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

This article is featured in Highlights of This Issue, p. 2093

Hodgkin lymphoma survivors treated with infradiaphragmatic radiotherapy (IRT) and/or procarbazine-containing chemotherapy have a higher risk of developing colorectal cancer in comparison with the general population with a relative risk between 2 and 7 (1–6). Overtime, the treatment for Hodgkin lymphoma changed resulting in a better survival and therefore these patients have a higher chance of developing late adverse events, among which the development of second primary malignancies (7). Colorectal cancer surveillance may be indicated as a higher prevalence of (advanced) adenomas and serrated polyps has been shown (6). Colonoscopy surveillance has the possibility to remove benign precursor lesions and to detect colorectal cancer in an earlier stage. Therefore, colorectal cancer surveillance potentially could decrease colorectal cancer incidence and improve colorectal cancer related mortality in Hodgkin lymphoma survivors. However, tailored recommendations are lacking for this population.

It is unknown whether surveillance could lead to a clinically meaningful reduction in colorectal cancer mortality for Hodgkin lymphoma survivors diagnosed at an adult age. In the United States, colonoscopy surveillance is recommended for young adults who survived childhood cancer (including Hodgkin lymphoma) diagnosed before the age of 21 years and were previously treated with IRT. However, so far patients treated with procarbazine-containing chemotherapy have not been included in the recommendations (8). Moreover, despite surveillance being recommended, participation rates in colonoscopy surveillance have been low among cancer survivors. An alternative colorectal cancer surveillance modality would be a noninvasive stool test, like a fecal immunochemical test (FIT) or multi-target stool DNA test (mt-sDNA), which were found to identify advanced neoplasia among Hodgkin lymphoma survivors diagnosed at an adult age (9). However, it is still unclear from which age to start colorectal cancer surveillance and which surveillance modality—colonoscopy or stool test—would be optimal and if it should vary according to previous Hodgkin lymphoma treatment.

In this study, we performed a cost-effectiveness analysis using a microsimulation modelling approach to determine the optimal colorectal cancer surveillance strategy for Hodgkin lymphoma survivors in the Netherlands, including both colonoscopy and stool test surveillance.

We adjusted well-established Microsimulation Screening Analysis-Colon (MISCAN-Colon; refs. 8, 10–13) model to reflect the Hodgkin lymphoma survivor population. Subsequently the model was used to evaluate benefits, harms, and costs of a range of potential surveillance strategies. An incremental cost-effectiveness analyses were performed to determine which strategy is optimal.

We adjusted the existing MISCAN-Colon model for the Dutch general population to reflect the colorectal cancer and the other-cause mortality risk observed among Hodgkin lymphoma survivors. MISCAN-Colon is a validated microsimulation model described extensively in previous papers (8, 10–13).

The adjustments for the Hodgkin lymphoma population were based on a large Dutch cohort study that aimed to prospectively assess the prevalence of colorectal neoplasia in Hodgkin lymphoma survivors, selecting. Five-year Hodgkin lymphoma survivors with first treatment performed between 1965 and 1995. The treatment strategies of that study were in accordance with treatment protocols of the European Organisation for Research and Treatment of Cancer. However, treatments for recurrence were not standardized. The adjustments are described in Table 1. In our analysis, we adjusted an existing version of the MISCAN-Colon model to reflect colorectal cancer risk and life expectancy of Hodgkin lymphoma survivors (Table 1). We adjusted our model parameters using the standardized incidence ratio (SIR) of colorectal cancer observed in a Dutch cohort of Hodgkin lymphoma survivors. Those rates detected a 3.0-fold increased risk of developing colorectal cancer for Hodgkin lymphoma survivors (regardless of the Hodgkin lymphoma treatment strategy, but treatment included IRT and/or procarbazine-containing chemotherapy) compared with the general population (1). The MISCAN-Colon model specifically simulates the adenoma–carcinoma sequence (14, 15), and does not directly simulate serrated lesions. In the current study, we assumed that the progression times from adenoma onset to colorectal cancer progression among Hodgkin lymphoma survivors were comparable with the general population. However, adenomas were assumed to be more often located in the proximal colon as seen in the cohort of Dutch Hodgkin lymphoma survivors. Our model assumptions (for the natural history of colorectal cancer) were tested replicating observed Dutch and worldwide data on Hodgkin lymphoma survivors (Supplementary Figs. S1 and S2; refs. 6, 16). In this modelling exercise (model validation), we tested both assumptions related to the causes of the higher colorectal cancer risk [as consequence of a higher onset of adenoma (base case analysis) versus as consequence of a combination of higher adenoma onset and faster progression from adenoma to carcinoma (sensitivity analysis)] as described in the Methods of our study. The results of the stool tests (FIT and Mt-sDNA) were based on a prospective study, which evaluated the diagnostic accuracy in Hodgkin lymphoma survivors (9).

Briefly, we used the SIR of colorectal cancer observed in a Dutch cohort of 5-year Hodgkin lymphoma survivors to assume a 3.0-fold increased risk of colorectal cancer in Hodgkin lymphoma survivors (for the entire cohort including all Hodgkin lymphoma treatment strategies including IRT and/or procarbazine-containing chemotherapy) compared with the general population (Fig. 1; ref. 1). We did not assume changes in risk over calendar time. In our model, we assumed that the higher colorectal cancer risk was a consequence of a higher incidence of adenomas. We assumed the same adenoma incidence as the Dutch general population before Hodgkin lymphoma diagnosis and treatment (from age 0–24 years), and increased adenoma incidence after that. Model validations are reported in Supplementary Document (Supplementary Figs. S1 and S2). We also adjusted the model to consider the 5.2 times higher risk of death for all causes (excluding anal and colorectal cancer mortality) observed among Hodgkin lymphoma survivors (compared with the general population in same age, gender, and calendar period; ref. 7).

The different treatment strategies for Hodgkin lymphoma resulted in different SIRs for developing colorectal cancer (1). Compared with the general population, Hodgkin lymphoma survivors treated with procarbazine without IRT had a 2.0-fold higher SIR for colorectal cancer, whereas in those treated with IRT and procarbazine the risk was 5.7-fold higher (1). We, therefore, also performed separate analyses considering differences in colorectal cancer risk based on Hodgkin lymphoma treatment (increasing or decreasing the risk accordingly). In those analyses, we assumed no difference in all-cause mortality by Hodgkin lymphoma treatment (i.e., 5.2-fold higher than the general population; ref. 7). Validation of these two separate model versions was performed and reported in Fig. 1.

We performed a cost-effectiveness analysis for each Hodgkin lymphoma survivor group to explore possible reasonable options to determine the most optimal surveillance strategy. We evaluated benefits and costs of 90 different surveillance strategies (including no surveillance) varying in test modality (colonoscopy, FIT with different positivity cutoffs, or mt-sDNA), age to start (35, 40, 45, 50 years), intervals (3, 5, and 10 years for colonoscopy, and 1 and 2 years for stool tests), and age to end (70 or 75 years). These variations were evaluated to determine the most beneficial strategy for the different subgroups. Test characteristics of the stool tests for detecting advanced neoplasia were based on diagnostic analysis previously performed in Hodgkin lymphoma survivors treated with IRT and/or procarbazine-containing chemotherapy who prospectively underwent a colonoscopy and performed stool tests prior to colonoscopy (Table 1; ref. 9). For FIT (OC-Sensor, Eiken Chemical, Tokyo, Japan), three different predetermined cutoffs were evaluated, specifically 10, 20, 47 μg Hb/g feces. The positivity at the mt-sDNA test (Cologuard, Exact Sciences Corporation, Madison, United States) was classified as described in previous studies (9, 17). Participants with a positive stool test were simulated to undergo a colonoscopy (6). We assumed that the completion rate of colonoscopy was 100% and the complication rate was similar to the general population. We assumed 100% participation in all surveillance and diagnostic follow-up.

We applied a modified societal perspective for the cost-effectiveness analysis, including patient time costs but no other indirect costs (i.e., traveling). Cost for colonoscopy and FIT surveillance has been informed from the monitoring report of the Dutch FIT organized screening programme (18). As information on the cost for the mt-sDNA test are lacking in the Netherlands, we assumed the maximum out-of-pocket cost ($649, 2017) of Cologuard in U.S. market (19, 20). Costs for treatment and care of colorectal cancer have previously been published (21). All costs were updated to the year 2019 using the cost price index from the Dutch Health Care Authority (22).

We simulated three cohorts of 10 million Hodgkin lymphoma survivors aged 35 years old in 2019 (with Hodgkin lymphoma diagnosed at age of 25 years) for the three treatment categories (entire cohort of Hodgkin lymphoma survivors including all Hodgkin lymphoma treatment strategies, Hodgkin lymphoma survivors treated with procarbazine without IRT, and Hodgkin lymphoma survivors treated with IRT and procarbazine). We simulated three cohorts of individuals all born in the same year. Although the actual number of Hodgkin lymphoma survivors in the Netherlands evidently is not in that order of magnitude (8, 11), the large cohort sample size was chosen to guarantee stable model outcomes in our simulations. To endorse generalizability to Hodgkin lymphoma survivor populations of different sizes all outcomes are reported per 1.000 survivors aged 35 years in 2019. Age 35 was chosen because the simulated increase in adenoma incidence from age 25 years onwards would require at least 10 years for these adenomas (caused by Hodgkin lymphoma treatment) to result in an increase in colorectal cancer incidence. As the information used to inform the model was limited, the increase in the adenoma incidence was assumed to not change according to period of Hodgkin lymphoma diagnosis.

For each surveillance strategy, the surveillance effectiveness [i.e., number of colorectal cancer deaths prevented, relative colorectal cancer mortality reduction and life-years gained (LYG)] and resources (colonoscopies, FIT, mt-sDNA test and cost) were analyzed, discounting the LYG and cost at the conventional 3% annual discount rate (Supplementary Tables S1–S3). We calculated the number of colonoscopies needed to prevent a colorectal cancer death by dividing the total number of colonoscopies performed (per 1,000) by the number of colorectal cancer deaths prevented per 1,000 Hodgkin lymphoma survivors screened, referred to as number needed to screen (NNS, Supplementary Tables S4–S6). For each group of Hodgkin lymphoma survivors, we also predicted colorectal cancer deaths and total costs simulating two existing surveillance recommendations indicated in the Netherlands: (i) the screening strategy for the Dutch general population (biennial FIT, i.e., once every 2 years, from age 55 to 75 years, 47 μg Hb/g feces); and (ii) the surveillance strategy for individuals with a family history of colorectal cancer (colonoscopy surveillance repeated every 5 years from age 45–75 years).

The optimal colorectal cancer surveillance strategy in Hodgkin lymphoma survivors was determined by first excluding strategies that were more expensive and less effective than (combinations of) other simulated strategies (23). For the remaining strategies (defined as ‘efficient strategies’), we calculated the incremental cost-effectiveness ratio (ICER) by comparing the ratio between additional costs and LYG to the next less expensive efficient strategy. The optimal strategy was defined as the most effective strategy with an ICER below the willingness-to-pay threshold of €20,000 per LYG (21, 24). Strategies with an ICER exceeding €20,000 were considered not cost-effective. A separate analysis was performed excluding the stool tests to evaluate which colonoscopy surveillance program was most cost-effective (results reported and discussed in the Supplementary Methods and Supplementary Tables S7–S9).

Multiple one-way sensitivity analyses were performed to reinforce the results under a variety of assumptions (Table 1). Those assumptions included an adjustment in the lifetables including different relative risks for different intervals after Hodgkin lymphoma treatment (25); another adjustment in the lifetables based on Anderson et al (26); higher colorectal cancer risk as shown in a prospective study in which Hodgkin lymphoma survivors underwent a colonoscopy and a higher prevalence of advanced neoplasia was detected; Supplementary Fig. S2 (6); different colorectal cancer localization (in line with the general Dutch population; ref. 6); a 1.33 lower colorectal cancer relative survival (27); systematic FIT negative results (28); FIT sensitivity for medium adenomas (6–9 mm) assumed as reported for the Dutch general population (29); a different assumption for the pathway to higher colorectal cancer risk in Hodgkin lymphoma survivors (colorectal cancer risk caused by a higher adenoma onset in combination with a twice-faster adenoma progression; Fig. 1); a lower complete colonoscopy examination rate (92% instead of 100%); higher costs for colorectal cancer treatment and care (50% and 100% higher); and 4% discount rate for costs and 1.5% for benefits as recommended by the Dutch Ministry of Health (30).

The data generated in this study are available within the article and its Supplementary Data files. Detailed data generated in this study about the MISCAN model is available upon request from the corresponding author.

In the entire Hodgkin lymphoma survivor cohort (not stratified by Hodgkin lymphoma treatment), 26 colorectal cancer deaths per 1000 Hodgkin lymphoma survivors (starting aged 35 years in 2019) were predicted over a lifetime in the absence of surveillance (Table 2). Up to 49% of those colorectal cancer deaths may be averted with the recommended screening strategy for the Dutch general population (Fig. 2) with biennial FIT 47 μg Hb/g feces between 55 to 75 years of age at the total costs of € 1.1 million per 1,000 Hodgkin lymphoma survivors (NNS = 75, data not included). The surveillance strategy indicated for individuals with family history of colorectal cancer being primary colonoscopy surveillance from age 45 years can prevent up to 80% of colorectal cancer mortality in Hodgkin lymphoma survivors, however, at higher costs (total costs €2.4 million per 1,000 Hodgkin lymphoma survivors, NNS = 222). The most optimal cost-effective colorectal cancer surveillance strategy was annual FIT surveillance from age 45 to 70 years using a positivity cut-off threshold of 47 μg Hb/g feces, which prevented up to 70% of colorectal cancer mortality, however, at lower costs than the previous colonoscopy strategy (compared with no surveillance; total costs € 1.4 million per 1,000 Hodgkin lymphoma survivors; NNS = 75; ICER = €18,000 per LYG; Fig. 3, Table 2, and Supplementary Table S4 and S10).

For Hodgkin lymphoma survivors treated with procarbazine without IRT, the model predicted 17 colorectal cancer deaths per 1,000 Hodgkin lymphoma survivors without surveillance. Up to 47% of those deaths could be prevented with the colorectal cancer screening strategy adopted for the Dutch general population (biennial FIT at cutoff 47 55 from age 75 years, total costs €0.8 million per 1,000 Hodgkin lymphoma survivors, NNS = 60, data not included); whereas 80% could be avoided by primary colonoscopy surveillance with a starting age of 45 years, however, at higher costs (total costs = €2.2 million per 1,000 Hodgkin lymphoma survivors, NNS = 336; Fig. 2). However, we found that biennial FIT surveillance (47 μg Hb/g feces) from age 45 and 70 years was the optimal strategy, preventing 56% of colorectal cancer mortality (compared with no surveillance) at an acceptable cost of €15,000/LYG (total costs = € 0.9 million per 1,000 Hodgkin lymphoma survivors; NNS = 79; Fig. 3, Table 2, and Supplementary Table S5 and S11).

In Hodgkin lymphoma survivors treated with IRT and procarbazine, 47 colorectal cancer deaths (per 1,000 Hodgkin lymphoma) were predicted without surveillance. Screening as suggested for the Dutch general population may prevent up to 50% of those deaths (at the costs €1.9 million per 1,000 Hodgkin lymphoma survivors, NNS = 32, data not included); whereas surveillance recommended for individuals with family history of colorectal cancer prevented up to 81% of colorectal cancer (at the cost of €2.8 million per 1,000 Hodgkin lymphoma survivors, NNS = 124; Fig. 2). Nevertheless, annual FIT surveillance (47 μg Hb/g feces) from age 40 and 70 years was optimal, averting 75% of colorectal cancer mortality (compared with no surveillance; total costs = € 2.2 million per 1,000 Hodgkin lymphoma survivors; ICER = €13,000 per LYG; NNS = 56; Fig. 3, Table 2, and Supplementary Table S6 and S12).

For each group of Hodgkin lymphoma survivors, colonoscopy surveillance was estimated not to be cost-effective in comparison with FIT (Supplementary Table S7–S9). Separate analyses were performed excluding stool test surveillance and only including colonoscopy surveillance. This analysis is described in Supplementary Methods and Supplementary Tables S7–S9.

In all sensitivity analyses, FIT surveillance was most cost-effective for all Hodgkin lymphoma treatment strategies. The optimal cutoff for FIT was quite sensitive to model assumptions. The optimal cutoff changed to a lower cutoff in 31% of the sensitivity analyses. This included among others the analyses which assumed: (i) higher all-cause mortality in the entire Hodgkin lymphoma cohort, (ii) the same FIT sensitivity for medium adenomas as in the general population, and (iii) higher colorectal cancer treatment costs (Table 3). The age range was quite robust, and only changed in the two sensitivity analyses that assumed: (i) a higher colorectal cancer risk in Hodgkin lymphoma survivors, and (ii) the Dutch discounting factors for the entire cohort. The most cost-effective interval changed in a few sensitivity analyses (Table 3).

Recent studies have suggested that Hodgkin lymphoma survivors, who received IRT, procarbazine-containing chemotherapy or both, should undergo colorectal cancer surveillance at an earlier age than recommended in population screening programs due to their increased risk of developing colorectal cancer before age 55 (1–4) and the high prevalence of colonic advanced neoplasia already at young ages (6). Using an established micro-simulation model, we found that FIT is the most cost-effective colorectal cancer surveillance strategy in this population, regardless of the Hodgkin lymphoma treatment associated colorectal cancer risk. Depending on the Hodgkin lymphoma treatment, the optimal age of commencing surveillance ranged from 40 to 45 years, which is earlier than practiced in most colorectal cancer screening programs. We showed that the optimal FIT positivity cutoff was 47 μg Hb/g feces when offering FIT annually to Hodgkin lymphoma survivors in general (the entire cohort) or to those treated with IRT and procarbazine. This FIT positivity cutoff is also used in the Dutch colorectal cancer screening programme for the average-risk population where, however, FIT is offered biennially. For those Hodgkin lymphoma survivors treated with procarbazine without IRT (patients at lower colorectal cancer risk than those with additional IRT) the same program as for the general population would be beneficial, only with a starting age at 45 (biennially and FIT positivity cutoff (47 μg Hb/g feces).

The earlier optimal age of surveillance invitation reflects the higher risk of colorectal cancer among Hodgkin lymphoma survivors at a younger age (1, 2, 6, 31) and is in line with the increased risk after 10 to over 30 years from Hodgkin lymphoma treatment (at a median age of 27 years; ref. 1). Moreover, our model shows that surveillance for Hodgkin lymphoma survivors could stop at age 70 years, 5 years earlier than recommended in most (European) colorectal cancer screening programs (75 years). This can be related to the high all-cause mortality observed among Hodgkin lymphoma survivors (7, 26). In Hodgkin lymphoma survivors, performing surveillance at an older age might directly result in colorectal cancer overdiagnosis and overtreatment with no improvement of life expectancy (no colorectal cancer death averted).

In line with previous studies on the cost-effectiveness of mt-sDNA in the asymptomatic population (32–35), we found that mt-sDNA was not cost-effective compared with other modalities. Although mt-sDNA was estimated to reduce colorectal cancer incidence and mortality, it was an inefficient surveillance option (less effective and higher costs; ref. 32).

This study has several limitations. Firstly, the MISCAN model assumes that all colorectal cancers arise through a traditional adenoma–carcinoma sequence, and the pathway of development of serrated polyps is not (yet) included in MISCAN. To avoid bias towards FIT surveillance, which is less sensitive for serrated lesions than mt-sDNA (9, 17, 36), we have modelled advanced serrated lesions as large adenomas, assuming the same progression rate for both types of lesions. Previously, in the prospective colonoscopy study, we detected significantly more advanced serrated polyps and serrated polyposis syndrome in Hodgkin lymphoma survivors compared with the general population (6), which may have impact on our model adjustments even though the colorectal cancer risk was considered. As we could not disentangle those colonoscopy results to correctly inform our current model structure, we decided to consider the advanced serrated lesions as advanced adenomas. With this assumption, we could compute the adenoma prevalence in Hodgkin lymphoma survivors in way which allow us to validate the model (Supplementary Fig. S2). Furthermore, by applying FIT parameters computed from data which include both adenomas and serrated lesions in Hodgkin lymphoma survivors, our model results were indirectly adjusted to account the potential presence of serrated lesions. A second limitation is that we cannot inform sensitivity of the FIT and mt-sDNA for colorectal cancer based on the prospective data in Hodgkin lymphoma survivors, because no colorectal cancer was detected in this cohort, only precursor lesions (6, 9). Thus, colorectal cancer sensitivity model parameters were based on data from the average-risk population (29). Furthermore, even for precursor lesions, the sample size was small for evaluating the stool test sensitivity (9). Moreover, the exact pathogenesis of colorectal cancer in Hodgkin lymphoma survivors remains unknown. Previous research by our group detected a higher prevalence of microsatellite instability colorectal cancer in Hodgkin lymphoma survivors due to double somatic mutations in mismatch-repair genes (37), suggesting a faster progression from precursor lesions to colorectal cancer (38). Hence, we performed a specific sensitivity analysis assuming faster progression from adenoma to colorectal cancer in Hodgkin lymphoma survivors. We found that the optimal surveillance strategy was not sensitive to this assumption. Furthermore, we assumed full adherence to follow-up and surveillance procedures because this provides unbiased estimates for optimal surveillance strategies. Results should therefore be used to guide policy, but not to take these results as the estimated impact of that policy. In practice, adherence to surveillance is usually lower, resulting in a lower impact of surveillance than suggested. When imperfect adherence is assumed, this would result in strategies with short intervals and larger age target to compensate for the suboptimal surveillance. This would result in Hodgkin lymphoma survivors who adhere to surveillance to be over-screened. If only 41% of the population would participate, the costs, benefits, and harms of the program would decrease proportionally. Considering the low uptake of colonoscopy screening observed among childhood cancer survivors in US (i.e., 11.5%; ref. 39), our findings about the benefits of FIT surveillance in Hodgkin lymphoma may have vital importance as stool tests are generally characterized by higher participation rates compared with colonoscopy (at least in the average-risk population; ref. 40). To assess the robustness of our modelling estimates, a full probabilistic sensitivity analysis was not performed as extremely resource-demanding. Thus, we focused our assessments carrying out several one-way sensitivity analyses on key specific model parameters. Finally, Hodgkin lymphoma treatment regimens have changed over the past decades with a reduction of radiotherapy volumes and doses and changes in chemotherapy regimens, although procarbazine is still used in e.g., the BEACOPP regimen (41). Hence, patients currently diagnosed with Hodgkin lymphoma might have a lower colorectal cancer risk and a less intensive surveillance could be optimal (2).

One of the strengths of this study is that this is the first cost-effectiveness analysis of stool testing performed for Hodgkin lymphoma survivors. Our study suggests that FIT stool tests are cost-effective modalities for colorectal cancer surveillance in this known high-risk group for developing colorectal cancer. FIT is easy to perform and noninvasive. Reducing the use of colonoscopy surveillance will reduce potential harms (i.e., colonoscopy burden and complications) and be beneficial for the national healthcare system limiting the demand of colonoscopy and the workload of gastroenterologists. This will not only impact Hodgkin lymphoma survivors, but also other high-risk groups. Currently, ongoing research is aiming to evaluate whether stool test surveillance might also be beneficial in other high-risk groups (42).

Colorectal cancer surveillance in Hodgkin lymphoma survivors at increased risk for colorectal cancer (treated with IRT and/or procarbazine-containing chemotherapy) is cost-effective and should commence earlier than in the general population. For all examined Hodgkin lymphoma subgroups, FIT surveillance was the most cost-effective strategy. This implies introduction of surveillance with a modality that is currently not used for surveillance in high-risk groups but is extensively used in population-based colorectal cancer screening programs.

M.C.W. Spaander reports other support from Sysmex, Sentinel; and other support from Norgine outside the submitted work. L.M.G. Moons reports Consultant for Boston Scientific. P.J. Lugtenburg reports grants from Takeda, Servier; personal fees from Celgene, Genmab, Roche, AbbVie, Incyte; and personal fees from Regeneron outside the submitted work. G.A. Meijer reports nonfinancial support from Exact Sciences, Sysmex, Sentinel Ch.SpA, Personal Genome Diagnostics (PGDX), Hartwig Medical Foundation; grants from CZ (OWM Centrale Zorgverzekeraars groep Zorgverzekeraar u.a); and nonfinancial support from DELFi outside the submitted work; in addition, G.A. Meijer has a patent for Several pending; and GA Meijer is cofounder and board member (CSO) of colorectal cancer bioscreen BV. P. Snaebjornsson reports other support from MSD, Bayer; and other support from MEDtalks outside the submitted work. B. Carvalho reports a patent for Protein biomarkers for detection of colorectal cancer licensed to NL 2008707;EP13720130.7;14/396,522;NL 2010276;PCT/NL13/50316;15/444,679;EP19201973.5, a patent for Protein biomarkers (II) for detection of colorectal cancer in stool licensed to 17172531.0;2017-009-02;2017-009-03;2017-009-04;2017-009-05;2017-009-06, and a patent for Progression markers for colorectal cancer licensed to EP19187894.1;PCT/NL2020/050482. M.E. van Leerdam reports grants from the Dutch Society of Gastroenterology and Hepatology (Maag Lever Darm Stichting (MLDS) funding project FP14-04 outside the submitted work. No disclosures were reported by the other authors.

B.L.M. Ykema: Conceptualization, data curation, formal analysis, validation, investigation, visualization, methodology, writing–original draft, project administration. A. Gini: Conceptualization, resources, data curation, software, formal analysis, validation, investigation, visualization, methodology, writing–original draft, project administration. L.S. Rigter: Conceptualization, data curation, methodology, writing–review and editing. M.C.W. Spaander: Conceptualization, investigation, writing–review and editing. L.M.G. Moons: Conceptualization, visualization, writing–review and editing. T.M. Bisseling: Conceptualization, investigation, writing–review and editing. J.P. de Boer: Investigation, writing–review and editing. W.H.M. Verbeek: Investigation, writing–review and editing. P.J. Lugtenburg: Investigation, writing–review and editing. C.P.M. Janus: Investigation, writing–review and editing. E.J. Petersen: Investigation, writing–review and editing. J.M. Roesink: Investigation, writing–review and editing. R.W.M. van der Maazen: Investigation, writing–review and editing. B.M.P. Aleman: Conceptualization, investigation, writing–review and editing. G.A. Meijer: Investigation, writing–review and editing. F.E. Van Leeuwen: Conceptualization, methodology, writing–review and editing. P. Snaebjornsson: Conceptualization, methodology, writing–review and editing. B. Carvalho: Conceptualization, methodology, writing–review and editing. M.E. van Leerdam: Conceptualization, resources, data curation, supervision, validation, investigation, methodology, writing–original draft. I. Lansdorp-Vogelaar: Conceptualization, resources, data curation, software, supervision, validation, investigation, methodology, writing–original draft.

The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.