A Review of the Impact of the COVID-19 Pandemic on Colorectal Cancer Screening: Implications and Solutions

The COVID-19 pandemic has impacted all aspects of medical care, including cancer screening and preventative measures. Colorectal cancer screening declined significantly at the onset of the pandemic as the result of an intentional effort to conserve resources, prioritize emergencies and reduce risk of transmission. There has already been an increase in diagnosis at more advanced stages and symptomatic emergencies due to suspended screenings. As endoscopy units find their way back to pre-pandemic practices, a backlog of cases remains. The missed CRC diagnoses amongst the missed screenings carry a risk of increased morbidity and mortality which will only increase as time-to-diagnosis grows. This review discusses the impact of COVID-19 on colonoscopy screening rates, trends in stages/symptoms/circumstances at diagnosis, and economic and social impact of delayed diagnosis. Triaging and use of FITs are proposed solutions to the challenge of catching up with the large number of pandemic-driven missed CRC screenings.


Introduction
The novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that has caused the COVID-19 pandemic is, like the previous coronaviruses and the pandemics of SARS in 2002 and Middle East Respiratory Syndrome (MERS) in 2012, a single-stranded RNA virus that originated from a zoonotic host and causes severe lower respiratory tract illness with poor mortality outcomes [1,2]. While most patients present with respiratory symptoms, many patients also have gastrointestinal (GI) symptoms. Additionally, COVID-19 patients with and without GI symptoms have shown detectable viral loads in fecal samples [3][4][5][6][7]. Given the high transmissibility of COVID-19, the first and most important international public health task has been outbreak control, identifying the infected and employing practices to limit spread to uninfected individuals [1,2,8]. As a result, healthcare resources were immediately diverted to those with the greatest need, i.e., critically ill patients, and non-critical and preventative medical interventions were held across all specialties.
We performed a PubMed literature search of keywords including "COVID," "colorectal cancer," "screening," "colon cancer," and "colonoscopy" to find articles that could further elucidate the impact that the pandemic has had on colorectal cancer (CRC) screenings and diagnoses numbers as well as the influence this shift may have on patients, including staging and life years lost. This paper provides a review of these findings. We included studies that published both quantitative and qualitative data from international Pathogens 2021, 10, 1508 2 of 9 populations in order to provide a robust review that captured varying patient populations.

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Since the onset of the COVID-19 pandemic, new systems have been put in place to gather vast data as variants arise, efficacious vaccines are available and we have gained more knowledge about COVID-19, including the risk of infection in different medical settings. It is important to make up for the backlog of cancer screenings and subsequent deficit of diagnoses in 2020 [8][9][10][11]. Colorectal cancer is the third most common cancer and second leading cause of cancer-related death in the United States [12]. There have been an estimated nearly 4 million missed colorectal screening examinations due to COVID-19 [9]. Discernibly, a lack of screenings will result in late or missed cancer diagnoses for many patients. This review highlights trends in colorectal cancer screening, the potential effects on the morbidity and mortality of colorectal cancer, and proposed solutions to overcome the negatives effects of missed cancer screenings. (Figure 1 provides a summary of the key aspects covered by this review).
ings and diagnoses numbers as well as the influence this shift may have on patients, including staging and life years lost. This paper provides a review of these findings. We included studies that published both quantitative and qualitative data from international populations in order to provide a robust review that captured varying patient populations.
Since the onset of the COVID-19 pandemic, new systems have been put in place to  gather vast data as variants arise, efficacious vaccines are available and we have gained  more knowledge about COVID-19, including the risk of infection in different medical settings;. It is important to make up for the backlog of cancer screenings and subsequent deficit of diagnoses in 2020 [8][9][10][11]. Colorectal cancer is the third most common cancer and second leading cause of cancer-related death in the United States [12]. There have been an estimated nearly 4 million missed colorectal screening examinations due to COVID-19 [9]. Discernibly, a lack of screenings will result in late or missed cancer diagnoses for many patients. This review highlights trends in colorectal cancer screening, the potential effects on the morbidity and mortality of colorectal cancer, and proposed solutions to overcome the negatives effects of missed cancer screenings. (Figure 1 provides a summary of the key aspects covered by this review).

Decrease in CRC Screening Procedures
Early in the pandemic, multiple GI and cancer societies put forth recommendations to postpone non-urgent procedures cancer screenings to conserve healthcare resources and reduce the exposure of healthcare workers to COVID-19 [13][14][15]. This guidance led to a significant decline in the number of new cancers identified during the pandemic internationally. (A summary of all retrospective studies on endoscopy volume and impact on CRC detection rates is found in

Decrease in CRC Screening Procedures
Early in the pandemic, multiple GI and cancer societies put forth recommendations to postpone non-urgent procedures cancer screenings to conserve healthcare resources and reduce the exposure of healthcare workers to COVID-19 [13][14][15]. This guidance led to a significant decline in the number of new cancers identified during the pandemic internationally. (A summary of all retrospective studies on endoscopy volume and impact on CRC detection rates is found in  [17]. Multiple retrospective studies at pathology sites in Italy report decreased CRC diagnosis rates ranging from 46-62%, the largest decline compared to other cancer diagnoses over a 10-week period during the first countrywide lockdown [18,19]. In the UK, Rutter et al. determined that from the end of March to the end of May 2020, at the first peak of COVID-19, there was a decrease of endoscopic procedures to a mere 12% of the pre-COVID volume and weekly cancer detection rates decreased by 58% over all cancers, 72% of which were missing colorectal cancer diagnoses [20]. These drastic rates of decline in endoscopy volumes correlate with a global survey of endoscopy units from 55 countries that reported an average of 85% decreased volume [21]. Morris et al. followed UK endoscopy trends through October 2020 and highlighted an important detail. There were over 60% fewer two week wait referrals for colonoscopies in high-risk patients with suspected CRC in April 2020 compared to 2019, but these numbers recovered to 2019 averages by October 2020. However, this resulted in a backlog of an estimated 3500 missed CRC diagnoses and treatments between April and October 2020 [22]. It can generally be agreed that the initial changes in procedural practices for non-urgent concerns was appropriate given the gravity of COVID-19 pandemic. However, the decrease in CRC screening endoscopies worldwide has important implications that will be devastatingly long-lasting if proper steps are not taken to address possible missed cases.

Impact on Severity and Stage of CRC Diagnoses
Moreover, there is also consistent evidence of higher rates of cancer-related emergencies and more advanced stages at detection due to COVID-19. A single center study at a tertiary care center in the UK found that over the entire year, 2020 saw a significant increase in patients presenting with emergent large bowel obstructions and T4 cancers at diagnosis than both 2018 and 2019 [23]. Mizuno et al. describe greater rates of emergent CRC cases due to complete large bowel obstructions in a cohort of patients who underwent surgery in a cancer treatment center in Japan during the first state of emergency [24]. In Spain, a single center study in Navarra reported a significant increase in CRC diagnoses in emergency setting during the first surge of the pandemic. Fewer diagnoses were made through the screening program and more patients were diagnosed with metastatic disease at diagnosis compared to the same period in 2019 [25]. Similar trends with more advanced disease at diagnosis was observed in Brazil [26]. (Studies summarized in Table 2)

Models Predicting Morbidity and Mortality Impact
With such significant reductions in screening and treatment, there is a reasonable expectation and concern that there will be an increase in CRC attributable deaths. Several models have been developed to estimate the impact of delayed screening on cancer deaths. According to a UK-based study by Maringe et al., compared to pre-pandemic figures, there will be an estimated increase of 1445-1563 additional deaths (15.2-16.6% increase) over five years as a result of the delayed diagnoses caused by the COVID-19 pandemic [27]. In a similar study, it was estimated that without implementing "catch-up" screening protocols, a 12-month disruption in screening will result in an expected increase of 1360-3968 additional deaths across the Netherlands, Australia, and Canada compared to no disruption in regular screenings [28].
In an Australian study, it was estimated that a six-month delay in colorectal cancer screening would result in an increase of over $1.2 million in healthcare costs [29]. Models and predictions are summarized in Table 2.

Triage and Alternate Screening Pathways
To address the growing backlog of cases seen at every endoscopy unit, multiple physician groups proposed adept triage pathways to identify high risk patients and prioritize alternate screening options like fecal immunochemical testing (FIT) for lower risk groups [30]. Studies of screening triage pathways are summarized in Table 1. Most studies that implemented these new pathways were completed in the UK in an effort to reduce the number of patients on the two week wait referral list for colonoscopy. In one study, Maclean et al. offered all referred patients a FIT test. 94% of samples were returned, of which 34% were interpreted and positive and were followed by colonoscopy. The CRC diagnosis rate with this pathway was 3.7% (14 CRC of 122 colonoscopies), comparable to the pre-COVID detection rate of 3.9% [31]. Miller et al. triaged referred patients to alternate testing modalities of FIT with CT scan, FIT only, direct colonoscopy or clinical follow up. 98% of patients were triaged to the FIT+CT or FIT groups and were followed up with colonoscopy if deemed appropriate based on results. Using this pathway, they achieved a CRC detection rate of 3.1%, which is clinically similar to the CRC detection rate from 2017-2019 (3.3%) [32]. Another study utilized only clinical evaluation, CT scan or direct colonoscopy as options for triaging referred patients, which also yielded an overall similar CRC detection rate to pre-pandemic rates [33].

Conclusions
COVID-19 has disrupted many aspects of daily life and has transformed how almost every industry functions. The practice of medicine and how and when we deliver care to patients is no exception. COVID-19 surges and lock-downs delayed colorectal cancer screening on many patients and while endoscopy units are slowly returning to pre-pandemic practices, the missed procedures must be addressed. Without utilizing evidence based tests and re-working screening algorithms, like the triage pathways discussed here, there will be a significant economic and social impact on quality of life and life years lost. Fortunately, we have multiple tools in our armory to ensure that we continue to provide patients with appropriate preventative care. It is important that we begin to consider these options as we continue to navigate this pandemic. Triaging low versus high risk patients and using FITs (both quantitive lab-read and point-of-care) allows timely screening and focuses the work-load of endscopy units on the highest risk patients. This is especially important because resistent strains and new surges remain a real threat in prolonging this pandemic. It would be prudent to establish practice guidelines that employ multiple clinical screening methods to risk-stratify patients, diagnose colorectal cancer early and treat it appropriately as we attempt to return to on-time screening of all eligible patients and catch up with the pandemic-driven missed screenings. The goal must be to catch missed diagnoses and reach the same detection, treatment and cure rates as before the COVID-19 pandemic, with as little delay as possible. The recent emergence of the Delta and other variants of COVID-19 has undoubtedly complicated matters, which will only serve to delay this goal.

Conflicts of Interest:
The authors declare no conflict of interest.