key: cord-0809385-b1cd21qj
authors: D'Ovidio, Valeria; Lucidi, Cristina; Bruno, Giovanni; Lisi, Daniele; Miglioresi, Lucia; Bazuro, Marco Emilio
title: Impact of COVID-19 pandemic on Colorectal Cancer Screening program
date: 2020-07-30
journal: Clin Colorectal Cancer
DOI: 10.1016/j.clcc.2020.07.006
sha: 97e409c13b8f30c18826771051a45b5b8d12c28c
doc_id: 809385
cord_uid: b1cd21qj

INTRODUCTION: One of the main cluster of coronavirus-disease-2019 (COVID-19) has been identified in Italy. Following European and local guidelines, Italian Endoscopy Units modulated their activity. We aimed at analyzing need and safety to continue selective CRCS colonoscopies during COVID-19 pandemic. PATIENTS AND METHODS: We carried out a retrospective controlled cohort study in our “COVID-free” hospital to compare data of CRCS colonoscopies of the lockdown period (9(th) March-4(th) May 2020) with those of the same period of 2019 (control group). A pre/post endoscopic sanitary surveillance for COVID-19 infection was organized for patients and sanitary staff. RESULTS: In the lockdown group, 60 out of 137 invited patients underwent endoscopy, whereas in the control group 238 CRCS colonoscopies (3.9-fold) were performed. In the lower number of examinations during the lockdown we found more colorectal cancers (5cases, 8%, vs 3cases,1%, p=0.002). The “high-risk” adenomas detection rate was also significantly higher in the “lockdown group” than in controls (47%vs25%,p=0.001). A multiple regression analysis selected relevant symptoms (HR3.1), familiarity (HR1.99) and lockdown-period (HR2.2) as independent predictors of high-risk lesions (high-risk adenomas and CRC). No COVID-19 infections were reported among staff and patients. CONCLUSIONS: The overall adherence to CRCS decreased during the pandemic, but the continuation of CRCS colonoscopies was anyway efficacious and safe.

An outbreak of coronavirus disease 2019 , caused by severe acute respiratory syndrome -Coronavirus -2 (SARS-CoV-2), has rapidly spread from China to almost all the world with over 800,000 people across 199 countries who have been infected so far [1] .

The World Health Organization (WHO) declared a public health emergency in late January 2020 and characterized it as a pandemic in March 2020.

Europe was severely affected with an exponential increase in the number of COVID-19 cases and deaths, leading to an overload of sanitary system and to a high infection rate among health care professionals (almost 10% in western countries) [1] [2] [3] .

One of the main cluster of COVID-19 at global level was identified in Italy.

The Italian Government officially declared the lockdown on 9 th March 2020 and the Phase 1 has started, with a significant impact on the lives of citizens and on daily hospital activities. As of that day total of 9172 cases were recorded in Italy, more than half of them (5469) were in the northern region of Lombardy, the most affected area (Figure1) [4] .

In our region (Lazio), there were 102 cases as of 9 th March 2020. The measures adopted in hospital setting in order to prevent the spread of the COVID-19 infection, were: (a) suspending of "non-urgent" outpatients consultations, examinations and surgical interventions (priority class>10 days), (b) recommending immune-suppressed patients to avoid hospital admissions (c), progressively re-organizing Hospitals in "COVID-19 dedicated" and "COVID-19 free" centers.

Nowadays, the results of this strategy are emerging, with an initial reduction in the number of infected patients, hospitalizations, ICU accesses, and virus-related mortality.

Typical presentations of this infection are fever, cough, myalgia, fatigue and pneumonia.

Several studies also reported early onset of gastrointestinal symptoms, such as diarrhea or nausea (1%-10%), even in patients without respiratory symptoms [5] [6] [7] [8] [9] [10] . It was demonstrated that the SARS-CoV-2 is present in the feces and that it can survive in the gastrointestinal tract where its receptors are expressed, even after respiratory clearance [11] [12] [13] [14] [15] [16] [17] . Although both the significance of virus detection in the stool/rectal swabs of asymptomatic subjects and the role angiotensin-converting enzyme2 (ACE2) as a direct mediator for SARS-CoV-2 in the gastrointestinal tract are still unclear, these observation emphasize the relevance of an accurate definition of preventive measures, clinical care and treatment strategies in the gastroenterological setting.

The need to protect patients, especially those with high risk of COVID-19 morbidity, led Endoscopy Units to re-schedule an elevated number of procedures, pondering the benefit of endoscopy against the risk of infection on a case-by-case basis.

In Endoscopic Units, the activities were modulated in compliance with recently published COVID-19 endoscopy unit standard operating procedures [17] [18] [19] [20] according to regional guidelines.

Associates (ESGE-ESGENA) position statement, colorectal cancer screening (CRCS) colonoscopies were guaranteed in the majority of referral centers and labelled as "high priority endoscopy procedures" [19] .

While the scheduling of treatments for oncological patients were not particularly influenced by the emergency, CRCS programs obviously were.

In Italy the organized CRCS program with fecal immunochemical test (FIT) is performed at regional level with different adherence rates [21] . Barriers to screening normally include lack of proper education on colorectal cancer prevention, low appreciation of the screening benefits, fatalism or simply fear of the screening tests; all these factors were exasperated by the pandemic.COVID-19 pandemic has resulted in decreased endoscopic testing for Colorectal cancer.

The purpose of our study was to establish whether the CRCS program is effective in detecting precancerous lesions and cancer even during the pandemic. We compared the lockdown period data with last year's data in the same time window.

Given the prognostic impact of COVID-19 infection, a secondary objective was to evaluate the safety of selective colonoscopies performed in strict compliance with protective measures.

In the context of patients' segregation in "COVID-19 free" and "COVID-19 dedicated" hospitals, the Regional Health Committee selected our Hospital as "COVID-free".

In line with regional guidance our endoscopic daily activities continued to encompass the treatment of emergencies, inpatients and high-priority outpatients.

Adequate protective measures were applied to ensure safety i.e.: personal protective equipment was distributed, re-processing of endoscopes was more frequently performed and premises were increasingly sanitized.

All patients with positive FIT as well as those waiting for polypectomy surveillance (as foreseen by the Colorectal Cancer Screening program), were invited over the phone to the pre-test medical interview to plan the second level screening test if not suspicious symptoms of COVID-19 were reported. All patients were called the day before the scheduled appointment by nurses for screening, and on the day of the procedure the same questions were asked about fever, new respiratory symptoms, anorexia, diarrhea, vomiting, abdominal pain, loss of smell or taste.

The option to reschedule the examination after the end of this sanitary emergency, was given to all patients, especially to those with comorbidities or older age. On the other hand, the relevance of this exam was underlined to patients waiting for surveillance of resected advanced adenomas.

During the "lockdown" period (from 9 th March to 4 th May 2020), data of selective CRCS colonoscopies performed in our Endoscopy Unit were accurately collected. Included patients were counted in the "lockdown group" whereas invited patients who decided to postpone the exam were recorded.

Collected information included demographical data, indications to examination, presence of relevant or systemic symptoms (paying particular attention to rectal bleeding, weight loss, anemia, changes in bowel habits), medical history, endoscopic and histopathological findings.

The data of CRCS colonoscopies performed in our Endoscopy Unit during the same period in 2019 (from 9 th March to 4 th May 2019), were collected separately to analyze the efficacy of scheduled CRCS program. These patients were named "control group".

The study protocol is in line with the ethical guidelines of the 1975 Declaration of Helsinky.

Written informed consent was obtained from all participants.

The only exclusion criterion was patients' refusal to participate.

All data on demography, colonoscopy and histopathology were recorded by the screening center in a regional database and in our Endoscopy Unit general data base.

Endoscopic management CRCS colonoscopies were performed in a dedicated session, with using high-resolution instruments (Olympus 190, EVIS EXERA III-Olympus Corporation ©Japan), CO2 insufflation and water pump jet.

All patients underwent conscious sedation and deep sedation was occasionally offered to selected fragile patients.

Boston Bowel Preparation Scale was used to assess bowel toilette. If poor or inadequate in any colonic tract (total score<6 or score<2 in a single segment) the colonoscopy was rescheduled [25] .

Superficial neoplastic lesions detected during the examinations were accurately studied also through optical and virtual chromo-endoscopy (vital colorants and NBI).

Endoscopically resectable superficial neoplastic lesions were removed during colonoscopy through polypectomy or endoscopic mucosal resection (en bloc or piecemeal according to morphology and sizing).

Based on morphological characteristics (mucosal and vascular pattern), colorectal superficial neoplastic lesions suspicious for deep submucosal infiltration were sent to referral centers for endoscopic submucosal dissection (ESD). Patients with evident advanced neoplastic lesions underwent biopsy, endoscopic tattooing to mark the lesions and multidisciplinary evaluation (gastroenterologist, surgeon, radiologist, pathologist and oncologist) as provided by the CRCS program.

All histopathological data (including surgical and endoscopic data coming from other centers) were collected.

Patients were considered as "negative" in case of no polyps or inflammatory or hyperplastic lesions.

Patients with adenomas were considered as "high-risk" according to ESGE criteria in case of more than 3 lesions, size ≥ 10 mm, serrated, detection of high grade dysplasia or villous component [26] .

Colorectal cancers were stratified according to TNM classification.

The same management was adopted in both cohorts.

All staff was submitted to an infectious surveillance program. In case of slight respiratory, systemic of gastrointestinal symptoms or "high-risk COVID 19" contacts (relatives or patients) an oropharyngeal swab was performed. At the end of the lockdown period, an oropharyngeal swabs and a serologic tests were done in all nurses and medical staff.

Patients who were visited during the "lockdown period" were called over the phone 14 days after the endoscopic procedure to determine whether they or their relatives were symptomatic or not.

Our analysis is aimed to compare demographical, clinical and histopathological data of the 2 cohorts of patients. Numerical variables are expressed in as the means ± SD (standard deviations) and were compared using Student's t test for unpaired data. Categorical variables are expressed as numbers and proportions and were compared using χ2 tests. P values less than 0.05 were considered significant.

Moreover, to identify possible predictors of "high-risk" lesions, a multiple regression analysis, considering 5 variables (age, sex, relevant symptoms, reported CRC familiarity and study period) was performed. Not significant variables were removed and the analysis was repeated to confirm the statistical significance of remaining factors.

The software NCSS (Number Cruncher Statistical System) 2007 was used for statistical analysis.

The majority of baseline patient characteristics of the 2 cohorts were comparable (gender, smoking habits, previous colorectal surgery). The main reasons behind the invitations to CRCS were also homogenous, all patients of both cohorts were called for FIT positivity, polypectomy surveillance as provided for in the organized CRCS program (table 1) .

Nevertheless the mean age and the proportion of male was slightly but not significantly lower in the lockdown group (59 ± 8.2 vs 65 ± 7 years, p=0.2; 43% vs 55% p = ns, respectively).

During the pre-endoscopic medical interview, relevant symptoms or familiarity ranked far higher in the lockdown group (table 1) (p=0.0149).

During the pandemic lockdown, 137 patients resulted positive for FIT and were invited to pre-endoscopic medical interview. Only 74 patients accepted the pre-endoscopic visit and 60 patients ("lockdown group") accepted to undergo colonoscopy after medical interview adhesion.

All patients gave their consent to participate to the study. For 2 patients (3%) the colonoscopy was interrupted and repeated after a few days due to inadequate bowel preparation.

In the control period instead, 238 patients accepted to undergo colonoscopy after medical interview adhesion ("control group") (3.9-fold). In this group, 3% of colonoscopies were interrupted and repeated shortly after because of inadequate bowel preparation.

Colorectal lesions were detected during 61% of colonoscopies in the lockdown group and 53% in the control group, with a similar adenoma detection rate (p=0.2).

All lesions were endoscopically resected during the diagnostic colonoscopy with the exception of 3 advanced neoplastic lesions per group (Kudo Vi, JNET 3) sent to surgery and 2 superficial neoplastic lesions per group (laterally spreading tumors "granular mixed nodular" or "flat pseudodepressed" range size 35-50 mm) sent to referral centres for ESD.

Given the histopathological results, we excluded 5% hyperplastic and 2% inflammatory lesions from the "colorectal lesions-analysis" ( Table 2 and Figure 2 ).

The adenoma detection rate (ADR) was slightly higher in the "lockdown group" than in the "control group" (57% vs 47.5%) but it failed to reach statistical significance (p=0.2).

The "high-risk" ADR was, instead, significantly higher in the "lockdown group" (47% vs 25%, p= 0.001). Based on a sub-analysis, 4 out of 5 high-risk variables, (adenoma >10 mm, villous component, high grade dysplasia and serrated) were observed far more frequently in the "lockdown group". Accordingly, overall and high-risk adenomas mean sizes were significantly higher in this group (table 2) (p <0.001).

After post-surgical examination and radiological staging, the previously described advanced neoplastic lesions were confirmed as stage I or IIA adenocarcinoma (pT2 or 3, N0, M0). In the "lockdown group" 2 adenocarcinomas limited to the submucosa (pT1), were found in two resected lesions with advanced pattern, whereas none of control group.

No high-risk findings for nodal metastasis (Grade>2, no vascular or lymphatic infiltration, high budding, submucosal infiltration >1mm) were documented in these 2 patients. In that case, the choice was to manage them by endoscopic and radiological follow up in line with patients' decisions.

All superficial neoplastic lesions sent to ESD, turned out to be high-risk adenomas.

A multiple regression analysis has identified selected symptoms (HR 3.1), familiarity (HR

No adverse events related either to diagnostic or operative CRCS colonoscopies were recorded in the two groups.

During the lockdown period no members of sanitary staff had any symptoms or high-risk COVID-19 contact. Oropharyngeal swabs and serological test collected at the end of the lockdown period from all staff members were negative.

During the post-endoscopic follow-up, no "nosocomial" COVID-19 infections of patients and of families were referred.

This epidemic is having an enormous impact on our lives and healthcare systems. While COVID-19 is related to a direct relevant mortality, the fear of the infection may cause numerous other deaths due to diagnostic delays of life threatening diseases. In the Italian cardiologic setting, a worrying increase in out-of-hospital cardiac arrests and related morbidity and mortality has already been described [27] . Given their relevance, CRCS programs are going on, albeit with some limitations. The recently published ESGE position statement clearly suggested that CRCS colonoscopies should be guaranteed as "high priority endoscopy procedures", but no data are available yet to confirm that this indication was followed in practice.

Based on these assumptions, we conducted a study to verify the effectiveness and safety in performing selective CRCS program in a "COVID-free" hospital. By comparing the same time window in 2019, we observed that, while the number of selective CRCS colonoscopies decreases sharply during the lockdown period, the ADR, the rate of detected cancer as well as high-risk adenomas increased.

Even though the increase in ADR was not significant (57 vs 47.5%, p=0.2) it was remarkably high in both periods. In our center main colonoscopy quality indicators for both periods were adequate for the requested standard of CRCS programs, being above the Italian average values reported by Zorzi et al (21) . Not only does this suggest that the standard endoscopic skill of medical staff was not significantly influenced by the events, but also emphasizes that the results of our monocentric study could be replicated in other CRCS centers (high-volume of CRCS colonoscopies>1000/year, dedicated session, endoscopists with adequate expertise).

The increase in "high-risk" adenomas and cancer detection rates (47 vs 25%, p=0.001, and 8 vs 1%, p=0.002) during the lockdown period were significantly higher while, on the other hand, the "low-risk" adenoma detection rate decreased sharply (9 vs 22%). More than half of the colonoscopies performed during the "lockdown period" allowed the detection of high risk pre-neoplastic or neoplastic lesion. As a result we can postulate that, given the reduction of patients in the "lockdown period", we might have missed only those without significant endoscopic findings. Rescheduling these colonoscopies is a less relevant issue, as it merely relates to the organization of our daily activities in Endoscopy Unit.

Interestingly, we observed significantly more frequent more high-risk factors (FIT positive, familiarity or relevant symptoms such as rectal bleeding, recent modification of bowel habits) in "lockdown" patients. It was probably in relation to a higher commitment in emphasizing to these patients the importance of this exam during the pre-endoscopic interview and to a self-selection by the patient trough balancing both fear of COVID-19

and finding a cancer. Only a few patients without risk factors asked for the chance to delay colonoscopy after the pre-endoscopic interview because of fear to be infected.

Our multivariate analysis clearly indicates that patients with one or more high-risk factors (FIT positive, familiarity or alarm symptoms), independently of sex and age, should still receive endoscopy as soon as possible, also in lockdown period [28] [29] [30] [31] . The lockdown period was proven to be an independent factor probably as a result of either the above mentioned patient self-selection and the related fear of COVID-19 infection.

During the lockdown period and the post-endoscopic follow-up not a single patient, relatives or medical staff member was tested positive for COVID-19 infection, nor did any of them reveal any symptoms.

We think that our results are novel as nowadays real data dealing with cancer screening or specific for colorectal cancer during pandemic were not available. The only clinical data concerning cancer care demonstrating a reduction of urgent any kind of cancer referrals in COVID-19 pandemic vs pre-pandemic period concern UK and Northern Ireland [32, 33] . A potential utility of enhanced DNA-based tool testing for CRCS during crises has been instead only hypotized in United States [34] .

Our results might be also very relevant for the practical healthcare "pandemic" and postpandemic management [35] . The choice to split hospitals in "COVID-dedicated" and "COVID-free" was very relevant to reduce infectious risk and infectious fear in non COVID-patients. Moreover in these hospitals less PPEs to perform exams were needed and they do not experience a shortage of personnel (necessary in any case to guarantee nondeferrable emergencies) available to carry on "not urgent high-risk" procedures.

In conclusion we proved, in fact, as Colorectal Cancer Screening program is:

(a) effective and worthwhile: the significantly higher proportion of "high-risk" lesions by selecting patients fully justified the inclusion of selective CRCS colonoscopies in "high risk procedures";

(b) safe: whenever it is performed in Endoscopy Units of "COVID-19 free" Hospitals and by following strictly rules in terms of COVID-19 prevention;

(c) cost-saving in terms of PPE and personal shortage if performed in "COVID-19 free" Hospitals.

Our take home message is that, following the prevention rules in terms of COVID-19 , a more selective CRCS program must ever go on also during current pandemic and even in case of any fallout. To ensure safety both for patients and staff that program has to be carried on selectively in Endoscopy Units of COVID free Hospitals (following the measures adopted in in Italy). 10 (17) 15 (25) 13 (22) 4 (7) 31 (13) 24 (10) 15 (6) 27 (11) 

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