Timely follow-up of positive cancer screening results: A systematic review and recommendations from the PROSPR Consortium.

Timely follow-up for positive cancer screening results remains suboptimal, and the evidence base to inform decisions on optimizing the timeliness of diagnostic testing is unclear. This systematic review evaluated published studies regarding time to follow-up after a positive screening for breast, cervical, colorectal, and lung cancers. The quality of available evidence was very low or low across cancers, with potential attenuated or reversed associations from confounding by indication in most studies. Overall, evidence suggested that the risk for poorer cancer outcomes rises with longer wait times that vary within and across cancer types, which supports performing diagnostic testing as soon as feasible after the positive result, but evidence for specific time targets is limited. Within these limitations, we provide our opinion on cancer-specific recommendations for times to follow-up and how existing guidelines relate to the current evidence. Thresholds set should consider patient worry, potential for loss to follow-up with prolonged wait times, and available resources. Research is needed to better guide the timeliness of diagnostic follow-up, including considerations for patient preferences and existing barriers, while addressing methodological weaknesses. Research is also needed to identify effective interventions for reducing wait times for diagnostic testing, particularly in underserved or low-resource settings. CA Cancer J Clin 2018;68:199-216. © 2018 American Cancer Society.

Association between racial residential segregation and screening uptake for colorectal and cervical cancer among Black and White patients in five US health care systems.

BACKGROUND: Despite increased recognition that structural racism contributes to poorer health outcomes for racial and ethnic minorities, there are knowledge gaps about how current patterns of racial residential segregation are associated with cancer screening uptake. The authors examined associations between Black residential segregation and screening for colorectal cancer (CRC) and cervical cancer among non-Hispanic Black and non-Hispanic White adults. METHODS: This was a retrospective study of CRC and cervical cancer screening-eligible adults from five health care systems within the Population-Based Research to Optimize the Screening Process (PROSPR II) Consortium (cohort entry, 2010-2012). Residential segregation was measured using site-specific quartiles of the Black local isolation score (LIS). The outcome was receipt of CRC or cervical cancer screening within 3 years of cohort entry (2010-2015). Logistic regression was used to calculate associations between the LIS and screening completion, adjusting for patient-level covariates. RESULTS: Among CRC (n = 642,661) and cervical cancer (n = 163,340) screening-eligible patients, 456,526 (71.0%) and 106,124 (65.0%), respectively, received screening. Across PROSPR sites, living in neighborhoods with higher LIS tended to be associated with lower odds of CRC screening (Kaiser Permanente Northern California: adjusted odds ratio [aOR] LIS trend in Black patients, 0.95 [p < .001]; aOR LIS trend in White patients, 0.98 [p < .001]; Kaiser Permanente Southern California: aOR LIS trend in Black patients, 0.98 [p = .026]; aOR LIS trend in White patients, 1.01 [p = .023]; Kaiser Permanente Washington: aOR LIS trend in White patients, 0.97 [p = .002]. However, for cervical cancer screening, associations with the LIS varied by site and race (Kaiser Permanente Washington: aOR LIS trend in White patients, 0.95 [p < .001]; Mass General Brigham: aOR LIS trend in Black patients, 1.12 [p < .001]; aOR LIS trend in White patients, 1.03 [p < .001]). CONCLUSIONS: Across five diverse health care systems, the direction of the association between Black residential segregation and screening varied by PROSPR site, race, and screening type. Additional research, including studies that examine multiple dimensions of segregation and structural racism using intersectional approaches, are needed to further disentangle these relationships.

Cure models, survival probabilities, and solid organ transplantation for patients with colorectal cancer.

A previous cancer diagnosis can preclude patients from consideration for solid organ transplantation. Statistical models may improve candidate selection. We fitted statistical cure models and estimated 5-year cancer-specific survival (5yCSS) for colorectal cancer patients in the United States using registry data. The median cure probability at cancer diagnosis for patients in the general population was 0.67. Among 956 colorectal cancer patients who underwent solid organ transplantation, the median time since diagnosis was 6.3 years and the median 5yCSS at transplantation was 0.96. Patients with a 5yCSS below 0.90 had increased posttransplant cancer-specific mortality (hazard ratio 3.31, 95% CI 1.52-7.21). Compared with recently published guidelines, our models suggested shorter wait times for some groups of colorectal cancer patients (eg, stage IIA cancers) and longer wait times for others (stages IIB, IIIB, IIIC, IV). In conclusion, colorectal cancer patients undergoing solid organ transplantation had excellent prognoses, reflecting selection incorporating existing guidelines and clinical judgment. Nonetheless, 5yCSS probabilities estimated from cure models offer additional prognostic information for patients considered for transplantation and identify situations where current guidelines might be revised. We developed a web-based tool for clinicians to calculate 5yCSS probabilities for use in transplant evaluation for individual colorectal cancer patients (https://dceg.cancer.gov/tools/risk-assessment/calculator-of-colorectal-cancer-survival-probability).

Effect of Helicobacter pylori Eradication Therapy on the Incidence of Noncardia Gastric Adenocarcinoma in a Large Diverse Population in the United States.

BACKGROUND & AIMS: High-quality data regarding the effect of Helicobacter pylori eradication on the risk of noncardia gastric adenocarcinoma (NCGA) remain limited in the United States. We investigated the incidence of NCGA after H pylori eradication therapy in a large, community-based US population. METHODS: We performed a retrospective cohort study of Kaiser Permanente Northern California members who underwent testing and/or treatment for H pylori between 1997 and 2015 and were followed through December 31, 2018. The risk of NCGA was evaluated using the Fine-Gray subdistribution hazard model and standardized incidence ratios. RESULTS: Among 716,567 individuals with a history of H pylori testing and/or treatment, the adjusted subdistribution hazard ratios and 95% confidence intervals of NCGA for H pylori-positive/untreated and H pylori-positive/treated individuals were 6.07 (4.20-8.76) and 2.68 (1.86-3.86), respectively, compared with H pylori-negative individuals. When compared directly with H pylori-positive/untreated individuals, subdistribution hazard ratios for NCGA in H pylori-positive/treated were 0.95 (0.47-1.92) at <8 years and 0.37 (0.14-0.97) ≥8 years of follow-up. Compared with the Kaiser Permanente Northern California general population, standardized incidence ratios (95% confidence interval) of NCGA steadily decreased after H pylori treatment: 2.00 (1.79-2.24) ≥1 year, 1.01 (0.85-1.19) ≥4 years, 0.68 (0.54-0.85) ≥7 years, and 0.51 (0.38-0.68) ≥10 years. CONCLUSION: In a large, diverse, community-based population, H pylori eradication therapy was associated with a significantly reduced incidence of NCGA after 8 years compared with no treatment. The risk among treated individuals became lower than the general population after 7 to 10 years of follow-up. The findings support the potential for substantial gastric cancer prevention in the United States through H pylori eradication.

Oral Antibiotic Use in Adulthood and Risk of Early-Onset Colorectal Cancer: A Case-Control Study.

BACKGROUND AND AIMS: Prior antibiotic use may be a factor in the rising incidence of colorectal cancer seen in those under 50 years of age (early-onset colorectal cancer [EOCRC]); however, the few studies to examine this link have reported conflicting results. Therefore, we evaluated the association between oral antibiotic use in adulthood and EOCRC in a large integrated healthcare system in the United States. METHODS: A population-based nested case-control study was conducted among Kaiser Permanente Northern California patients 18-49 years of age diagnosed with EOCRC (adenocarcinoma of the colon or rectum) in 1998-2020 who had ≥2 years of continuous pharmacy benefit prior to diagnosis. Cases were matched 4:1 to healthy controls on birth year, sex, race and ethnicity, medical facility, and duration of pharmacy benefit. Antibiotic exposure >1 year before the diagnosis/index date was assessed using prescribing records. Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals. A sensitivity analysis was performed among those with ≥10 years of continuous prescribing records. RESULTS: A total of 1359 EOCRC cases were matched to 4711 healthy controls. Antibiotic use in adulthood was not significantly associated with EOCRC in unadjusted or adjusted analyses (adjusted odds ratio, 1.04; 95% confidence interval, 0.94-1.26). No associations were seen for cumulative number of oral antibiotic dispensations or for any prior period of antibiotic exposure. CONCLUSIONS: In a large U.S. healthcare setting, there was no conclusive evidence of an association between oral antibiotic use in adulthood and risk of EOCRC.

Randomized Trial of Patient Outreach Approaches to De-implement Outdated Colonoscopy Surveillance Intervals.

BACKGROUND AND AIMS: Guidelines now recommend patients with low-risk adenomas receive colonoscopy surveillance in 7-10 years and those with the previously recommended 5-year interval be re-evaluated. We tested 3 outreach approaches for transitioning patients to the 10-year interval recommendation. METHODS: This was a 3-arm pragmatic randomized trial comparing telephone, secure messaging, and mailed letter outreach. The setting was Kaiser Permanente Northern California, a large integrated healthcare system. Participants were patients 54-70 years of age with 1-2 small (<10 mm) tubular adenomas at baseline colonoscopy, due for 5-year surveillance in 2022, without high-risk conditions, and with access to all 3 outreach modalities. Patients were randomly assigned to the outreach arm (telephone [n = 200], secure message [n = 203], and mailed letter [n = 201]) stratified by age, sex, and race/ethnicity. Outreach in each arm was performed by trained medical assistants (unblinded) communicating in English with 1 reminder attempt at 2-4 weeks. Participants could change their assigned interval to 10 years or continue their planned 5-year interval. RESULTS: Sixty-day response rates were higher for telephone (64.5%) and secure messaging outreach (51.7%) vs mailed letter (31.3%). Also, more patients adopted the 10-year surveillance interval in the telephone (37.0%) and secure messaging arms (32.0%) compared with mailed letter (18.9%) and rate differences were significant for telephone (18.1%; 97.5% confidence interval: 8.3%-27.9%) and secure message outreach (13.1%; 97.5% confidence interval: 3.5%-22.7%) vs mailed letter outreach. CONCLUSIONS: Telephone and secure messaging were more effective than mailed letter outreach for de-implementing outdated colonoscopy surveillance recommendations among individuals with a history of low-risk adenomas in an integrated healthcare setting. (ClinicalTrials.gov, Number: NCT05389397).

Projected Colorectal Cancer Incidence and Mortality Based on Observed Adherence to Colonoscopy and Sequential Stool-Based Screening.

INTRODUCTION: Modeling supporting recommendations for colonoscopy and stool-based colorectal cancer (CRC) screening tests assumes 100% sequential participant adherence. The impact of observed adherence on the long-term effectiveness of screening is unknown. We evaluated the effectiveness of a program of screening colonoscopy every 10 years vs annual high-sensitivity guaiac-based fecal occult blood testing (HSgFOBT) using observed sequential adherence data. METHODS: The MIcrosimulation SCreening ANalysis (MISCAN) model used observed sequential screening adherence, HSgFOBT positivity, and diagnostic colonoscopy adherence in HSgFOBT-positive individuals from the National Colonoscopy Study (single-screening colonoscopy vs ≥4 HSgFOBT sequential rounds). We compared CRC incidence and mortality over 15 years with no screening or 10 yearly screening colonoscopy vs annual HSgFOBT with 100% and differential observed adherence from the trial. RESULTS: Without screening, simulated incidence and mortality over 15 years were 20.9 (95% probability interval 15.8-26.9) and 6.9 (5.0-9.2) per 1,000 participants, respectively. In the case of 100% adherence, only screening colonoscopy was predicted to result in lower incidence; however, both tests lowered simulated mortality to a similar level (2.1 [1.6-2.9] for screening colonoscopy and 2.5 [1.8-3.4] for HSgFOBT). Observed adherence for screening colonoscopy (83.6%) was higher than observed sequential HSgFOBT adherence (73.1% first round; 49.1% by round 4), resulting in lower simulated incidence and mortality for screening colonoscopy (14.4 [10.8-18.5] and 2.9 [2.1-3.9], respectively) than HSgFOBT (20.8 [15.8-28.1] and 3.9 [2.9-5.4], respectively), despite a 91% adherence to diagnostic colonoscopy with FOBT positivity. The relative risk of CRC mortality for screening colonoscopy vs HSgFOBT was 0.75 (95% probability interval 0.68-0.80). Findings were similar in sensitivity analyses with alternative assumptions for repeat colonoscopy, test performance, risk, age, and projection horizon. DISCUSSION: Where sequential adherence to stool-based screening is suboptimal and colonoscopy is accessible and acceptable-as observed in the national colonoscopy study, microsimulation, comparative effectiveness, screening recommendations.

Predicting Risk of Colorectal Cancer After Adenoma Removal in a Large Community-Based Setting.

INTRODUCTION: Colonoscopy surveillance guidelines categorize individuals as high or low risk for future colorectal cancer (CRC) based primarily on their prior polyp characteristics, but this approach is imprecise, and consideration of other risk factors may improve postpolypectomy risk stratification. METHODS: Among patients who underwent a baseline colonoscopy with removal of a conventional adenoma in 2004-2016, we compared the performance for postpolypectomy CRC risk prediction (through 2020) of a comprehensive model featuring patient age, diabetes diagnosis, and baseline colonoscopy indication and prior polyp findings (i.e., adenoma with advanced histology, polyp size ≥10 mm, and sessile serrated adenoma or traditional serrated adenoma) with a polyp model featuring only polyp findings. Models were developed using Cox regression. Performance was assessed using area under the receiver operating characteristic curve (AUC) and calibration by the Hosmer-Lemeshow goodness-of-fit test. RESULTS: Among 95,001 patients randomly divided 70:30 into model development (n = 66,500) and internal validation cohorts (n = 28,501), 495 CRC were subsequently diagnosed; 354 in the development cohort and 141 in the validation cohort. Models demonstrated adequate calibration, and the comprehensive model demonstrated superior predictive performance to the polyp model in the development cohort (AUC 0.71, 95% confidence interval [CI] 0.68-0.74 vs AUC 0.61, 95% CI 0.58-0.64, respectively) and validation cohort (AUC 0.70, 95% CI 0.65-0.75 vs AUC 0.62, 95% CI 0.57-0.67, respectively). DISCUSSION: A comprehensive CRC risk prediction model featuring patient age, diabetes diagnosis, and baseline colonoscopy indication and polyp findings was more accurate at predicting postpolypectomy CRC diagnosis than a model based on polyp findings alone.

Biopsy of Non-tumor Sites After Biopsy of a Colorectal Cancer is not Associated With Metachronous Cancers: A Case-control Study.

BACKGROUND & AIMS: Recent research has demonstrated biologic plausibility for iatrogenic tumor seeding via colonoscopy as a cause of metachronous colorectal cancers (CRC). This study evaluated the association between biopsy of non-tumor sites after CRC biopsy and risk of metachronous CRC in a large community-based health care organization. METHODS: This was a retrospective case-control study of adults with an initial CRC diagnosed by colonoscopy between January 2006 and June 2018 who underwent curative resection. Cases developed a second primary (metachronous) CRC diagnosed 6 months to 4 years after the initial CRC, and were matched by age, sex, diagnosis of inflammatory bowel disease, race, and ethnicity with up to 5 controls without a second CRC diagnosis. The exposure was biopsy in the colonic segment of the metachronous CRC (or corresponding segment in controls) after tumor biopsy, ascertained with blinding to case status. Associations were evaluated using conditional logistic regression and adjusted for potential cofounders. RESULTS: Among 14,119 patients diagnosed with an initial CRC during colonoscopy, 107 received a second CRC diagnosis. After exclusions for recurrent or synchronous CRC, 45 cases and 212 controls were included. There was no significant association between biopsy of non-tumor sites after initial CRC biopsy and risk of metachronous CRC in the segment of the additional biopsy site (adjusted odds ratio, 2.29; 95% confidence interval, 0.77-6.81). CONCLUSIONS: Metachronous cancers are not significantly associated with biopsy of non-tumor sites after biopsy of the primary cancer. Although the sample size does not allow definite exclusion of any association, these findings do not support iatrogenic tumor seeding as a common risk factor for metachronous CRC.

Age-Stratified Prevalence and Predictors of Neoplasia Among U.S. Adults Undergoing Screening Colonoscopy in a National Endoscopy Registry.

BACKGROUND & AIMS: Several U.S. organizations now recommend starting average-risk colorectal cancer screening at age 45 years, but the prevalence of colonic neoplasia in individuals younger than 50 years has not been well characterized. We used a national endoscopic registry to calculate age-stratified prevalence and predictors of colorectal neoplasia. METHODS: Outpatient screening colonoscopies performed during 2010-2020 in the GI Quality Improvement Consortium registry were analyzed. We measured the prevalence of advanced neoplasia and adenomas by age, sex, and race/ethnicity, as well as the prevalence ratio of neoplasia compared with the reference group of 50- to 54-year-olds. Multivariable logistic regression models were used to identify predictors of neoplasia. RESULTS: We identified 3,928,727 screening colonoscopies, of which 129,736 (3.3%) were performed on average-risk individuals younger than 50 years. The prevalence of advanced neoplasia was 6.2% for 50- to 54-year-olds and 5.0% (prevalence ratio, 0.81; 95% confidence interval, 0.78-0.83) for average-risk 45- to 49-year-olds. Men had higher prevalence of neoplasia than women for all age groups. White individuals had higher prevalence of advanced neoplasia than persons of other racial/ethnic groups in most age groups, which was partially driven by serrated lesions. On multivariable regression, White individuals had higher odds of advanced neoplasia than Black, Hispanic, and Asian individuals in both younger and older age groups. CONCLUSIONS: In a large U.S. endoscopy registry, the prevalence of advanced neoplasia in 45- to 49-year-olds was substantial and supports beginning screening at age 45 years. White individuals had higher risk of advanced neoplasia than Black, Hispanic, and Asian individuals across the age spectrum. These findings may inform adenoma detection benchmarks and risk-based screening strategies.

Impact of the COVID-19 Pandemic on Fecal Immunochemical Testing, Colonoscopy Services, and Colorectal Neoplasia Detection in a Large United States Community-based Population.

BACKGROUND & AIMS: The COVID-19 pandemic has affected clinical services globally, including colorectal cancer (CRC) screening and diagnostic testing. We investigated the pandemic's impact on fecal immunochemical test (FIT) screening, colonoscopy utilization, and colorectal neoplasia detection across 21 medical centers in a large integrated health care organization. METHODS: We performed a retrospective cohort study in Kaiser Permanente Northern California patients ages 18 to 89 years in 2019 and 2020 and measured changes in the numbers of mailed, completed, and positive FITs; colonoscopies; and cases of colorectal neoplasia detected by colonoscopy in 2020 vs 2019. RESULTS: FIT kit mailings ceased in mid-March through April 2020 but then rebounded and there was an 8.7% increase in kits mailed compared with 2019. With the later mailing of FIT kits, there were 9.0% fewer FITs completed and 10.1% fewer positive tests in 2020 vs 2019. Colonoscopy volumes declined 79.4% in April 2020 compared with April 2019 but recovered to near pre-pandemic volumes in September through December, resulting in a 26.9% decline in total colonoscopies performed in 2020. The number of patients diagnosed by colonoscopy with CRC and advanced adenoma declined by 8.7% and 26.9%, respectively, in 2020 vs 2019. CONCLUSIONS: The pandemic led to fewer FIT screenings and colonoscopies in 2020 vs 2019; however, after the lifting of shelter-in-place orders, FIT screenings exceeded, and colonoscopy volumes nearly reached numbers from those same months in 2019. Overall, there was an 8.7% reduction in CRC cases diagnosed by colonoscopy in 2020. These data may help inform the development of strategies for CRC screening and diagnostic testing during future national emergencies.

Risk-Stratified Screening for Colorectal Cancer Using Genetic and Environmental Risk Factors: A Cost-Effectiveness Analysis Based on Real-World Data.

BACKGROUND & AIMS: Previous studies on the cost-effectiveness of personalized colorectal cancer (CRC) screening were based on hypothetical performance of CRC risk prediction and did not consider the association with competing causes of death. In this study, we estimated the cost-effectiveness of risk-stratified screening using real-world data for CRC risk and competing causes of death. METHODS: Risk predictions for CRC and competing causes of death from a large community-based cohort were used to stratify individuals into risk groups. A microsimulation model was used to optimize colonoscopy screening for each risk group by varying the start age (40-60 years), end age (70-85 years), and screening interval (5-15 years). The outcomes included personalized screening ages and intervals and cost-effectiveness compared with uniform colonoscopy screening (ages 45-75, every 10 years). Key assumptions were varied in sensitivity analyses. RESULTS: Risk-stratified screening resulted in substantially different screening recommendations, ranging from a one-time colonoscopy at age 60 for low-risk individuals to a colonoscopy every 5 years from ages 40 to 85 for high-risk individuals. Nevertheless, on a population level, risk-stratified screening would increase net quality-adjusted life years gained (QALYG) by only 0.7% at equal costs to uniform screening or reduce average costs by 1.2% for equal QALYG. The benefit of risk-stratified screening improved when it was assumed to increase participation or costs less per genetic test. CONCLUSIONS: Personalized screening for CRC, accounting for competing causes of death risk, could result in highly tailored individual screening programs. However, average improvements across the population in QALYG and cost-effectiveness compared with uniform screening are small.

Impact of a scalable training program on the quality of colonoscopy performance and risk of postcolonoscopy colorectal cancer.

BACKGROUND AND AIMS: Endoscopist adenoma detection rates (ADRs) vary widely and are associated with patients' risk of postcolonoscopy colorectal cancers (PCCRCs). However, few scalable physician-directed interventions demonstrably both improve ADR and reduce PCCRC risk. METHODS: Among patients undergoing colonoscopy, we evaluated the influence of a scalable online training on individual-level ADRs and PCCRC risk. The intervention was a 30-minute, interactive, online training, developed using behavior change theory, to address factors that potentially impede detection of adenomas. Analyses included interrupted time series analyses for pretraining versus posttraining individual-physician ADR changes (adjusted for temporal trends) and Cox regression for associations between ADR changes and patients' PCCRC risk. RESULTS: Across 21 endoscopy centers and all 86 eligible endoscopists, ADRs increased immediately by an absolute 3.13% (95% confidence interval [CI], 1.31-4.94) in the 3-month quarter after training compared with .58% per quarter (95% CI, .40-.77) and 0.33% per quarter (95% CI, .16-.49) in the 3-year pretraining and posttraining periods, respectively. Posttraining ADR increases were higher among endoscopists with pretraining ADRs below the median. Among 146,786 posttraining colonoscopies (all indications), each 1% absolute increase in screening ADR posttraining was associated with a 4% decrease in their patients' PCCRC risk (hazard ratio, .96; 95% CI, .93-.99). An ADR increase of ≥10% versus <1% was associated with a 55% reduced risk of PCCRC (hazard ratio, .45; 95% CI, .24-.82). CONCLUSIONS: A scalable, online behavior change training intervention focused on modifiable factors was associated with significant and sustained improvements in ADR, particularly among endoscopists with lower ADRs. These ADR changes were associated with substantial reductions in their patients' risk of PCCRC.

Evaluation of Harms Reporting in U.S. Cancer Screening Guidelines.

BACKGROUND: Cancer screening should be recommended only when the balance between benefits and harms is favorable. This review evaluated how U.S. cancer screening guidelines reported harms, within and across organ-specific processes to screen for cancer. OBJECTIVE: To describe current reporting practices and identify opportunities for improvement. DESIGN: Review of guidelines. SETTING: United States. PATIENTS: Patients eligible for screening for breast, cervical, colorectal, lung, or prostate cancer according to U.S. guidelines. MEASUREMENTS: Information was abstracted on reporting of patient-level harms associated with screening, diagnostic follow-up, and treatment. The authors classified harms reporting as not mentioned, conceptual, qualitative, or quantitative and noted whether literature was cited when harms were described. Frequency of harms reporting was summarized by organ type. RESULTS: Harms reporting was inconsistent across organ types and at each step of the cancer screening process. Guidelines did not report all harms for any specific organ type or for any category of harm across organ types. The most complete harms reporting was for prostate cancer screening guidelines and the least complete for colorectal cancer screening guidelines. Conceptualization of harms and use of quantitative evidence also differed by organ type. LIMITATIONS: This review considers only patient-level harms. The authors did not verify accuracy of harms information presented in the guidelines. CONCLUSION: The review identified opportunities for improving conceptualization, assessment, and reporting of screening process-related harms in guidelines. Future work should consider nuances associated with each organ-specific process to screen for cancer, including which harms are most salient and where evidence gaps exist, and explicitly explore how to optimally weigh available evidence in determining net screening benefit. Improved harms reporting could aid informed decision making, ultimately improving cancer screening delivery. PRIMARY FUNDING SOURCE: National Cancer Institute.

Provider- and Facility-Level Variation in Precancerous Cervical Biopsy Diagnoses.

OBJECTIVES: Reproducibility of cervical biopsy diagnoses is low and may vary based on where the diagnostic test is performed and by whom. Our objective was to measure multilevel variation in diagnoses across colposcopists, pathologists, and laboratory facilities. METHODS: We cross-sectionally examined variation in cervical biopsy diagnoses within the 5 sites of the Population-Based Research Optimizing Screening through Personalized Regimens (PROSPR I) consortium within levels defined by colposcopists, pathologists, and laboratory facilities. Patients aged 18 to 65 years with a colposcopy with biopsy performed were included, with diagnoses categorized as normal, cervical intraepithelial neoplasia grade 1 (CIN1), grade 2 (CIN2), and grade 3 (CIN3). Using Markov Chain Monte-Carlo methods, we fit mixed-effects logistic regression models for biopsy diagnoses and presented median odds ratios (MORs), which reflect the variability within each level. Median odds ratios can be interpreted as the average increased odds a patient would have for a given outcome (e.g., CIN2 or CIN3 vs normal or CIN1) when switching to a provider with higher odds of diagnosing that outcome. The MOR is always 1 or greater, and a value of 1 indicates no variation in outcome for that level, with higher values indicating greater variation. RESULTS: A total of 130,110 patients were included who received care across 82 laboratory facilities, 2,620 colposcopists, and 489 pathologists. Substantial variation in biopsy diagnoses was found at each level, with the most occurring between laboratory facilities, followed by pathologists and colposcopists. Substantial variation in biopsy diagnoses of CIN2 or CIN3 (vs normal or CIN1) was present between laboratory facilities (MOR: 1.26; 95% credible interval = 1.19-1.36). CONCLUSIONS: Improving consistency in cervical biopsy diagnoses is needed to reduce underdiagnosis, overdiagnosis, and unnecessary treatment resulting from variation in cervical biopsy diagnoses.

Program Components and Results From an Organized Colorectal Cancer Screening Program Using Annual Fecal Immunochemical Testing.

BACKGROUND AND AIMS: Programmatic colorectal cancer (CRC) screening increases uptake, but the design and resources utilized for such models are not well known. We characterized program components and participation at each step in a large program that used mailed fecal immunochemical testing (FIT) with opportunistic colonoscopy. METHODS: Mixed-methods with site visits and retrospective cohort analysis of 51-75-year-old adults during 2017 in the Kaiser Permanente Northern California integrated health system. RESULTS: Among 1,023,415 screening-eligible individuals, 405,963 (40%) were up to date with screening at baseline, and 507,401 of the 617,452 not up-to-date were mailed a FIT kit. Of the entire cohort (n = 1,023,415), 206,481 (20%) completed FIT within 28 days of mailing, another 61,644 (6%) after a robocall at week 4, and 40,438 others (4%) after a mailed reminder letter at week 6. There were over 800,000 medical record screening alerts generated and about 295,000 FIT kits distributed during patient office visits. About 100,000 FIT kits were ordered during direct-to-patient calls by medical assistants and 111,377 people (11%) completed FIT outside of the automated outreach period. Another 13,560 (1.3%) completed a colonoscopy, sigmoidoscopy, or fecal occult blood test unrelated to FIT. Cumulatively, 839,463 (82%) of those eligible were up to date with screening at the end of the year and 12,091 of 14,450 patients (83.7%) with positive FIT had diagnostic colonoscopy. CONCLUSIONS: The >82% screening participation achieved in this program resulted from a combination of prior endoscopy (40%), large initial response to mailed FIT kits (20%), followed by smaller responses to automated reminders (10%) and personal contact (12%).

Assessment of genetic susceptibility to multiple primary cancers through whole-exome sequencing in two large multi-ancestry studies.

BACKGROUND: Up to one of every six individuals diagnosed with one cancer will be diagnosed with a second primary cancer in their lifetime. Genetic factors contributing to the development of multiple primary cancers, beyond known cancer syndromes, have been underexplored. METHODS: To characterize genetic susceptibility to multiple cancers, we conducted a pan-cancer, whole-exome sequencing study of individuals drawn from two large multi-ancestry populations (6429 cases, 165,853 controls). We created two groupings of individuals diagnosed with multiple primary cancers: (1) an overall combined set with at least two cancers across any of 36 organ sites and (2) cancer-specific sets defined by an index cancer at one of 16 organ sites with at least 50 cases from each study population. We then investigated whether variants identified from exome sequencing were associated with these sets of multiple cancer cases in comparison to individuals with one and, separately, no cancers. RESULTS: We identified 22 variant-phenotype associations, 10 of which have not been previously discovered and were significantly overrepresented among individuals with multiple cancers, compared to those with a single cancer. CONCLUSIONS: Overall, we describe variants and genes that may play a fundamental role in the development of multiple primary cancers and improve our understanding of shared mechanisms underlying carcinogenesis.

The association of bowel function, participation in life activities, and quality of life in rectal cancer survivors.

PURPOSE: To evaluate whether limited participation in life activities is associated with quality of life (QOL) in rectal cancer survivors, and if so, whether this association is independent of bowel function difficulties. METHODS: We surveyed rectal cancer survivors from four healthcare systems about their QOL, bowel function, and participation in life activities. Additional demographic and clinical variables were extracted from the electronic health record. We examined independent associations between bowel function, participation in life activities, and QOL, controlling for potential confounders. We also identified factors, including ostomy status, that correlate with participation in life activities. RESULTS: Of the 527 respondents, 52% were male, 80% were non-Hispanic white, and the mean age was 63. In fully adjusted models for all rectal cancer survivors, participation in life activities was positively associated with QOL, while bowel function was not. Bowel function retained an independent association with QOL for those who previously had an ostomy and were therefore more likely to have a low rectal anastomosis. Lower participation in life activities was correlated with lower self-reported physical and cognitive function, younger age, financial difficulty, and being non-Hispanic white. CONCLUSIONS: Rectal cancer survivors' participation in life activities was strongly associated with QOL, even when controlling for numerous confounders, including bowel function. Identifying ways to improve participation in life activities may be critical to developing rehabilitative and other supportive interventions that optimize QOL among rectal cancer survivors.

Association of Physician Adenoma Detection Rates With Postcolonoscopy Colorectal Cancer.

Importance: Although colonoscopy is frequently performed in the United States, there is limited evidence to support threshold values for physician adenoma detection rate as a quality metric. Objective: To evaluate the association between physician adenoma detection rate values and risks of postcolonoscopy colorectal cancer and related deaths. Design, Setting, and Participants: Retrospective cohort study in 3 large integrated health care systems (Kaiser Permanente Northern California, Kaiser Permanente Southern California, and Kaiser Permanente Washington) with 43 endoscopy centers, 383 eligible physicians, and 735 396 patients aged 50 to 75 years who received a colonoscopy that did not detect cancer (negative colonoscopy) between January 2011 and June 2017, with patient follow-up through December 2017. Exposures: The adenoma detection rate of each patient's physician based on screening examinations in the calendar year prior to the patient's negative colonoscopy. Adenoma detection rate was defined as a continuous variable in statistical analyses and was also dichotomized as at or above vs below the median for descriptive analyses. Main Outcomes and Measures: The primary outcome (postcolonoscopy colorectal cancer) was tumor registry-verified colorectal adenocarcinoma diagnosed at least 6 months after any negative colonoscopy (all indications). The secondary outcomes included death from postcolonoscopy colorectal cancer. Results: Among 735 396 patients who had 852 624 negative colonoscopies, 440 352 (51.6%) were performed on female patients, median patient age was 61.4 years (IQR, 55.5-67.2 years), median follow-up per patient was 3.25 years (IQR, 1.56-5.01 years), and there were 619 postcolonoscopy colorectal cancers and 36 related deaths during more than 2.4 million person-years of follow-up. The patients of physicians with higher adenoma detection rates had significantly lower risks for postcolonoscopy colorectal cancer (hazard ratio [HR], 0.97 per 1% absolute adenoma detection rate increase [95% CI, 0.96-0.98]) and death from postcolonoscopy colorectal cancer (HR, 0.95 per 1% absolute adenoma detection rate increase [95% CI, 0.92-0.99]) across a broad range of adenoma detection rate values, with no interaction by sex (P value for interaction = .18). Compared with adenoma detection rates below the median of 28.3%, detection rates at or above the median were significantly associated with a lower risk of postcolonoscopy colorectal cancer (1.79 vs 3.10 cases per 10 000 person-years; absolute difference in 7-year risk, -12.2 per 10 000 negative colonoscopies [95% CI, -10.3 to -13.4]; HR, 0.61 [95% CI, 0.52-0.73]) and related deaths (0.05 vs 0.22 cases per 10 000 person-years; absolute difference in 7-year risk, -1.2 per 10 000 negative colonoscopies [95%, CI, -0.80 to -1.69]; HR, 0.26 [95% CI, 0.11-0.65]). Conclusions and Relevance: Within 3 large community-based settings, colonoscopies by physicians with higher adenoma detection rates were significantly associated with lower risks of postcolonoscopy colorectal cancer across a broad range of adenoma detection rate values. These findings may help inform recommended targets for colonoscopy quality measures.

Risk stratification for colorectal cancer in individuals with subtypes of serrated polyps.

OBJECTIVE: The longitudinal risk of colorectal cancer (CRC) associated with subtypes of serrated polyps (SPs) remains incompletely understood. DESIGN: This community-based, case-control study included 317 178 Kaiser Permanente Northern California members who underwent their first colonoscopy during 2006-2016. Nested within this population, we identified 695 cases of CRC and 3475 CRC-free controls (matched 5:1 to cases for age, sex and year of colonoscopy). Two expert pathologists reviewed the tissue slides of all SPs identified on the first colonoscopy and reclassified them to sessile serrated lesions (SSLs), hyperplastic polyps (HPs) and traditional serrated adenomas. SPs with borderline characteristics of SSLs but insufficient to make a definitive diagnosis were categorised as unspecified SPs. The association with development of CRC was assessed using multivariable logistic regression. RESULTS: Compared with individuals with no polyp, the adjusted ORs (aORs) for SSL alone or with synchronous adenoma were 2.9 (95% CI: 1.8 to 4.8) and 4.4 (95% CI: 2.7 to 7.2), respectively. The aORs for SSL with dysplasia, large proximal SSL,and small proximal SSL were 10.3 (95% CI: 2.1 to 50.3), 12.8 (95% CI: 3.5 to 46.9) and 1.9 (95% CI: 0.8 to 4.7), respectively. Proximal unspecified SP also conferred an increased risk (aOR: 5.8, 95% CI: 2.2 to 15.2). Women with SSL were associated with higher risk (aOR: 4.4; 95% CI: 2.3 to 8.2) than men (aOR: 1.7; 95% CI: 0.8 to 3.8). CONCLUSION: Increased risk of CRC was observed in individuals with SSLs, particularly large proximal ones or with dysplasia, supporting close endoscopic surveillance. Proximal unspecified SPs were also associated with increased risk of CRC and should be managed as SSLs.