ObjectiveEndoscopic mucosal resection (EMR) is the preferred treatment for non-invasive large (>= 20 mm) non-pedunculated colorectal polyps (LNPCPs) but is associated with an early recurrence... Show moreObjectiveEndoscopic mucosal resection (EMR) is the preferred treatment for non-invasive large (>= 20 mm) non-pedunculated colorectal polyps (LNPCPs) but is associated with an early recurrence rate of up to 30%. We evaluated whether standardised EMR training could reduce recurrence rates in Dutch community hospitals.DesignIn this multicentre cluster randomised trial, 59 endoscopists from 30 hospitals were randomly assigned to the intervention group (e-learning and 2-day training including hands-on session) or control group. From April 2019 to August 2021, all consecutive EMR-treated LNPCPs were included. Primary endpoint was recurrence rate after 6 months.ResultsA total of 1412 LNPCPs were included; 699 in the intervention group and 713 in the control group (median size 30 mm vs 30 mm, 45% vs 52% size, morphology, site and access (SMSA) score IV, 64% vs 64% proximal location). Recurrence rates were lower in the intervention group compared with controls (13% vs 25%, OR 0.43; 95% CI 0.23 to 0.78; p=0.005) with similar complication rates (8% vs 9%, OR 0.93; 95% CI 0.64 to 1.36; p=0.720). Recurrences were more often unifocal in the intervention group (92% vs 76%; p=0.006). In sensitivity analysis, the benefit of the intervention on recurrence rate was only observed in the 20-40 mm LNPCPs (5% vs 20% in 20-29 mm, p=0.001; 10% vs 21% in 30-39 mm, p=0.013) but less evident in >= 40 mm LNPCPs (24% vs 31%; p=0.151). In a post hoc analysis, the training effect was maintained in the study group, while in the control group the recurrence rate remained high.ConclusionA compact standardised EMR training for LNPCPs significantly reduced recurrences in community hospitals. This strongly argues for a national dedicated training programme for endoscopists performing EMR of >= 20 mm LNPCPs. Interestingly, in sensitivity analysis, this benefit was limited for LNPCPs >= 40 mm.Trial registration numberNTR7477. Show less
Zwager, L.W.; Moons, L.M.G.; Sarasqueta, A.F.; Lacle, M.M.; Albers, S.C.; Hompes, R.; ... ; Dutch eFTR Working Group 2022
Background: T1 colorectal cancer (CRC) without histological high-risk factors for lymph node metastasis (LNM) can potentially be cured by endoscopic resection, which is associated with... Show moreBackground: T1 colorectal cancer (CRC) without histological high-risk factors for lymph node metastasis (LNM) can potentially be cured by endoscopic resection, which is associated with significantly lower morbidity, mortality and costs compared to radical surgery. An important prerequisite for endoscopic resection as definite treatment is the histological confirmation of tumour-free resection margins. Incomplete resection with involved (R1) or indeterminate (Rx) margins is considered a strong risk factor for residual disease and local recurrence. Therefore, international guidelines recommend additional surgery in case of R1/Rx resection, even in absence of high-risk factors for LNM. Endoscopic full-thickness resection (eFTR) is a relatively new technique that allows transmural resection of colorectal lesions. Local scar excision after prior R1/Rx resection of low-risk T1 CRC could offer an attractive minimal invasive strategy to achieve confirmation about radicality of the previous resection or a second attempt for radical resection of residual luminal cancer. However, oncologic safety has not been established and long-term data are lacking. Besides, surveillance varies widely and requires standardization. Methods/design: In this nationwide, multicenter, prospective cohort study we aim to assess feasibility and oncological safety of completion eFTR following incomplete resection of low-risk T1 CRC. The primary endpoint is to assess the 2 and 5 year luminal local tumor recurrence rate. Secondary study endpoints are to assess feasibility, percentage of curative eFTR-resections, presence of scar tissue and/or complete scar excision at histopathology, safety of eFTR compared to surgery, 2 and 5 year nodal and/or distant tumor recurrence rate and 5-year disease-specific and overall-survival rate. Discussion: Since the implementation of CRC screening programs, the diagnostic rate of T1 CRC is steadily increasing. A significant proportion is not recognized as cancer before endoscopic resection and is therefore resected through conventional techniques primarily reserved for benign polyps. As such, precise histological assessment is often hampered due to cauterization and fragmentation and frequently leads to treatment dilemmas. This first prospective trial will potentially demonstrate the effectiveness and oncological safety of completion eFTR for patients who have undergone a previous incomplete T1 CRC resection. Hereby, substantial surgical overtreatment may be avoided, leading to treatment optimization and organ preservation. Show less
BackgroundT1 colorectal cancer (CRC) without histological high-risk factors for lymph node metastasis (LNM) can potentially be cured by endoscopic resection, which is associated with significantly... Show moreBackgroundT1 colorectal cancer (CRC) without histological high-risk factors for lymph node metastasis (LNM) can potentially be cured by endoscopic resection, which is associated with significantly lower morbidity, mortality and costs compared to radical surgery. An important prerequisite for endoscopic resection as definite treatment is the histological confirmation of tumour-free resection margins. Incomplete resection with involved (R1) or indeterminate (Rx) margins is considered a strong risk factor for residual disease and local recurrence. Therefore, international guidelines recommend additional surgery in case of R1/Rx resection, even in absence of high-risk factors for LNM. Endoscopic full-thickness resection (eFTR) is a relatively new technique that allows transmural resection of colorectal lesions. Local scar excision after prior R1/Rx resection of low-risk T1 CRC could offer an attractive minimal invasive strategy to achieve confirmation about radicality of the previous resection or a second attempt for radical resection of residual luminal cancer. However, oncologic safety has not been established and long-term data are lacking. Besides, surveillance varies widely and requires standardization.Methods/designIn this nationwide, multicenter, prospective cohort study we aim to assess feasibility and oncological safety of completion eFTR following incomplete resection of low-risk T1 CRC. The primary endpoint is to assess the 2 and 5 year luminal local tumor recurrence rate. Secondary study endpoints are to assess feasibility, percentage of curative eFTR-resections, presence of scar tissue and/or complete scar excision at histopathology, safety of eFTR compared to surgery, 2 and 5 year nodal and/or distant tumor recurrence rate and 5-year disease-specific and overall-survival rate.DiscussionSince the implementation of CRC screening programs, the diagnostic rate of T1 CRC is steadily increasing. A significant proportion is not recognized as cancer before endoscopic resection and is therefore resected through conventional techniques primarily reserved for benign polyps. As such, precise histological assessment is often hampered due to cauterization and fragmentation and frequently leads to treatment dilemmas. This first prospective trial will potentially demonstrate the effectiveness and oncological safety of completion eFTR for patients who have undergone a previous incomplete T1 CRC resection. Hereby, substantial surgical overtreatment may be avoided, leading to treatment optimization and organ preservation. Show less
INTRODUCTION: Local full-thickness resections of the scar (FTRS) after local excision of a T1 colorectal cancer (CRC) with uncertain resection margins is proposed as an alternative strategy to... Show moreINTRODUCTION: Local full-thickness resections of the scar (FTRS) after local excision of a T1 colorectal cancer (CRC) with uncertain resection margins is proposed as an alternative strategy to completion surgery (CS), provided that no local intramural residual cancer (LIRC) is found. However, a comparison on long-term oncological outcome between both strategies is missing.METHODS: A large cohort of patients with consecutive T1 CRC between 2000 and 2017 was used. Patients were selected if they underwent a macroscopically complete local excision of a T1 CRC but positive or unassessable (R1/Rx) resection margins at histology and without lymphovascular invasion or poor differentiation. Patients treated with CS or FTRS were compared on the presence of CRC recurrence, a 5-year overall survival, disease-free survival, and metastasis-free survival.RESULTS: Of 3,697 patients with a T1 CRC, 434 met the inclusion criteria (mean age 66 years, 61% men). Three hundred thirty-four patients underwent CS, and 100 patients underwent FTRS. The median follow-up period was 64 months. CRC recurrence was seen in 7 patients who underwent CS (2.2%, 95% CI 0.9%-4.6%) and in 8 patients who underwent FTRS (9.0%, 95% CI 3.9%-17.7%). Disease-free survival was lower in FTRS strategy (96.8% vs 89.9%, P=0.019), but 5 of the 8 FTRS recurrences could be treated with salvage surgery. The metastasis-free survival (CS 96.8% vs FTRS 92.1%, P=0.10) and overall survival (CS 95.6% vs FTRS 94.4%, P=0.55) did not differ significantly between both strategies.DISCUSSION: FTRS after local excision of a T1 CRC with R1/Rx resection margins as a sole risk factor, followed by surveillance and salvage surgery in case of CRC recurrence, could be a valid alternative strategy to CS. Show less
Background Current risk stratification models for early invasive (T1) colorectal cancer are not able to discriminate accurately between prognostic favourable and unfavourable tumours, resulting in... Show moreBackground Current risk stratification models for early invasive (T1) colorectal cancer are not able to discriminate accurately between prognostic favourable and unfavourable tumours, resulting in over-treatment of a large (>80%) proportion of T1 colorectal cancer patients. The tumour-stroma ratio (TSR), which is a measure for the relative amount of desmoplastic tumour stroma, is reported to be a strong independent prognostic factor in advanced-stage colorectal cancer, with a high stromal content being associated with worse prognosis and survival. We aimed to investigate whether the TSR predicts clinical outcome in patients with non-pedunculated T1 colorectal cancer.Methods Haematoxylin and eosin (H&E)-stained tumour tissue slides from a retrospective multicentre case cohort of patients with nonpedunculated surgically treated T1 colorectal cancer were assessed for TSR by two independent observers who were blinded for clinical outcomes. The primary end point was adverse outcome, which was defined as the presence of lymph node metastasis in the resection specimen or colorectal cancer recurrence during follow-up.Results All 261 patients in the case cohort had H&E slides available for TSR scoring. Of these, 183 were scored as stroma-low, and 78 were scored as stroma-high. There was moderate inter-observer agreement kappa = 0.42). In total, 41 patients had lymph node metastasis, 17 patients had recurrent cancer and five had both. Stroma-high tumours were not associated with an increased risk for an adverse outcome (adjusted hazard ratio = 0.66, 95% confidence interval 0.37-1.18; p = 0.163).Conclusions Our study emphasises that existing prognosticators may not be simply extrapolated to T1 colorectal cancers, even though their prognostic value has been widely validated in more advanced-stage tumours. Show less
BackgroundEndoscopic mucosal resection (EMR) for large colorectal polyps is in most cases the preferred treatment to prevent progression to colorectal carcinoma. The most common complication after... Show moreBackgroundEndoscopic mucosal resection (EMR) for large colorectal polyps is in most cases the preferred treatment to prevent progression to colorectal carcinoma. The most common complication after EMR is delayed bleeding, occurring in 7% overall and in approximately 10% of polyps >= 2cm in the proximal colon. Previous research has suggested that prophylactic clipping of the mucosal defect after EMR may reduce the incidence of delayed bleeding in polyps with a high bleeding risk.MethodsThe CLIPPER trial is a multicenter, parallel-group, single blinded, randomized controlled superiority study. A total of 356 patients undergoing EMR for large (>= 2cm) non-pedunculated polyps in the proximal colon will be included and randomized to the clip group or the control group. Prophylactic clipping will be performed in the intervention group to close the resection defect after the EMR with a distance of <1cm between the clips. Primary outcome is delayed bleeding within 30days after EMR. Secondary outcomes are recurrent or residual polyps and clip artifacts during surveillance colonoscopy after 6months, as well as cost-effectiveness of prophylactic clipping and severity of delayed bleeding.DiscussionThe CLIPPER trial is a pragmatic study performed in the Netherlands and is powered to determine the real-time efficacy and cost-effectiveness of prophylactic clipping after EMR of proximal colon polyps 2cm in the Netherlands. This study will also generate new data on the achievability of complete closure and the effects of clip placement on scar surveillance after EMR, in order to further promote the debate on the role of prophylactic clipping in everyday clinical practice.Trial registrationClinicalTrials.gov NCT03309683. Registered on 13 October 2017. Start recruitment: 05 March 2018. Planned completion of recruitment: 31 August 2021. Show less
Background In the recent years two innovative approaches have become available for minimally invasiveen blocresections of large non-pedunculated rectal lesions (polyps and early cancers). One is... Show moreBackground In the recent years two innovative approaches have become available for minimally invasiveen blocresections of large non-pedunculated rectal lesions (polyps and early cancers). One is Transanal Minimally Invasive Surgery (TAMIS), the other is Endoscopic Submucosal Dissection (ESD). Both techniques are standard of care, but a direct randomised comparison is lacking. The choice between either of these procedures is dependent on local expertise or availability rather than evidence-based. The European Society for Endoscopy has recommended that a comparison between ESD and local surgical resection is needed to guide decision making for the optimal approach for the removal of large rectal lesions in Western countries. The aim of this study is to directly compare both procedures in a randomised setting with regard to effectiveness, safety and perceived patient burden. Methods Multicenter randomised trial in 15 hospitals in the Netherlands. Patients with non-pedunculated lesions > 2 cm, where the bulk of the lesion is below 15 cm from the anal verge, will be randomised between either a TAMIS or an ESD procedure. Lesions judged to be deeply invasive by an expert panel will be excluded. The primary endpoint is the cumulative local recurrence rate at follow-up rectoscopy at 12 months. Secondary endpoints are: 1) Radical (R0-) resection rate; 2) Perceived burden and quality of life; 3) Cost effectiveness at 12 months; 4) Surgical referral rate at 12 months; 5) Complication rate; 6) Local recurrence rate at 6 months. For this non-inferiority trial, the total sample size of 198 is based on an expected local recurrence rate of 3% in the ESD group, 6% in the TAMIS group and considering a difference of less than 6% to be non-inferior. Discussion This is the first European randomised controlled trial comparing the effectiveness and safety of TAMIS and ESD for theen blocresection of large non-pedunculated rectal lesions. This is important as the detection rate of these adenomas is expected to further increase with the introduction of colorectal screening programs throughout Europe. This study will therefore support an optimal use of healthcare resources in the future. Show less
Advanced colorectal cancer (CRC) consensus molecular subtype 4 (CMS4) or CRC with a low immunoscore is associated with shorter survival times. Non-metastatic CRC with microsatellite instability ... Show moreAdvanced colorectal cancer (CRC) consensus molecular subtype 4 (CMS4) or CRC with a low immunoscore is associated with shorter survival times. Non-metastatic CRC with microsatellite instability (MSI) is associated with a lower risk of recurrence. We evaluated outcome (lymph node metastases [LNM] or cancer recurrence) in these tumor subtypes in patients with surgically-removed non-pedunculated T1 CRC by performing a multicenter case-cohort study. We included all patients in 13 hospitals in the Netherlands from 2000-2014 (n = 651). We randomly selected a subgroup of patients (n = 223) and all patients with LNM or recurrence (n = 63), and median follow-up of 44 months. We centrally reviewed tumor-slides, and constructed and immunostained tissue microarrays determining MSI, CMS (MSI/CMS1, CMS2/3, or CMS4), and immunoscore (I-low/I-high). We used weighted Cox proportional hazard models to evaluate the association of MSI, CMS, and immunoscore with LNM or recurrence, adjusting for conventional histologic risk factors. In the randomly selected subgroup of patients, 7.1% of tumors were MSI/CMS1, 91.0% CMS2/3, 1.8% CMS4, and 25% I-low. In the case-cohort, patients with CMS4 tumors had an increased risk for LNM or recurrence compared with patients with tumors of other CMSs (adjusted hazard ratio [HR], 3.97; 95% CI, 1.12-14.06;P = 0.03). Albeit not significant, tumors with MSI had a lower risk for LNM or recurrence than other tumor subtypes (adjusted HR, 0.52; 95% CI, 0.12-2.30;P = 0.39), whereas tumors with a low immunoscore had an increased risk for LNM or recurrence (adjusted HR, 1.30; 95% CI, 0.68-2.48;P = 0.43). In conclusion, in a case-cohort study of patients with non-pedunculated T1 CRC, MSI, and immunoscore were not significantly associated with adverse outcome after surgery. CMS4 substantially increased the risk of adverse outcome. However, CMS4 is rare in T1 CRCs, limiting its value for determining the risk in patients. Show less
Kessels, K.; Backes, Y.; Elias, S.G.; Blink, A. van den; Offerhaus, G.J.A.; Bergeijk, J.D. van; ... ; Dutch T1 Colorectal Canc Working 2019
Discussion: If this trial confirms ESD to be favorable on the long-term, the burden of extra colonoscopies and repeated procedures can be prevented for future patients.
