapy, not primary cN, but restaging ycN category was significantly associated with LR rate (9.1%, 17.4% and 18.5%; p = 0.006) in univariable analysis. In multivariable analysis, no association was observed between ycN and LR (p = 0.088). CONCLUSION:Evaluation of nationwide clinical practice did not reveal significant associations between cN category and LR rate after rectal cancer resection within three neo-adjuvant treatment groups, which questions its validity for clinical decision-making.

Introduction The role of mismatch repair deficiency (dMMR) in colon cancer has gained increasing attention due to its association with response to neoadjuvant therapy. In contrast, its significance in rectal cancer remains less comprehensively explored. The influence of dMMR on pathological response following neoadjuvant (chemo)radiotherapy ((C)RT) in rectal cancer is not well understood. This study aimed to compare pathological response to neoadjuvant treatment between dMMR and proficient mismatch repair (pMMR) rectal cancer. Methods A retrospective cohort study was conducted using data from the Dutch ColoRectal Cancer Audit database, including patients who underwent rectal cancer resection between 2018 and 2021. Primary outcomes of this study were the incidence of dMMR and pathological complete response (pCR). A multinomial logistic regression analysis was performed to determine if MMR-status was an independent predictor of pCR. Results Out of 8570 patients, MMR-status was determined in 4659 (54.4%) patients, of whom 4516 (96.9%) were pMMR and 143 (3.1%) dMMR. A total of 1562 patients with known MMR-status underwent neoadjuvant treatment. 1514 (96.9%) had pMMR tumors and 48 (3.1%) dMMR tumors. The pCR rate was significantly higher in dMMR patients (29.2%) compared to pMMR patients (13.5%, P = .008). Multivariable logistic regression analysis showed that MMR-status was independently associated with pCR (OR 2.422 [95% CI, 1.236-4.746], P = .010). Conclusion In this cross-sectional national rectal cancer cohort, the incidence of dMMR was 3.1%, and dMMR appeared to be an independent predictor for higher chance of pathological complete response after neoadjuvant (chemo)radiotherapy.

Background Screening has increased the incidence of early-stage rectal cancer and interest in rectal-preserving treatment strategies. Although guidelines recommend completion total mesorectal excision (cTME) in the presence of histological risk factor(s) after local excision, surgery-related morbidity often deters patients from cTME. Additionally, locoregional recurrences (LR) identified during surveillance may still be salvageable. This study evaluates oncological and surgical outcomes in pT1-2 rectal cancer patients who received local excision with or without additional therapy. Methods A retrospective cross-sectional national cohort study was conducted in 67 Dutch hospitals, including all patients who underwent curative surgical resection for rectal cancer in 2016. Patients with pT1-2 tumours who received surveillance, cTME or adjuvant chemoradiotherapy after local excision were selected. The primary outcome was LR. Secondary endpoints included ostomy rate, disease-free survival (DFS), and overall survival (OS). Results Of 3057 patients, 219 underwent local excision, followed by surveillance in 74% (n=162), cTME in 23% (n=51), and adjuvant (chemo)radiation in 3% (n=6). Median follow-up was 46 months (IQR 29-54). Four-year LR rates were 14% and 4% after surveillance and cTME, respectively (p=0.033). In the surveillance group, 16 of 20 patients (80%) who developed LR were treated with curative intent. cTME resulted in a substantially higher ostomy rate (43% vs 4%, p=0.001). No significant differences were found in 4-year DFS and OS. Conclusion Despite a LR rate of 14% after local excision alone, the majority of these recurrences could be treated with curative intent. Additionally, the risk of stoma was 10-fold lower after surveillance compared to cTME. Trial registration ClinicalTrials.gov, identifier: NCT05539417, https://www.clinicaltrials.gov/ct2/show/NCT05539417

In our previous phase 2 trial, patients with locally advanced (LARC) or locally recurrent rectal cancer (LRRC) received SGM-101, a CEA-targeted fluorescent agent, to enable real-time near-infrared fluorescence (NIRF) guided surgery. This study demonstrated that SGM-101 enabled additional tumor removal in some patients and supported less invasive surgery in others. Despite this positive intraoperative effect, the impact on long-term tumor control is unknown. Therefore, in this article we report the long-term outcomes of all rectal cancer patients that participated to the trial. For all 29 LARC and LRRC patients that participated in the SGM-101 phase 2 trial, follow-up data were collected. Main outcome measure was 5-year local tumor control. The median follow-up of all patients was 5.0 years (IQR 4.5–5.5). Of the 12 LARC patients, three (25

BACKGROUND:Distal, locally advanced rectal cancer might spread to lateral lymph nodes (LLNs), posing a risk of lateral local recurrence (LLR). This study evaluated quality-controlled implementation of lateral lymph node dissection (LLND) in the Netherlands. METHODS:This retrospective multicenter cohort study included consecutively treated rectal cancer patients who underwent neoadjuvant therapy, total mesorectal excision (TME) surgery, and nerve-sparing minimally invasive LLND by trained surgeons across 10 Dutch hospitals. Training involved cadaver sessions, monthly video meetings, and proctoring. Outcome measures included intra- and postoperative complications, urogenital dysfunction and 18-month LLR, local recurrence (LR), and disease-free survival (DFS). RESULTS:The study comprised 41 patients (median follow-up period, 16 months; interquartile range, IQR, 8-21 months) with advanced tumors (27% cT4, 49% cN2, 7% cM1), and a mean LLN size of 11 mm on primary-staging MRI. Abdominoperineal resection was performed for 29 patients (70%). A beyond TME procedure was performed for 11 patients (28%). The median blood-loss was 250 ml (IQR, 100-400 ml), with obturator nerve injury reported in one patient. Malignant LLNs were found in 41% of the LLND specimens. Complications occurred for 22 patients (54%), 21% (9/41) of which were grade 3 or higher. Nine patients (22%, four of whom underwent beyond TME surgery) had a Foley or intermittent urinary catheter at the end of the follow-up period. Sexual dysfunction of three patients was reported. No ipsilateral LLRs occurred. The 18-month LR rate was 14%, and the DFS was 55%. CONCLUSION:Minimally invasive nerve-sparing LLND by trained Dutch surgeons showed acceptable complication rates and good oncologic control of the lateral compartment to date.

PURPOSE:In rectal cancer, accurate delineation is crucial for patients with enlarged lateral lymph nodes to minimize lateral local recurrence risk. This study aims to evaluate interphysician variation in delineation of the lateral compartments, and the impact of training and implementation of standardized delineation protocols. METHODS AND MATERIALS:Twenty-three radiation oncologists from 15 institutes delineated the clinical target volume (CTV) on computed tomography scan in 1 example of a patient with rectal cancer. Parallel to this, the national consensus guideline was updated. Participating radiation oncologists completed an e-learning and online training session. Subsequently, 12 radiation oncologists redelineated the same case. Variation was measured with the Dice score and 95% Hausdorff distance. RESULTS:Considerable interphysician variation was present before guideline distribution; and larger in the anterior compartment than the posterior compartment (Dice score 0.66 vs 0.80, P < .01). After training, there was a significant improvement in 95% Hausdorff distance for the lateral compartments together (0.71 vs 1.02, P = .02), but not in Dice score (0.76 vs 0.78, P = .31), and neither for the anterior and posterior compartment separately. Whereas delineation variation in the ventral and lateral sides decreased, the variation in the caudal side of the anterior compartment increased. CONCLUSIONS:Substantial delineation variation in CTV of the lateral compartments in rectal cancer cases exists. This can be reduced by implementation of a delineation guideline with clear anatomic borders and subsequent training. Despite reduction in 95% Hausdorff distance, there is still need for further improvement in specific areas to assure adequate delineation.

Since the adoption of neoadjuvant chemoradiation and total mesorectal excision as the standard in rectal cancer care, there has been marked improvement in the local recurrence rates. In this context, restaging magnetic resonance imaging (MRI) plays a key role in the assessment of tumor response, occasionally enabling organ-sparing approaches. However, the role of restaging MRI in evaluating lateral lymph nodes remains limited. Most studies suggest a high risk of lateral local recurrence regardless of a decrease in lymph node size on restaging MRI. Therefore, it is recommended that clinical decisions should rely on the primary MRI scan. Watchful waiting may be appropriate only in cases of a clinical complete response with substantial downsizing of lateral lymph nodes (≤ 4.0 mm). Notably, some lateral lymph nodes may enlarge during follow-up despite complete tumor response, in which case, lateral lymph node dissection can be considered while preserving the rectum. Thus, continuous surveillance of lateral lymph nodes is essential during watchful waiting. Restaging MRI may hold greater importance for smaller lymph nodes (5.0–6.9 mm), as those with persistent malignant features on imaging carry a 13

Aims Advances in transanal surgical and endoscopic resection techniques have increased the use of local excision (LE) as a diagnostic and potentially organ-sparing approach for early-stage (cT1-2N0) rectal cancer (RC). For pT1 RC, total mesorectal excision (TME) can be omitted if histological risk factors for lymph node metastasis (LNM) and local recurrence are absent, regardless of submucosal invasion depth, as defined by the current Dutch CRC guideline. However, for pT2 RC, completion TME is recommended, irrespective of the presence of histological risk factors and despite the potentially varying associated risks for LNM. At present, little is known about the incidence and predictive value of histological risk factors in pT2 RC. This study aims to describe the association between histological risk factors and LNM rate in pT2 RC.

BACKGROUND:Detection of grade 3-4 extra mural venous invasion (mrEMVI) on magnetic resonance imaging (MRI) is associated with an increased distant metastases (DM)-rate. This study aimed to determine the impact of different grades of mrEMVI and their disappearance after neoadjuvant therapy. METHODS:A Dutch national retrospective cross-sectional study was conducted, including patients who underwent resection for rectal cancer in 2016 from 60/69 hospitals performing rectal surgery. Patients with a cT3-4 tumour ≤8 cm from the anorectal junction were selected and their MRI-scans were reassessed by trained abdominal radiologists. Positive mrEMVI grades (3 and 4) were analyzed in regard to 4-year local recurrence (LR), DM, disease-free survival (DFS) and overall survival (OS). RESULTS:The 1213 included patients had a median follow-up of 48 months (IQR 30-54). Positive mrEMVI was present in 324 patients (27%); 161 had grade 3 and 163 had grade 4. A higher mrEMVI stage (grade 4 vs grade 3 vs no mrEMVI) increased LR-risk (21% vs 18% vs 7%, <0.001) and DM-risk (49% vs 30% vs 21%, p < 0.001) and decreased DFS (42% vs 55% vs 69%, p < 0.001) and OS (62% vs 76% vs 81%, p < 0.001), which remained independently associated in multivariable analysis. When mrEMVI had disappeared on restaging MRI, DM-rate was comparable to initial absence of mrEMVI (both 26%), whereas LR-rate remained high (22% vs 9%, p = 0.006). CONCLUSION:The negative oncological impact of mrEMVI on recurrence and survival rates was dependent on grading. Disappearance of mrEMVI on restaging MRI decreased the risk of DM, but not of LR.

AIM:This study aimed to determine the consequences of the new definition of rectal cancer for decision-making in multidisciplinary team meetings (MDT). The new definition of rectal cancer, the lower border of the tumour is located below the sigmoid take-off (STO), was implemented in the Dutch guideline in 2019 after an international Delphi consensus meeting to reduce interhospital variations. METHOD:All patients with rectal cancer according to the local MDT, who underwent resection in 2016 in the Netherlands were eligible for this nationwide collaborative cross-sectional study. MRI-images were rereviewed, and the tumours were classified as above or on/below the STO. RESULTS:This study registered 3107 of the eligible 3178 patients (98%), of which 2784 patients had an evaluable MRI. In 314 patients, the tumour was located above the STO (11%), with interhospital variation between 0% and 36%. Based on TN-stage, 175 reclassified patients with colon cancer (6%) would have received different treatment (e.g., omitting neoadjuvant radiotherapy, candidate for adjuvant chemotherapy). Tumour location above the STO was independently associated with lower risk of 4-year locoregional recurrence (HR 0.529; p = 0.030) and higher 4-year overall survival (HR 0.732; p = 0.037) compared to location under the STO. CONCLUSION:By using the STO, 11% of the prior MDT-based diagnosis of rectal cancer were redefined as sigmoid cancer, with potential implications for multimodality treatment and prognostic value. Given the substantial interhospital variation in proportion of redefined cancers, the use of the STO will contribute to standardisation and comparability of outcomes in both daily practice and trial settings.

AIM:Literature on nationwide long-term permanent stoma rates after rectal cancer resection in the minimally invasive era is scarce. The aim of this population-based study was to provide more insight into the permanent stoma rate with interhospital variability (IHV) depending on surgical technique, with pelvic sepsis, unplanned reinterventions and readmissions as secondary outcomes. METHOD:Patients who underwent open or minimally invasive resection of rectal cancer (lower border below the sigmoid take-off) in 67 Dutch centres in 2016 were included in this cross-sectional cohort study. RESULTS:Among 2530 patients, 1470 underwent a restorative resection (58%), 356 a Hartmann's procedure (14%, IHV 0%-42%) and 704 an abdominoperineal resection (28%, IHV 3%-60%). Median follow-up was 51 months. The overall permanent stoma rate at last follow-up was 50% (IHV 13%-79%) and the unintentional permanent stoma rate, permanent stoma after a restorative procedure or an unplanned Hartmann's procedure, was 11% (IHV 0%-29%). A total of 2165 patients (86%) underwent a minimally invasive resection: 1760 conventional (81%), 170 transanal (8%) and 235 robot-assisted (11%). An anastomosis was created in 59%, 80% and 66%, with corresponding unintentional permanent stoma rates of 12%, 24% and 14% (p = 0.001), respectively. When corrected for age, American Society of Anesthesiologists classification, cTNM, distance to the anorectal junction and neoadjuvant (chemo)radiotherapy, the minimally invasive technique was not associated with an unintended permanent stoma (p = 0.071) after a restorative procedure. CONCLUSION:A remarkable IHV in the permanent stoma rate after rectal cancer resection was found. No beneficial influence of transanal or robot-assisted laparoscopy on the unintentional permanent stoma rate was found, although this might be caused by the surgical learning curve. A reduction in IHV and improving preoperative counselling for decision-making for restorative procedures are required.

INTRODUCTION:Data regarding the incidence and outcomes of mismatch repair deficient (dMMR) rectal cancer is limited. This study characterizes dMMR rectal cancer patients, comparing response after neoadjuvant radiotherapy and oncological outcomes to mismatch repair proficient (pMMR) rectal cancer patients. METHOD:A retrospective cross-sectional cohort study was conducted in 67 Dutch centers. Data including patient and tumor characteristics, radiological and pathological reports and oncological follow-up outcomes were gathered from documentation in electronic patient files for patients who underwent a curative resection for primary rectal cancer in 2016. MMR-status was verified in pathology reports from immunohistochemistry or PCR microsatellite instability testing. RESULTS:MMR-status was determined in 1645 (54.9%) of 3001 stage I-IV rectal cancer patients, of which 46 (2.8%) were dMMR. Median follow up was 50 months (IQR 38-55). MMR-status was determined more often in younger patients. DMMR tumors were more locally advanced (cT4 23.9% vs. 8.8%, P = .010), and more distally located (mean distance to anorectal junction 3.6 cm vs. 5.3 cm, P = .004) than pMMR tumors. While radiological response after neoadjuvant (chemo)radiotherapy was similar, pathological complete response was significantly higher in dMMR compared to pMMR tumors (24.0% vs. 10.0%, P = .039). Four-year local recurrence, distant metastases, cancer-specific or overall survival rate between patients with dMMR or pMMR tumors were similar. CONCLUSION:In this population-based cohort, 2.8% of rectal cancers in which MMR-status was determined were subtyped as dMMR. Surprisingly, dMMR was associated with higher pathological complete response rate to neoadjuvant (chemo) radiotherapy than pMMR. MMR-status did not impact oncological outcomes.

Importance Neoadjuvant short-course radiotherapy was routinely applied for nonlocally advanced rectal cancer (cT1-3N0-1M0 with >1 mm distance to the mesorectal fascia) in the Netherlands following the Dutch total mesorectal excision trial. This policy has shifted toward selective application after guideline revision in 2014. Objective To determine the association of decreased use of neoadjuvant radiotherapy with cancer-related outcomes and overall survival at a national level. Design, Setting, and Participants This multicenter, population-based, nationwide cross-sectional cohort study analyzed Dutch patients with rectal cancer who were treated in 2011 with a 4-year follow-up. A similar study was performed in 2021, analyzing all patients that were surgically treated in 2016. From these cohorts, all patients with cT1-3N0-1M0 rectal cancer and radiologically unthreatened mesorectal fascia were included in the current study. The data of the 2011 cohort were collected between May and October 2015, and the data of the 2016 cohort were collected between October 2020 and November 2021. The data were analyzed between May and October 2022. Main Outcomes and Measures The main outcomes were 4-year local recurrence and overall survival rates. Results Among the 2011 and 2016 cohorts, 1199 (mean [SD] age, 68 [11] years; 430 women [36%]) of 2095 patients (57.2%) and 1576 (mean [SD] age, 68 [10] years; 547 women [35%]) of 3057 patients (51.6%) had cT1-3N0-1M0 rectal cancer and were included, with proportions of neoadjuvant radiotherapy of 87% (2011) and 37% (2016). Four-year local recurrence rates were 5.8% and 5.5%, respectively (P = .99). Compared with the 2011 cohort, 4-year overall survival was significantly higher in the 2016 cohort (79.6% vs 86.4%; P < .001), with lower non-cancer-related mortality (13.8% vs 6.3%; P < .001). Conclusions and Relevance The results of this cross-sectional study suggest that an absolute 50% reduction in radiotherapy use for nonlocally advanced rectal cancer did not compromise cancer-related outcomes at a national level. Optimizing clinical staging and surgery following the Dutch total mesorectal excision trial has potentially enabled safe deintensification of treatment.