Colorectal cancer risk after removal of polyps in fecal immunochemical test based screening

Background: Colonoscopy surveillance intervals are based on the predicted risk of metachronous colorectal cancer (CRC) after polyp removal. However, risk estimation per polyp subtype is difficult due to the fact that many patients have multiple polyps. To enable risk estimation per polyp subtypes we examined the metachronous CRC risk of subgroups based on presence or absence of co-occurring findings. Methods: Using high-quality screening colonoscopies performed after a positive fecal immunochemical test between 2014 and 2020 within the Dutch CRC screening program, we applied Cox regression analysis to evaluate the association between findings at baseline colonoscopy and metachronous CRCs. For our primary outcome, we appointed each patient to unique subgroups based on removed polyp subtypes that were present or absent at baseline colonoscopy and used the groups without polyps as reference. High-risk subgroups were individuals with high-risk serrated polyps, defined as serrated polyp ≥10 mm, sessile serrated lesions with dysplasia, or traditional serrated adenomas, as well as high-risk adenomas, defined as adenoma ≥10 mm or containing high-grade dysplasia. Findings: In total 253,833 colonoscopies were included. Over a median follow-up of 36 months (IQR, 21–57), we identified 504 metachronous CRCs. Hazard ratios for metachronous CRC was 1.70 (95% CI, 1.07–2.69) for individuals with high-risk serrated polyps without high-risk adenomas, 1.22 (0.96–1.55) for individuals with high-risk adenomas without high-risk serrated polyps, and 2.00 (1.19–3.39) for individuals with high-risk serrated polyps and high-risk adenomas, compared to patients without polyps. Interpretation: Accounting for co-occurring findings, we observed an increased metachronous CRC risk for individuals that had high-risk serrated polyps with the presence of high-risk adenomas, or individuals with high-risk serrated polyps without high-risk adenomas. These findings could provide more evidence to support post-polypectomy surveillance guidelines. Funding: None.</p

Preferences for colorectal cancer screening strategies: a discrete choice experiment

Background:Guidelines underline the role of individual preferences in the selection of a screening test, as insufficient evidence is available to recommend one screening test over another. We conducted a study to determine the preferences of individuals and to predict uptake for colorectal cancer (CRC) screening programmes using various screening tests. Methods:A discrete choice experiment (DCE) questionnaire was distributed among naive subjects, yet to be screened, and previously screened subjects, aged 50-75 years. Subjects were asked to choose between scenarios on the basis of faecal occult blood test (FOBT), flexible sigmoidoscopy (FS), total colonoscopy (TC) with various test-specific screening intervals and mortality reductions, and no screening (opt-out). Results:In total, 489 out of 1498 (33%) screening-naïve subjects (52% male; mean age±s.d. 61±7 years) and 545 out of 769 (71%) previously screened subjects (52% male; mean age±s.d. 61±6 years) returned the questionnaire. The type of screening test, screening interval, and risk reduction of CRC-related mortality influenced subjects' preferences (all P<0.05). Screening-naive and previously screened subjects equally preferred 5-yearly FS and 10-yearly TC (P=0.24; P=0.11), but favoured both strategies to annual FOBT screening (all P-values <0.001) if, based on the literature, realistic risk reduction of CRC-related mortality was applied. Screening-naive and previously screened subjects were willing to undergo a 10-yearly TC instead of a 5-yearly FS to obtain an additional risk reduction of CRC-related mortality of 45% (P<0.001). Conclusion:These data provide insight into the extent by which interval and risk reduction of CRC-related mortality affect preferences for CRC screening tests. Assuming realistic test characteristics, subjects in the target population preferred endoscopic screening over FOBT screening, partly, due to the more favourable risk reduction of CRC-related mortality by endoscopy screening. Increasing the knowledge of potential screenees regarding risk reduction by different screening strategies is, therefore, warranted to prevent unrealistic expectations and to optimise informed choice.British Journal of Cancer advance online publication, 2 March 2010; doi:10.1038/sj.bjc.6605566 www.bjcancer.com

First-Line everolimus and cisplatin in patients with advanced extrapulmonary neuroendocrine carcinoma:a nationwide phase 2 single-arm clinical trial

BACKGROUND: Extrapulmonary neuroendocrine carcinoma (EP-NEC) are an aggressive subgroup of neuroendocrine neoplasms (NEN). Advanced EP-NEC is generally treated with platinum-based cytotoxic regimens, but progressive disease occurs rapidly, resulting in a poor prognosis. Genetic alterations in the mammalian target for rapamycin (mTOR) pathway have been identified in NEN, providing a rationale for treatment with the mTOR-inhibitor everolimus. METHODS: A prospective phase 2 single-arm study included patients with advanced EP-NEC from three Dutch NEN expertise centres between March 2016 and January 2020. Treatment consisted of cisplatin 75 mg/m(2) every 3 weeks in combination with daily everolimus 7.5 mg for a maximum of six cycles, followed by maintenance everolimus until disease progression. Primary endpoint was disease control rate (DCR), defined as the sum of overall response rate (ORR) plus the rate of stable disease according to RECIST 1.1, assessed at 9-week intervals. Toxicity was evaluated according to CTCAE version 5.0. RESULTS: Thirty-nine patients, with a median age of 64 years (range: 28–74), of whom 20 (51%) were male, were enrolled. DCR was 82.1% (95% confidence interval (CI): 66.4–92.4), with an ORR of 58.9% (CI: 42.1–74.4). Median duration of response was 6.4 (CI: 5.8–7.0) months and median progression-free survival was 6.0 (CI: 4.3–7.8) months. Three patients (8%) had durable responses lasting  > 12 months. Median overall survival was 8.7 (CI: 7.8–9.6) months. Most common grade 3/4 toxicities were haematological (36%) and renal (21%). CONCLUSION: Everolimus in combination with cisplatin is an effective first-line treatment option for advanced EP-NEC, especially in highly selected patients. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02695459, https://clinicaltrials.gov/ct2/show/NCT02695459

Face-to-face vs telephone pre-colonoscopy consultation in colorectal cancer screening; A randomised trial

Background: A pre-colonoscopy consultation in colorectal cancer (CRC) screening is necessary to assess a screenees general health status and to explain benefits and risks of screening. The first option allows for personal attention, whereas a telephone consultation does not require travelling. We hypothesised that a telephone consultation would lead to higher response and participation in CRC screening compared with a face-to-face consultation. Methods:A total of 6600 persons (50-75 years) were 1: 1 randomised for primary colonoscopy screening with a pre-colonoscopy consultation either face-to-face or by telephone. In both arms, we counted the number of invitees who attended a pre-colonoscopy consultation (response) and the number of those who subsequently attended colonoscopy (participation), relative to the number invited for screening. A questionnaire regarding satisfaction with the consultation and expected burden of the colonoscopy (scored on five-point rating scales) was sent to invitees. Besides, a questionnaire to assess the perceived burden of colonoscopy was sent to participants, 14 days after the procedure.Results:In all, 3302 invitees were allocated to the telephone group and 3298 to the face-to-face group, of which 794 (24%) attended a telephone consultation and 822 (25%) a face-to-face consultation (P=0.41). Subsequently, 674 (20%) participants in the telephone group and 752 (23%) in the face-to-face group attended colonoscopy (P=0.018). Invitees and responders in the telephone group expected the bowel preparation to be more painful than those in the face-to-face group while perceived burden scores for the full screening procedure were comparable. More subjects in the face-to-face group than in the telephone group were satisfied by the consultation in general: (99.8% vs 98.5%, P=0.014).Conclusion:Using a telephone rather than a face-to-face consultation in a population-based CRC colonoscopy screening progr

Differences in treatment of stage I colorectal cancers:A population-based study of colorectal cancers detected within and outside of a screening program

Background:Screen-detected colorectal cancers (CRCs) are often treated less invasively than stage-matched nonscreen-detected CRCs, but the reasons for this are not fully understood. This study evaluated the treatment of stage I CRCs detected within and outside of the screening program in the Netherlands. Methods:Data from the Netherlands Cancer Registry for all stage I CRCs diagnosed between January 1, 2008 and December 31, 2020 were analyzed, comparing patient, tumor, and treatment characteristics of screen-detected and nonscreen-detected stage I CRCs. Multivariable logistic regression was used to assess the association between treatment (local excision only vs. surgical oncologic resection) and patient and tumor characteristics, stratified for T stage and tumor location. Results:Screen-detected stage I CRCs were relatively more often T1 than T2 compared with non-screen-detected stage I CRCs (66.9 % vs. 53.3 %; P 0.001). When only T1 tumors were considered, both screen-detected colon and rectal cancers were more often treated with local excision only than non-screen-detected T1 cancers (odds ratio [OR] 2.19, 95%CI 1.93 2.49; and OR 1.29, 95 %CI 1.05 1.59, respectively), adjusted for sex, tumor location, lymphovascular invasion (LVI) status, and tumor differentiation. Conclusions:Less invasive treatment of screen-detected stage I CRC is partly explained by the higher rate of T1 cancers compared with non-screen-detected stage I CRCs. T1 stage I screen-detected CRCs were also more likely to undergo less invasive treatment than non-screen-detected CRCs, adjusted for risk factors such as LVI and tumor differentiation. Future research should investigate whether the choice of local excision was related to unidentified cancerrelated factors or the expertise of the endoscopists.</p

Omineca Herald, May, 23, 1924

Background: LKB1 mutations are the underlying genetic abnormality causing Peutz-Jeghers syndrome (PJS) and are a potential target for everolimus. In this phase II study, the efficacy of everolimus on polyp and tumor growth in PJS patients was investigated. Methods: Adult patients with a proven LKB1 mutation and who were suitable for everolimus treatment were included in two different PJS cohorts: (a) patients with unresectable malignancies and (b) patients with high-risk polyps. Treatment in both groups was oral everolimus, 10 mg daily. Response rates were primary endpoints for both cohorts. Results: Between October 2011 and April 2016, only two patients were enrolled, one in each cohort. A 49-year-old patient with advanced pancreatic cancer in cohort 1 was progressive after 2 months. A 52-year-old male patient in cohort 2 experienced severe toxicity and refused treatment after 4 months, even though endoscopy suggested stabilization of polyps. Adverse

Systematic review: non-endoscopic surveillance for colorectal neoplasia in individuals with Lynch syndrome

Background: Individuals with Lynch syndrome are at high risk for colorectal cancer (CRC). Regular colonoscopies have proven to decrease CRC incidence and mortality. However, colonoscopy is burdensome and interval CRCs still occur. Hence, an accurate, less-invasive screening method that guides the timing of colonoscopy would be of important value.Aim: To outline the performance of non-endoscopic screening modalities for Lynch-associated CRC and adenomas.Methods: Systematic literature search in MEDLINE and EMBASE to identify studies investigating imaging techniques and biomarkers for detection of CRC and adenomas in Lynch syndrome. The QUADAS-2 tool was used for the quality assessment of included studies.Results: Seven of 1332 screened articles fulfilled the inclusion criteria. Two studies evaluated either CT colonography or MR colonography; both techniques were unable to detect CRC and (advanced) adenomas <10 mm. The other five studies evaluated plasma methylated-SEPTIN9, faecal immunochemical test (FIT), faecal tumour DNA markers (BAT-26, hMLH1, p53, D9S171, APC, D9S162, IFNA and DCC) and faecal microbiome as screening modalities. Sensitivity for CRC varied from 33% (BAT-26) to 70% (methylated-SEPTIN9) to 91% (hMLH1). High specificity (94-100%) for CRC and/or adenomas was observed for methylated-SEPTIN9, FIT and BAT-26. Desulfovibrio was enriched in the stool of patients having adenomas. However, all these studies were characterised by small populations, high/unclear risk of bias and/or low prevalence of adenomas.Conclusions: Imaging techniques are unsuitable for colon surveillance in Lynch syndrome, whereas biomarkers are understudied. Having outlined biomarker research in Lynch-associated and sporadic CRC/adenomas, we believe that these non-invasive markers may hold potential (whether or not combined) for this population. As they could be of great value, (pre-)clinical studies in this field should be prioritised.Cellular mechanisms in basic and clinical gastroenterology and hepatolog