Overtreatment in nonmalignant lesions detected in a colorectal cancer screening program: a retrospective cohort study

Background Although colorectal cancer (CRC) screening programs reduce CRC incidence and mortality, they are associated with risks in healthy subjects. However, the risk of overtreatment and overdiagnosis has not been determined yet. The aim of this study was to report the surgery rates in patients with nonmalignant lesions detected within the first round of a fecal immunochemical test (FIT) based CRC screening program and the factors associated with it. Methods We included in this analysis all patients with nonmalignant lesions detected between May 2013 and June 2019 in the Galician (Spain) CRC screening program. We calculated surgery rate according to demographic variables, the risk classification according to the colonoscopy findings (European guidelines for quality assurance), the endoscopist’s adenoma detection rate (ADR) classified into quartiles and the hospital’s complexity level. We determined which variables were independently associated with surgery rate and expressed the association as Odds Ratio and its 95% confidence interval (CI). Results We included 15,707 patients in the analysis with high (19.9%), intermediate (26.9%) low risk (23.3%) adenomas and normal colonoscopy (29.9%) detected in the analyzed period. Colorectal surgery was performed in 162 patients (1.03, 95% CI 0.87–1.19), due to colonoscopy complications (0.02, 95% CI 0.00–0.05) and resection of colorectal benign lesions (1.00, 95% CI 0.85–1.16). Median hospital stay was 6 days with 17.3% patients developing minor complications, 7.4% major complications and one death. After discharge, complications developed in 18.4% patients. In benign lesions, an endoscopic resection was performed in 25.4% and a residual premalignant lesion was detected in 89.9%. The variables independently associated with surgery in the multivariable analysis were age (≥60 years = 1.57, 95% CI 1.11–2.23), sex (female = 2.10, 95% CI 1.52–2.91), the European guidelines classification (high risk = 67.94, 95% CI 24.87–185.59; intermediate risk = 5.63, 95% CI 1.89–16.80; low risk = 1.43; 95% CI 0.36–5.75), the endoscopist’s ADR (Q4 = 0.44, 95% CI 0.28–0.68; Q3 = 0.44, 95% CI 0.27–0.71; Q2 = 0.71, 95% CI 0.44–1.14) and the hospital (tertiary = 0.54, 95% CI 0.38–0.79). Conclusions In a CRC screening program, the surgery rate and the associated complications in patients with nonmalignant lesions are low, and related to age, sex, endoscopic findings, endoscopist’s ADR and the hospital’s complexity. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08606-w.

Conclusions: In a CRC screening program, the surgery rate and the associated complications in patients with nonmalignant lesions are low, and related to age, sex, endoscopic findings, endoscopist's ADR and the hospital's complexity.
Keywords: Adenoma detection rate, Colorectal cancer, Overtreatment, Screening, Surgical resection Background Colorectal cancer (CRC) is the second most frequent cancer worldwide with almost two million incident cases and one million related deaths in 2020 [1]. In order to reduce the disease burden, population-based CRC screening programs have been established in the Western world. This strategy has demonstrated their efficacy to reduce CRC mortality and incidence in randomized controlled trials [2]. Furthermore, CRC screening programs have demonstrated their efficiency in reducing both CRC mortality and incidence [3,4].
Screening programs are directed to asymptomatic subjects. A key point o is the minimization of risks. The benefit gained by individuals should outweigh any harm [5]. Although complications related to the diagnostic tests are well established in CRC screening [2,6], there is no such certainty regarding overdiagnosis and overtreatment. Overdiagnosis is defined as the diagnosis of a medical condition or disease that would not cause symptoms or death during a patient's lifetime. In the case of CRC screening, treatment of overdiagnosed CRC and polyps should be called overtreatment [7].
Endoscopic resection of colorectal polyps is the key to reduce CRC incidence and mortality [8]. Although side effects are limited, mainly postpolypectomy syndrome, rectal bleeding and perforation, they account for most colonoscopy-related injury during CRC screening [2]. Endoscopic resection removes up to 90% of advanced complex polyps [9]. However, the introduction of CRC screening programs has increased the number of colectomies due to benign polyps. In the US, up to 25% of colectomies were performed for non-malignant polyps [10]. Related mortality and morbidity attains 0.8 and 25.3%, respectively [11]. However, there is little information regarding the incidence of surgery and associated risks in subjects with benign lesions detected in a CRC screening program [12] Thus, we decided to perform a retrospective cohort analysis in the first round of the Galician (northwestern Spain) CRC screening program to determine the surgery rate in patients with non-malignant lesions detected on colonoscopy, the surgery-related complications, the motivation for surgery and finally, the factors independently associated with it.

Study design
We designed a retrospective cohort multicenter study using the Galician (Northwestern Spain) CRC screening program database to identify patients. We included in this analysis all patients that underwent at least one colonoscopy in the first round of the CRC screening program from its implementation (May 2013) until July 2019. We excluded patients with an invasive CRC as the final diagnosis.

Description of the Galician CRC screening program
Galician CRC mass screening and its implementation have been described elsewhere [13]. The CRC screening program includes the central coordination and management of patient follow-up after polyp resection depending on their risk according to EU guidelines for quality assurance on CRC screening recommendations [14]. The Coordination Unit personnel introduces the data obtained from the different sources in the screening program information system regarding CRC stage according to the AJCC classification [15], the final classification of patients with a positive result [14] as well as several quality endoscopist indicators according to Spanish guidelines on quality in screening colonoscopy [16].

Baseline data
From each patient, we collected the information available in the screening program database: sex, age, fecal hemoglobin concentration, performance status, associated medical illnesses graded according to the American Society of Anesthesiologists' Physical Status Classification (ASA grade), number of baseline colonoscopies (colonoscopies performed after the positive FIT result), number of polyps, adenomas and size of the largest adenoma. Patients were classified as high risk (≥ 20 mm or ≥ 5 adenomas), intermediate risk (3 to 4 adenomas, 1 ≥ 10 mm and < 20 mm, with a villous component or high grade dysplasia), low risk (1-2 tubular adenomas < 10 mm in size) and no adenomas according to the European guidelines for quality assurance in CRC screening [17]. Data regarding the center and the endoscopist that performed the first complete colonoscopy were collected. The adenoma detection rate (ADR) and number of colonoscopies performed during the first round were calculated for each endoscopist in the first round. Endoscopists were classified into quartiles according to their ADR and number of colonoscopies performed. Finally, hospitals were classified according to their complexity level (tertiary versus secondary).

Surgery
We identified all the patients that required surgery after colonoscopy using the Spanish Health System′s Hospital Discharge Records Database (CMBD in Spanish) and the CRC screening program database. The CMBD includes information on hospital discharges using a list of clinical codes to establish the diagnosis that justified the admission The CMBD database receives notifications from approximately 98% of Spanish public hospitals [18]. Mandatory health insurance covers an estimated 99.5% of the Spanish population, although subjects not covered by health insurance can still receive treatment in public hospitals. All subjects included in the Galician CRC screening programme are attended in the Galician Public health System. The International classification of diseases (ICD) codes used to identify colorectal surgeries were: ICD-9-MC 48.6 over the period 2013-2015 and ICD-10-ES ODT(C,E-N,P)(0,4) ZZ; ODB(C,E-N,P)(0,4) ZZ and ODBP7ZZ over the period 2016-2019. We subsequently searched manually the clinical records of identified patients to confirm that colorectal surgery was related to the screening colonoscopy. Moreover, we retrieved the following data: reason for surgery, type of surgery, length of hospital stay and complications either during hospitalization or after discharge (first year). We searched the clinical information in IANUS, the Galician electronic health record system that covers both all the Galician hospitals and the primary healthcare centers. Inhospital complications were classified according to the Clavien-Dindo classification [19]. We classified surgery complications as minor if they were grade I-II and major if they were grade III-V. If surgery was due to resection of colorectal lesions, we collected data regarding size, morphology according to the Paris classification [20], location, endoscopic resection and histologic findings in the endoscopic and surgical specimen. Based on endoscopic reports we calculated the Size, Morphology, Site and Access (SMSA) score and we classified lesions accordingly [21].

Analysis
First, we described the characteristics of the subjects included. We reported continuous and categorical variables as median and interquartile range (IQR), and total number and percentage, respectively. Thereafter, we calculated the surgery rate according to the different variables assessed. We performed a bivariate analysis using the Chi-square test for categorical variables and the Student's t test for continuous variables to determine those related to surgery. Finally, we included statistically significant or clinically relevant variables in a multivariable analysis using logistic regression (forward conditional) to determine which variables were independently related to surgery. We performed a secondary analysis after excluding transanal surgery to determine the colectomy rate, related complications and independently associated factors. Associations were expressed as Odds Ratio (OR) with a 95% confidence interval (CI). Statistical analyses were performed with IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY, USA: IBM Corp.

Ethics issues
The local Institutional Review Board assessed and approved the study (code 2018/593). As long as the study was based on database operation, no informed consent was required. The information was accessed according to prevailing European and Spanish legislation.

Description of the sample
Between May 2013 and June 2019, a total of 16,720 subjects underwent at least one colonoscopy during the first round of the Galician CRC screening program. We excluded 1013 subjects with CRC as the final diagnosis from this analysis. Therefore, we included in the analysis 15,707 patients without a CRC in the first round. After linking this data with the CMBD database, we identified 352 patients with any of the codes related to colorectal surgery. After verifying the clinical records, we confirmed that 162 underwent colorectal surgery related to participation in the screening program, four due to colonoscopy-related complications and 158 due to resection of colorectal lesions ( Fig. 1 and Table 1). The surgery rate was as follows: global: 1.03% (95% CI 0.87-

Characteristics of the resected colorectal lesions
As we show in Table 3, most commonly surgically resected lesions were either right-sided (49.6%) or located in the rectum (22.2%). Median endoscopic size was 35 mm and most lesions were either sessile, flat or laterally spreading tumors. The lesions had a SMSA score above 12 in most cases (76.7%). An endoscopic resection was attempted in 23.5% of patients either in the work-up colonoscopy or in scheduled therapeutic colonoscopy. Median surgical size of the lesion was 25 mm and, as in the endoscopic histology, the most common histology was adenomatous (81.8%).

Factors associated with surgery
During bivariate analysis, several factors related to the patient (age), screening program (FIT result and number of baseline colonoscopies performed), characteristics of the lesions detected (number of polyps and adenomas, adenoma size and classification according to the European guidelines for CRC screening), endoscopist quality metrics (ADR and number of colonoscopies performed), and hospital complexity were significantly associated with the surgery rate as shown in Table 2. With respect

Discussion
Our study reports the surgery rate in patients with nonmalignant lesions detected within a mass CRC screening program and the factors related to it. Most surgeries are related to resection of colorectal lesions and, exceptionally, to endoscopic complications. This information is extremely relevant to measure overtreatment risks in this setting. Fortunately, the surgery rate is low and the associated risk of mortality is as expected: one related death in 15,000 subjects. However, we have determined that not only factors associated with the patient and endoscopic findings but also the endoscopist's performance measured with the ADR and hospital level of complexity are independently associated with surgery rate.
Our study has several strengths. The first is related to its population-based perspective. We have collected data from the first round of the Galician CRC screening program. During this initial round, FIT was offered to 721,349 subjects aged 50-69 years, colonoscopies were performed in seven hospitals and quality indicators of seventy-one endoscopists were collected in a centralized database. This database enabled us to calculate surgery rate according to the different variables available. Thus, we could accurately determine the risk of overtreatment in a mass screening program and the side effects related to surgery. There is not much information available to compare our data. As an example, in a retrospective study performed within the scope of the national English Bowel Cancer Screening Program, surgery rate in large polyps (≥20 mm flat or sessile) attained 21.7% [22]. Our data are not comparable because the European guidelines high risk group includes adenomas of any morphology ≥20 mm in size and/or ≥ 5 adenomas. In fact, most surgically resected lesions in our study were either sessile, flat or laterally spreading tumors (93%) with a SMSA > 12 in most cases. A French study evaluated the frequency and risk factors for the surgical resection of non-malignant polyps detected in a FIT based mass CRC screening program [12]. In this study, the surgery rate in patients with any polyp detected was 4.1% and was related with factors related to the size, location, histology, endoscopy center and the endoscopist. In our study, the surgery rate in the patients with at least one adenoma was clearly lower. We have detected an association between the ADR and the surgery rate independent from the endoscopic findings. ADR is the endoscopist's main quality indicator and has been associated with the risk of interval CRC [23], CRC death [24], detection of serrated polyps [25] and the adenoma detection during surveillance [26]. Although ADR is considered a surrogate for meticulous inspection of the colorectal mucosa, correlation with other important outcomes has never been found. In our case, we hypothesize that our findings reflect an association between the assessment of the mucosa and the endoscopists' resection skills. Out results confirm that endoscopists are a risk factor for surgery in patients with polyps detected in a screening program [12]. Nevertheless, we must draw attention to the high ADR of the endoscopists taking part in the Galician screening program. Although an ADR above 45% is recommended in a FITbased screening programs [27], in our case 75% of endoscopists attained a 60% ADR.
Our study has several limitations related to quality of the data collected in the CRC screening database. First, we used the CMBD to identify all the colorectal surgeries. Although we do not have information regarding the accuracy of the data obtained from the Spanish CMBD, an evaluation of the ICD-9-CM for CRC in an Italian administrative database showed a sensitivity ranging between 98 and 99% [28]. Unfortunately, information regarding location, morphology of the most advanced lesion, SMSA classification or the visual predicted histology of the lesions detected was not stored. We cannot provide information regarding on the visual suspicion of malignancy of the polyp that could explain some of the referrals to surgery. Additionally this information could explain one of the most striking findings of our study. Although males have an increased risk of advanced neoplasia detection in CRC screening [29] and account for 75% of the high risk lesions detected [30], in our study, females have an increased risk of surgery. The reason is unclear and we suggest it may be related to differences in the natural history of CRC. There is evidence that the serrated carcinogenic pathway, through hypermethylation and BRAF V600E mutation, with flat or sessile serrated lesions located proximally [31,32], is more common among females and this could explain our findings. In fact, as the study by Le Roy et al. [12] shows, location is a risk factor for surgery in polyps detected in a screening program. Unfortunately, this information was unavailable for patients not requiring surgery.
Colorectal complications and mortality in our study are within the ranges expected. Data analyzed from a National Surgical Quality Improvement Program from 2011 to 2014, including 12,732 patients who underwent elective surgery for nonmalignant colorectal lesions, revealed a 0.7% 30-day mortality rate and 14% risk of major postoperative adverse events [10]. We also analyzed the long term complications that mainly impair the subject's quality of life [33]. In contrast, endoscopic resection is more cost-effective, has few side effects, complications no greater than 1 to 2% and mortality below 1/10,000 [2]. In large colorectal lesions, endoscopic resection-related mortality ranges between 0 and 0.08% [34,35]. Despite professional society guidelines and recommendations [9,36], colectomies for benign colon lesions have increased in the last few years. In the US, surgery incidence for nonmalignant lesions has increased from 5.9/100,000 to 9.4/100,000 adults in 2000 and 2014, respectively [10].
Our study highlights the need for improved endoscopic resection techniques. First, endoscopists need to be trained specifically in visual assessment of colorectal lesions and in resection techniques and their results should be continuously monitored. In this sense, we require contrasted quality indicators adapted to each screening scenario (FIT, colonoscopy). Quality indicators such as visual diagnostic yield, complete resection, complications, relapse and colectomy rates in large colorectal polyps should be monitored both per endoscopist and per endoscopy unit. However, complex endoscopic resection techniques such as submucosal dissection and endoscopic full thickness resection should be available and patients should be referred to centralized units where these techniques are performed on a regular basis [36].

Conclusions
To conclude, the surgery rate in patients with nonmalignant lesions detected in a mass screening program is low and mainly associated with treatment of unresectable polyps. Although complications related to surgery are acceptable, this is an area both endoscopists and endoscopy units can improve upon. In order to reduce the number of subjects referred to surgery, we need to improve the endoscopist resection skills and centralized units for complex techniques should be available. Finally, we require endoscopic resection quality indicators that enable us to continuously monitor endoscopic resection results.