Tanya M. Bisseling

Background: Higher circulating vitamin D concentrations have been associated with a decreased colorectal neoplasm (CRN) risk in the general population. However, this association has not yet been investigated in individuals with Lynch syndrome (LS), an inherited predisposition to colorectal cancer. Methods: The study population included 2,351 LS carriers from the GEOLynch and the Colon Cancer Family Registry cohorts. Total plasma 25-hydroxyvitamin D [25(OH)D; 25(OH)D2 and 25(OH)D3] concentrations were measured using isotope dilution LC/MS-MS. CRNs included adenomas, serrated lesions, and colorectal cancer. Multivariable Cox proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association between 25(OH)D concentrations and CRN risk, overall and by pathogenic variant type, age, sex, CRN history, and geographic region. Results: During a median follow-up of 7.2 years (IQR, 3.3–12.6), 647 (27.5%) LS carriers developed a CRN. No association was observed for deficient (<50 nmol/L or <20 ng/mL; HR, 1.12; 95% CI, 0.91–1.39) or optimal (≥75 nmol/L or ≥30 ng/mL; HR, 0.94; 95% CI, 0.77–1.15) compared with sufficient (50 to <75 nmol/L or 20 to <30 ng/mL) vitamin D concentrations. No association was observed for each 10 nmol/L or 4 ng/mL increment in vitamin D concentration. Among PMS2 carriers, a 10 nmol/L increment was associated with a 27% lower CRN risk (HR, 0.73; 95% CI, 0.58–0.91). Conclusions: Vitamin D concentrations were not associated with CRN risk among LS carriers, whereas the association observed among PMS2 carriers warrants further investigation. Impact: If confirmed, these findings could inform personalized risk reduction strategies for PMS2 carriers.

To optimize surveillance in individuals with a family history (FH) of colorectal cancer (CRC), knowledge on the incidence rate of non-advanced adenomas (nAAs) and their progression rate to advanced neoplasia (AN) is crucial. We jointly estimated personalized adenoma incidence and progression rates using a novel statistical approach. We used data of individuals with ≥ 1 first-degree relative with CRC who underwent ≥ 2 colonoscopies ( n = 876 individuals; n = 2384 colonoscopies). Interval-censored data on timing and yield (no adenomas/nAA/AN) of each colonoscopy were available. nAA incidence and progression time from nAA to AN were estimated using a Bayesian progressive three-state model. Over a median follow-up of 6 years (interquartile range 5–6), 60 (6.8%) individuals developed AN (2 CRC, 58 AA) while 246 (28.1%) developed a nAA. The 5-year risk of developing nAA from baseline was estimated to be 29% (95% Crl: 21–39%). This risk was significantly associated with age and FH type. Estimated risk of progressing to AN within 5 years since nAA onset was 29% (95% Crl: 21–39%), and was significantly associated with having advanced adenomas at baseline. This resulted in a 5-year risk of transitioning from ‘no adenomas’ to AN of 7% (95% Crl: 5–9%). We showed that only 7% of individuals develop AN (primarily AAs) within the current 5-year colonoscopy surveillance interval. Future studies should evaluate whether this relatively low risk justifies slight extension of the surveillance interval or the use of fecal testing to guide colonoscopy timing. Furthermore, surveillance intensity could potentially be tailored based on age and FH.

Supplementary Figure from Cost-Effectiveness of Colorectal Cancer Surveillance in Hodgkin Lymphoma Survivors Treated with Procarbazine and/or Infradiaphragmatic Radiotherapy

Background:Hodgkin lymphoma survivors treated with infradiaphragmatic radiotherapy (IRT) and/or procarbazine have an increased risk of developing colorectal cancer. We investigated the cost-effectiveness of colorectal cancer surveillance in Dutch Hodgkin lymphoma survivors to determine the optimal surveillance strategy for different Hodgkin lymphoma subgroups.Methods:The Microsimulation Screening Analysis-Colon model was adjusted to reflect colorectal cancer and other-cause mortality risk in Hodgkin lymphoma survivors. Ninety colorectal cancer surveillance strategies were evaluated varying in starting and stopping age, interval, and modality [colonoscopy, fecal immunochemical test (FIT, OC-Sensor; cutoffs: 10/20/47 μg Hb/g feces), and multi-target stool DNA test (Cologuard)]. Analyses were also stratified per primary treatment (IRT and procarbazine or procarbazine without IRT). Colorectal cancer deaths averted (compared with no surveillance) and incremental cost-effectiveness ratios (ICER) were primary outcomes. The optimal surveillance strategy was identified assuming a willingness-to-pay threshold of €20,000 per life-years gained (LYG).Results:Overall, the optimal surveillance strategy was annual FIT (47 μg) from age 45 to 70 years, which might avert 70% of colorectal cancer deaths in Hodgkin lymphoma survivors (compared with no surveillance; ICER:€18,000/LYG). The optimal surveillance strategy in Hodgkin lymphoma survivors treated with procarbazine without IRT was biennial FIT (47 μg) from age 45 to 70 years (colorectal cancer mortality averted 56%; ICER:€15,000/LYG), and when treated with IRT and procarbazine, annual FIT (47 μg) surveillance from age 40 to 70 was most cost-effective (colorectal cancer mortality averted 75%; ICER:€13,000/LYG).Conclusions:Colorectal cancer surveillance in Hodgkin lymphoma survivors is cost-effective and should commence earlier than screening occurs in population screening programs. For all subgroups, FIT surveillance was the most cost-effective strategy.Impact:Colorectal cancer surveillance should be implemented in Hodgkin lymphoma survivors.

Supplementary Data from Cost-Effectiveness of Colorectal Cancer Surveillance in Hodgkin Lymphoma Survivors Treated with Procarbazine and/or Infradiaphragmatic Radiotherapy

Supplementary Table from Cost-Effectiveness of Colorectal Cancer Surveillance in Hodgkin Lymphoma Survivors Treated with Procarbazine and/or Infradiaphragmatic Radiotherapy

Background:Hodgkin lymphoma survivors treated with infradiaphragmatic radiotherapy (IRT) and/or procarbazine have an increased risk of developing colorectal cancer. We investigated the cost-effectiveness of colorectal cancer surveillance in Dutch Hodgkin lymphoma survivors to determine the optimal surveillance strategy for different Hodgkin lymphoma subgroups.Methods:The Microsimulation Screening Analysis-Colon model was adjusted to reflect colorectal cancer and other-cause mortality risk in Hodgkin lymphoma survivors. Ninety colorectal cancer surveillance strategies were evaluated varying in starting and stopping age, interval, and modality [colonoscopy, fecal immunochemical test (FIT, OC-Sensor; cutoffs: 10/20/47 μg Hb/g feces), and multi-target stool DNA test (Cologuard)]. Analyses were also stratified per primary treatment (IRT and procarbazine or procarbazine without IRT). Colorectal cancer deaths averted (compared with no surveillance) and incremental cost-effectiveness ratios (ICER) were primary outcomes. The optimal surveillance strategy was identified assuming a willingness-to-pay threshold of €20,000 per life-years gained (LYG).Results:Overall, the optimal surveillance strategy was annual FIT (47 μg) from age 45 to 70 years, which might avert 70% of colorectal cancer deaths in Hodgkin lymphoma survivors (compared with no surveillance; ICER:€18,000/LYG). The optimal surveillance strategy in Hodgkin lymphoma survivors treated with procarbazine without IRT was biennial FIT (47 μg) from age 45 to 70 years (colorectal cancer mortality averted 56%; ICER:€15,000/LYG), and when treated with IRT and procarbazine, annual FIT (47 μg) surveillance from age 40 to 70 was most cost-effective (colorectal cancer mortality averted 75%; ICER:€13,000/LYG).Conclusions:Colorectal cancer surveillance in Hodgkin lymphoma survivors is cost-effective and should commence earlier than screening occurs in population screening programs. For all subgroups, FIT surveillance was the most cost-effective strategy.Impact:Colorectal cancer surveillance should be implemented in Hodgkin lymphoma survivors.

Supplementary Table from Cost-Effectiveness of Colorectal Cancer Surveillance in Hodgkin Lymphoma Survivors Treated with Procarbazine and/or Infradiaphragmatic Radiotherapy

Supplementary Table from Cost-Effectiveness of Colorectal Cancer Surveillance in Hodgkin Lymphoma Survivors Treated with Procarbazine and/or Infradiaphragmatic Radiotherapy

Supplementary Figure from Cost-Effectiveness of Colorectal Cancer Surveillance in Hodgkin Lymphoma Survivors Treated with Procarbazine and/or Infradiaphragmatic Radiotherapy