•Comorbidity and frailty are strong prognostic factors of survival in CRC patients.•The effect of comorbidity on CRC prognosis appears to decrease with cancer stage.•Comprehensive geriatric ...assessment might help to optimize care of CRC patients.•More large prospective studies providing stage-specific analysis are warranted.
Colorectal cancer (CRC) is largely diagnosed at old age, when comorbidities and frailty are common and might be important prognostic factors of CRC. We aimed to systematically review epidemiological evidence on the prognostic role of comorbidity and frailty in CRC patients.
We systematically searched the PubMed and Web of Science databases up to August 08, 2017 for observational studies that used a standardized index to assess comorbidity or frailty, investigated and reported odds ratios (OR) or hazard ratios (HR) of their associations with any of the following CRC prognostic outcomes: thirty-day, overall or CRC-specific mortality and disease-free or recurrence-free survival. The study was conducted using standard meta-analysis methodology.
Thirty-seven cohort studies were identified and included in this review: 35 on comorbidity and 2 on frailty. Of the 35 studies, 13 with comparable methodology were eligible for a meta-analysis. Compared to CRC patients without comorbidity, those with mild/moderate and severe comorbidity had, respectively, a higher risk of 30-day (OR = 1.71; 95% confidence interval (CI): 1.26–2.31 and OR = 2.62; 95% CI: 1.97–3.47), overall (HR = 1.41; 95% CI: 1.23–1.62 and HR = 2.03; 95% CI: 1.76–2.34), and CRC-specific mortality (HR = 1.06; 95% CI: 1.02–1.10 and HR = 1.14; 95% CI: 1.04–1.23). Frail CRC patients showed higher overall mortality than non-frail patients (HRrange: 2.60–3.39).
Comorbidity and frailty are strong prognostic factors of survival in CRC patients apart from the commonly considered sociodemographic and tumor characteristics. Comprehensive geriatric assessment might help to optimize care of CRC patients, by improving early identification and management of comorbidities and geriatric syndromes.
Microsatellite instability determines whether patients with gastrointestinal cancer respond exceptionally well to immunotherapy. However, in clinical practice, not every patient is tested for MSI, ...because this requires additional genetic or immunohistochemical tests. Here we show that deep residual learning can predict MSI directly from H&E histology, which is ubiquitously available. This approach has the potential to provide immunotherapy to a much broader subset of patients with gastrointestinal cancer.
Screening colonoscopy was introduced in Germany in October 2002. We aimed to quantify its effects on prevention, early detection, and overdiagnosis of colorectal cancer (CRC) in the 10 years since ...its introduction.
We analyzed data from more than 4.4 million screening colonoscopies (conducted on individuals 55-79 years old from 2003 through 2012) available through the national screening colonoscopy registry. CRCs prevented, detected earlier than they would have been without screening, and overdiagnosed (cancers detected at screening colonoscopy that would not have become clinically manifest during the patient's lifetime) were estimated by Markov models. Model parameters included sex-specific and age-specific findings at screening colonoscopy; mortality; rates of transition from nonadvanced to advanced adenoma, advanced adenoma to preclinical cancer, or preclinical cancer to clinically manifest cancer; and protection from screening colonoscopy.
Overall, approximately 180,000 CRCs (1/28 screening colonoscopies) were estimated to have been prevented, and more than 40,000 CRCs (1/121 screening colonoscopies) were detected earlier than they would have been without screening, compared with approximately 4500 overdiagnoses (1/1089 screening colonoscopies). Almost all CRCs prevented or detected earlier than they would have been without screening resulted from screening colonoscopies performed on individuals up to 75 years old (97% and 89%, respectively), whereas 28% of overdiagnoses occurred from screening colonoscopies of individuals older than 75 years old.
On the basis of a 10-year analysis of data from a national registry in Germany, screening colonoscopies have large potential for prevention and early detection of CRC, with low risk of overdiagnosis.
For virtually every patient with colorectal cancer (CRC), hematoxylin-eosin (HE)-stained tissue slides are available. These images contain quantitative information, which is not routinely used to ...objectively extract prognostic biomarkers. In the present study, we investigated whether deep convolutional neural networks (CNNs) can extract prognosticators directly from these widely available images.
We hand-delineated single-tissue regions in 86 CRC tissue slides, yielding more than 100,000 HE image patches, and used these to train a CNN by transfer learning, reaching a nine-class accuracy of >94% in an independent data set of 7,180 images from 25 CRC patients. With this tool, we performed automated tissue decomposition of representative multitissue HE images from 862 HE slides in 500 stage I-IV CRC patients in the The Cancer Genome Atlas (TCGA) cohort, a large international multicenter collection of CRC tissue. Based on the output neuron activations in the CNN, we calculated a "deep stroma score," which was an independent prognostic factor for overall survival (OS) in a multivariable Cox proportional hazard model (hazard ratio HR with 95% confidence interval CI: 1.99 1.27-3.12, p = 0.0028), while in the same cohort, manual quantification of stromal areas and a gene expression signature of cancer-associated fibroblasts (CAFs) were only prognostic in specific tumor stages. We validated these findings in an independent cohort of 409 stage I-IV CRC patients from the "Darmkrebs: Chancen der Verhütung durch Screening" (DACHS) study who were recruited between 2003 and 2007 in multiple institutions in Germany. Again, the score was an independent prognostic factor for OS (HR 1.63 1.14-2.33, p = 0.008), CRC-specific OS (HR 2.29 1.5-3.48, p = 0.0004), and relapse-free survival (RFS; HR 1.92 1.34-2.76, p = 0.0004). A prospective validation is required before this biomarker can be implemented in clinical workflows.
In our retrospective study, we show that a CNN can assess the human tumor microenvironment and predict prognosis directly from histopathological images.
Screening the population for colorectal cancer (CRC) by colonoscopy could reduce the disease burden. However, targeted screening of individuals at high risk could increase its cost effectiveness.
We ...developed a scoring system to identify individuals with at least 1 advanced adenoma, based on easy-to-collect risk factors among 7891 participants of the German screening colonoscopy program. The system was validated in an independent sample of 3519 participants. Multiple logistic regression was used to develop the algorithm, and the regression coefficient-based scores were used to determine individual risks. Relative risk and numbers of colonoscopies needed for detecting one or more advanced neoplasm(s) were calculated for quintiles of the risk score. The predictive ability of the scoring system was quantified by the area under the curve.
We identified 9 risk factors (sex, age, first-degree relatives with a history of CRC, cigarette smoking, alcohol consumption, red meat consumption, ever regular use at least 2 times/wk for at least 1 y of nonsteroidal anti-inflammatory drugs, previous colonoscopy, and previous detection of polyps) that were associated significantly with risk of advanced neoplasms. The developed score was associated strongly with the presence of advanced neoplasms. In the validation sample, individuals in the highest quintile of scores had a relative risk for advanced neoplasm of 3.86 (95% confidence interval, 2.71-5.49), compared with individuals in the lowest quintile. The number needed to screen to detect 1 or more advanced neoplasm(s) varied from 20 to 5 between quintiles of the risk score. In the validation sample, the scoring system identified patients with CRC or any advanced neoplasm with area under the curve values of 0.68 and 0.66, respectively.
We developed a scoring system, based on easy-to-collect risk factors, to identify individuals most likely to have advanced neoplasms. This system might be used to stratify individuals for CRC screening.
Background & Aims Data from randomized controlled trials on the effects of screening colonoscopies on colorectal cancer (CRC) incidence and mortality are not available. Observational studies have ...suggested that colonoscopies strongly reduce the risk of CRC, but there is little specific evidence on the effects of screening colonoscopies. Methods We performed a population-based case-control study of 3148 patients with a first diagnosis of CRC (cases) and 3274 subjects without CRC (controls) from the Rhine-Neckar region of Germany from 2003 to 2010. Detailed information on previous colonoscopy and potential confounding factors was collected by standardized personal interviews. Self-reported information on colonoscopies and their indications was validated by medical records. We used multiple logistic regression to assess the association between colonoscopy conducted for specific indications within the past 10 years and risk of CRC. Results A history of colonoscopy was associated with a reduced subsequent risk of CRC, independently of the indication for the examination. However, somewhat stronger associations were found for examinations with screening indications (adjusted odds ratio OR 0.09, 95% confidence interval CI 0.07–0.13) than for examinations with diagnostic indications, such as positive fecal occult blood test result (OR, 0.33; 95% CI, 0.19–0.57), surveillance after a preceding colonoscopy (OR, 0.33; 95% CI, 0.24–0.45), rectal bleeding (OR, 0.28; 95% CI, 0.20–0.40), abdominal symptoms (OR, 0.15; 95% CI, 0.10–0.21), or other (OR, 0.21; 95% CI, 0.14–0.30). Colonoscopy was also associated with a reduced risk of cancer in the right colon, regardless of the indication, although to a smaller extent than for other areas of the colon (OR for screening colonoscopy, 0.22; 95% CI, 0.14–0.33). Conclusions In a population-based case-control study, the risk of CRC was strongly reduced up to 10 years after colonoscopy for any indication. Risk was particularly low after screening colonoscopy, even for cancer in the right colon.
Many risk scores have been proposed to predict presence of advanced colorectal neoplasms, but a comprehensive comparison conducted in the same population is sparse. The aim of this study was to ...evaluate and directly compare the diagnostic performance of published risk prediction models for advanced colorectal neoplasms.
Data were drawn from 2 cohorts of subjects undergoing screening colonoscopy in Germany, i.e., KolosSal (n = 16,195) and BliTz (n = 7,444). Absolute risks and relative risks were generated for the presence of at least 1 advanced neoplasm, taking the lowest risk group as the reference group. Performance of risk models was assessed by the area under the receiver operating characteristic curve (AUC) and compared by the net reclassification improvement.
The 2 cohorts included 1,917 (11.8%) and 848 (11.4%) participants with advanced neoplasm, respectively. Absolute risks were mostly between 5% and 10% among participants in the lowest risk group and between 15% and 20% among participants in the highest risk group, and relative risks mostly ranged from 2.0 to 4.0 across the risk models in both cohorts. The AUCs ranged from 0.58 to 0.65 in KolosSal and from 0.57 to 0.61 in BliTz for all risk scores. Compared to models with lower AUC, classification was significantly improved in most models with higher AUC.
Risk models for advanced colorectal neoplasms generally yielded modest discriminatory power, despite some variation in performance between models. Future studies should evaluate the performance of these risk models in racially diverse populations and investigate possible extensions, such as combination with polygenic risk scores.
Background The current organized screening program for colorectal cancer in Germany offers both sexes 5 annual fecal immunochemical tests (FITs) between ages 50 and 54 years, followed by a first ...screening colonoscopy at age 55 years if all of these FITs were negative. We sought to assess the implications of this approach for key parameters of diagnostic performance. Methods and findings Using a multistate Markov model, we estimated the expected detection rates of advanced neoplasms (advanced adenomas and cancers) and number needed to scope (NNS) to detect 1 advanced neoplasm at a first screening colonoscopy conducted at age 55 after 5 preceding negative FITs and compared them with the corresponding estimates for a first screening colonoscopy at age 55 with no preceding FIT testing. In individuals with 5 consecutive negative FITs undergoing screening colonoscopy at age 55, expected colonoscopy detection rate (NNS) was 3.7% (27) and 0.10% (1,021) for any advanced neoplasm and cancer, respectively, in men, and 2.1% (47) and 0.05% (1,880) for any advanced neoplasm and cancer, respectively, in women. These NNS values for detecting 1 advanced neoplasm are approximately 3-fold higher, and the NNS values for detecting 1 cancer are approximately 8-fold higher, than those for a first screening colonoscopy at age 55 without prior FITs. This study is limited by model simplifying assumptions and uncertainties related to input parameters. Conclusions Screening colonoscopy at age 55 after 5 consecutive negative FITs at ages 50-54, as currently offered in the German cancer early detection program, is expected to have very low positive predictive value. Our results may inform efforts to enhance the design of screening programs.
Microsatellite instability (MSI) and mismatch-repair deficiency (dMMR) in colorectal tumors are used to select treatment for patients. Deep learning can detect MSI and dMMR in tumor samples on ...routine histology slides faster and less expensively than molecular assays. However, clinical application of this technology requires high performance and multisite validation, which have not yet been performed.
We collected H&E-stained slides and findings from molecular analyses for MSI and dMMR from 8836 colorectal tumors (of all stages) included in the MSIDETECT consortium study, from Germany, the Netherlands, the United Kingdom, and the United States. Specimens with dMMR were identified by immunohistochemistry analyses of tissue microarrays for loss of MLH1, MSH2, MSH6, and/or PMS2. Specimens with MSI were identified by genetic analyses. We trained a deep-learning detector to identify samples with MSI from these slides; performance was assessed by cross-validation (N = 6406 specimens) and validated in an external cohort (n = 771 specimens). Prespecified endpoints were area under the receiver operating characteristic (AUROC) curve and area under the precision-recall curve (AUPRC).
The deep-learning detector identified specimens with dMMR or MSI with a mean AUROC curve of 0.92 (lower bound, 0.91; upper bound, 0.93) and an AUPRC of 0.63 (range, 0.59–0.65), or 67% specificity and 95% sensitivity, in the cross-validation development cohort. In the validation cohort, the classifier identified samples with dMMR with an AUROC of 0.95 (range, 0.92–0.96) without image preprocessing and an AUROC of 0.96 (range, 0.93–0.98) after color normalization.
We developed a deep-learning system that detects colorectal cancer specimens with dMMR or MSI using H&E-stained slides; it detected tissues with dMMR with an AUROC of 0.96 in a large, international validation cohort. This system might be used for high-throughput, low-cost evaluation of colorectal tissue specimens.
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In the past two decades, an extensive rollout of colorectal cancer (CRC) screening programmes has been initiated in European countries with a large heterogeneity of screening offers. Using data from ...a population-based cross-sectional survey conducted between 2013 and 2016 in all European Union countries, we analysed the utilisation of faecal tests and colonoscopy among people aged 50–74 years and the factors associated with uptake by type of screening offer. We observed the highest utilisation of either test for countries with fully rolled out organised programmes with faecal tests (ranging from 29.7% in Croatia to 66.7% in the UK) and countries offering both faecal tests and colonoscopy (from 22.7% in Greece to 70.9% in Germany). Utilisation was very low for countries with no programme (from 6.3% in Romania to 30.5% in Norway). Younger age (50–54 years), longer time since last consultation with a doctor and a lifestyle score associated with increased CRC risk were significantly associated with lower test use, a pattern observed across all types of screening offers. Our results suggest that more countries should implement organised programmes with faecal immunochemical tests, in combination with alternative endoscopy offers where resources allow. Furthermore, there is a large potential for increasing screening use in Europe by better reaching the younger eligible individuals, those who have not been to the doctor recently and those at increased risk for CRC.
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