Use of a Cytosponge biomarker panel to prioritise endoscopic Barrett's oesophagus surveillance: a cross-sectional study followed by a real-world prospective pilot.

BACKGROUND: Endoscopic surveillance is recommended for patients with Barrett's oesophagus because, although the progression risk is low, endoscopic intervention is highly effective for high-grade dysplasia and cancer. However, repeated endoscopy has associated harms and access has been limited during the COVID-19 pandemic. We aimed to evaluate the role of a non-endoscopic device (Cytosponge) coupled with laboratory biomarkers and clinical factors to prioritise endoscopy for Barrett's oesophagus. METHODS: We first conducted a retrospective, multicentre, cross-sectional study in patients older than 18 years who were having endoscopic surveillance for Barrett's oesophagus (with intestinal metaplasia confirmed by TFF3 and a minimum Barrett's segment length of 1 cm [circumferential or tongues by the Prague C and M criteria]). All patients had received the Cytosponge and confirmatory endoscopy during the BEST2 (ISRCTN12730505) and BEST3 (ISRCTN68382401) clinical trials, from July 7, 2011, to April 1, 2019 (UK Clinical Research Network Study Portfolio 9461). Participants were divided into training (n=557) and validation (n=334) cohorts to identify optimal risk groups. The biomarkers evaluated were overexpression of p53, cellular atypia, and 17 clinical demographic variables. Endoscopic biopsy diagnosis of high-grade dysplasia or cancer was the primary endpoint. Clinical feasibility of a decision tree for Cytosponge triage was evaluated in a real-world prospective cohort from Aug 27, 2020 (DELTA; ISRCTN91655550; n=223), in response to COVID-19 and the need to provide an alternative to endoscopic surveillance. FINDINGS: The prevalence of high-grade dysplasia or cancer determined by the current gold standard of endoscopic biopsy was 17% (92 of 557 patients) in the training cohort and 10% (35 of 344) in the validation cohort. From the new biomarker analysis, three risk groups were identified: high risk, defined as atypia or p53 overexpression or both on Cytosponge; moderate risk, defined by the presence of a clinical risk factor (age, sex, and segment length); and low risk, defined as Cytosponge-negative and no clinical risk factors. The risk of high-grade dysplasia or intramucosal cancer in the high-risk group was 52% (68 of 132 patients) in the training cohort and 41% (31 of 75) in the validation cohort, compared with 2% (five of 210) and 1% (two of 185) in the low-risk group, respectively. In the real-world setting, Cytosponge results prospectively identified 39 (17%) of 223 patients as high risk (atypia or p53 overexpression, or both) requiring endoscopy, among whom the positive predictive value was 31% (12 of 39 patients) for high-grade dysplasia or intramucosal cancer and 44% (17 of 39) for any grade of dysplasia. INTERPRETATION: Cytosponge atypia, p53 overexpression, and clinical risk factors (age, sex, and segment length) could be used to prioritise patients for endoscopy. Further investigation could validate their use in clinical practice and lead to a substantial reduction in endoscopy procedures compared with current surveillance pathways. FUNDING: Medical Research Council, Cancer Research UK, Innovate UK.

Impact of changes to the interscreening interval and faecal immunochemical test threshold in the national bowel cancer screening programme in England: results from the FIT pilot study.

INTRODUCTION: The NHS Bowel Cancer Screening Programme (BCSP) faces endoscopy capacity challenges from the COVID-19 pandemic and plans to lower the screening starting age. This may necessitate modifying the interscreening interval or threshold. METHODS: We analysed data from the English Faecal Immunochemical Testing (FIT) pilot, comprising 27,238 individuals aged 59-75, screened for colorectal cancer (CRC) using FIT. We estimated screening sensitivity to CRC, adenomas, advanced adenomas (AA) and mean sojourn time of each pathology by faecal haemoglobin (f-Hb) thresholds, then predicted the detection of these abnormalities by interscreening interval and f-Hb threshold. RESULTS: Current 2-yearly screening with a f-Hb threshold of 120 µg/g was estimated to generate 16,092 colonoscopies, prevent 186 CRCs, detect 1142 CRCs, 7086 adenomas and 4259 AAs per 100,000 screened over 15 years. A higher threshold at 180 µg/g would reduce required colonoscopies to 11,500, prevent 131 CRCs, detect 1077 CRCs, 4961 adenomas and 3184 AAs. A longer interscreening interval of 3 years would reduce required colonoscopies to 10,283, prevent 126 and detect 909 CRCs, 4796 adenomas and 2986 AAs. CONCLUSION: Increasing the f-Hb threshold was estimated to be more efficient than increasing the interscreening interval regarding overall colonoscopies per screen-benefited cancer. Increasing the interval was more efficient regarding colonoscopies per cancer prevented.

Cancer incidence and mortality in Australia from 2020 to 2044 and an exploratory analysis of the potential effect of treatment delays during the COVID-19 pandemic: a statistical modelling study.

BACKGROUND: Long-term projections of cancer incidence and mortality estimate the future burden of cancer in a population, and can be of great use in informing the planning of health services and the management of resources. We aimed to estimate incidence and mortality rates and numbers of new cases and deaths up until 2044 for all cancers combined and for 21 individual cancer types in Australia. We also illustrate the potential effect of treatment delays due to the COVID-19 pandemic on future colorectal cancer mortality rates. METHODS: In this statistical modelling study, cancer incidence and mortality rates in Australia from 2020 to 2044 were projected based on data up to 2017 and 2019, respectively. Cigarette smoking exposure (1945-2019), participation rates in the breast cancer screening programme (1996-2019), and prostate-specific antigen testing rates (1994-2020) were included where relevant. The baseline projection model using an age-period-cohort model or generalised linear model for each cancer type was selected based on model fit statistics and validation with pre-COVID-19 observed data. To assess the impact of treatment delays during the COVID-19 pandemic on colorectal cancer mortality, we obtained data on incidence, survival, prevalence, and cancer treatment for colorectal cancer from different authorities. The relative risks of death due to system-caused treatment delays were derived from a published systematic review. Numbers of excess colorectal cancer deaths were estimated using the relative risk of death per week of treatment delay and different durations of delay under a number of hypothetical scenarios. FINDINGS: Projections indicate that in the absence of the COVID-19 pandemic effects, the age-standardised incidence rate for all cancers combined for males would decline over 2020-44, and for females the incidence rate would be relatively stable in Australia. The mortality rates for all cancers combined for both males and females are expected to continuously decline during 2020-44. The total number of new cases are projected to increase by 47·4% (95% uncertainty interval [UI] 35·2-61·3) for males, from 380 306 in 2015-19 to 560 744 (95% UI 514 244-613 356) in 2040-44, and by 54·4% (95% UI 40·2-70·5) for females, from 313 263 in 2015-19 to 483 527 (95% UI 439 069-534 090) in 2040-44. The number of cancer deaths are projected to increase by 36·4% (95% UI 15·3-63·9) for males, from 132 440 in 2015-19 to 180 663 (95% UI 152 719-217 126) in 2040-44, and by 36·6% (95% UI 15·8-64·1) for females, from 102 103 in 2015-19 to 139 482 (95% UI 118 186-167 527) in 2040-44, due to population ageing and growth. The example COVID-19 pandemic scenario of a 6-month health-care system disruption with 16-week treatment delays for colorectal cancer patients could result in 460 (95% UI 338-595) additional deaths and 437 (95% UI 314-570) deaths occurring earlier than expected in 2020-44. INTERPRETATION: These projections can inform health service planning for cancer care and treatment in Australia. Despite the continuous decline in cancer mortality rates, and the decline or plateau in incidence rates, our projections suggest an overall 51% increase in the number of new cancer cases and a 36% increase in the number of cancer deaths over the 25-year projection period. This means that continued efforts to increase screening uptake and to control risk factors, including smoking exposure, obesity, physical inactivity, alcohol use, and infections, must remain public health priorities. FUNDING: Partly funded by Cancer Council Australia.

Risk-stratified FIT for urgent colonoscopy in Lynch Syndrome: A clinical service throughout the COVID-19 pandemic

IntroductionLynch syndrome (LS) is an autosomal dominant inherited disorder characterised by pathogenic variants within the mismatch repair (MMR) genes, MLH1, MSH2, MSH6, PMS2, and a variant in EPCAM, which regulates MSH2 expression and results in an increased risk of several cancers, particularly colorectal cancer with an annual incidence rate of 3-5%.The faecal immunochemical test (FIT) is currently used in non-LS symptomatic and screening populations to guide subsequent colonoscopy. We report preliminary results from an NHS England endorsed clinical service implemented during the COVID-19 pandemic (June-December 2020) which used FIT to prioritise colonoscopy in the highest risk LS patients in response to limited colonoscopy capacity throughout the pandemic.MethodsRegional genetic and endoscopy services across England were invited to participate, with the support of the British Society of Gastroenterology (BSG). Patient eligibility was determined by 1) Diagnosis of Lynch Syndrome 2) Planned colonoscopic surveillance between 1 March 2020 and 31 December 2020. Requests for FIT testing from participating NHS Trusts were sent to the NHS Bowel Cancer Screening South of England Hub in Guildford. The Hub sent patients a FIT kit (OC-Sensor™ (Eiken, Japan)), instructions for use, a questionnaire, and a pre-paid return envelope. Laboratory reports with faecal haemoglobin (f-Hb) results were returned electronically for clinical action. LS patients were risk-stratified for colonoscopy based upon the following f-Hb thresholds: (1) f-Hb ≥ 10µg Hb/g faeces: triaged for colonoscopy via the two-week wait (2WW) pathway, (2) f-Hb ≤10µg Hb/g faeces: schedule patients for colonoscopy within 6-12 weeks, where local endoscopy service availability permits.ResultsFourteen centres across England participated in the clinical service evaluation from 9th June 2020 to 1st December 2020. An uptake rate of 63% was observed from this cohort (269/428 invites). Of the 269 patients who returned their FIT devices, 20% (n=55) had f-Hb ≥ 10µg Hb/g faeces and met criteria for urgent colonoscopy triage via the 2WW pathway. 29% (n=77) of patients had a f-Hb that was greater than the limit of detection of the assay (6µg Hb/g faeces) yet below 10µg Hb/g faeces. 22 patients (8%) had f-Hb between 6 and 9.9µg Hb/g faeces. In a subgroup analysis of 67 patients from St Mark’s Hospital, the adenoma detection rate was 42.4%, and 9/67 proceeded to priority colonoscopy based on their FIT findings.ConclusionsImplementation of this clinical service during the COVID-19 pandemic has demonstrated clinical value for LS patients requiring routine surveillance. Further investigation on the efficacy of this novel intervention is warranted, namely as it pertains to additional data analysis to include endoscopy findings for participating LS patients to discern FIT sensitivity and specificity, which will be further explored under the auspices of a multi-centre prospective research study which is presently in development.

Recovery strategies following COVID-19 disruption to cervical cancer screening and their impact on excess diagnoses.

BACKGROUND: The COVID-19 pandemic has disrupted cervical cancer screening services. Assuming increases to screening capacity are unrealistic, we propose two recovery strategies: one extends the screening interval by 6 months for all and the other extends the interval by 36/60 months, but only for women who have already missed being screened. METHODS: Using routine statistics from England we estimate the number of women affected by delays to screening. We used published research to estimate the proportion of screening age women with high-grade cervical intraepithelial neoplasia and progression rates to cancer. Under two recovery scenarios, we estimate the impact of COVID-19 on cervical cancer over one screening cycle (3 years at ages 25-49 and 5 years at ages 50-64 years). The duration of disruption in both scenarios is 6 months. In the first scenario, 10.7 million women have their screening interval extended by 6 months. In the second, 1.5 million women (those due to be screened during the disruption) miss one screening cycle, but most women have no delay. RESULTS: Both scenarios result in similar numbers of excess cervical cancers: 630 vs. 632 (both 4.3 per 100,000 women in the population). However, the scenario in which some women miss one screening cycle creates inequalities-they would have much higher rates of excess cancer: 41.5 per 100,000 delayed for screened women compared to those with a 6-month delay (5.9 per 100,000). CONCLUSION: To ensure equity for those affected by COVID-19 related screening delays additional screening capacity will need to be paired with prioritising the screening of overdue women.

Weekly COVID-19 testing with household quarantine and contact tracing is feasible and would probably end the epidemic.

The COVID-19 epidemic can probably be ended and normal life restored, perhaps quite quickly, by weekly SARS-CoV-2 RNA testing together with household quarantine and systematic contact tracing. Isolated outbreaks could then be contained by contact tracing, supplemented if necessary by temporary local reintroduction of population testing or lockdown. Leading public health experts have recommended that this should be tried in a demonstration project in which a medium-sized city introduces weekly testing and lifts lockdown completely. The idea was not considered by the groups whose predictions have guided UK policy, so we have examined the statistical case for such a study. The combination of regular testing with strict household quarantine, which was not analysed in their models, has remarkable power to reduce transmission to the community from other household members as well as providing earlier diagnosis and facilitating rapid contact tracing.