The influence of BRAF and KRAS mutation status on the association between aspirin use and survival after colon cancer diagnosis

Background: Use of aspirin after diagnosis of colon cancer has been associated with improved survival. Identification of cancer subtypes that respond to aspirin treatment may help develop personalized treatment regimens. The aim of this study was to investigate the influence of BRAF and KRAS mutation status on the association between aspirin use and overall survival after colon cancer diagnosis. Methods: A random selection of 599 patients with colon cancer were analyzed, selected from the Eindhoven Cancer Registry, and BRAF and KRAS mutation status was determined. Data on aspirin use (80 mg) were obtained from the PHARMO Database Network. Parametric survival models with exponential (Poisson) distribution were used. Results: Aspirin use after colon cancer diagnosis was associated with improved overall survival in wild-type BRAF tumors, adjusted rate ratio (RR) of 0.60 (95% CI 0.44-0.83). In contrast, aspirin use in BRAF mutated tumors was not associated with an improved survival (RR 1.11, 95% CI 0.57-2.16). P-value for interaction was non-significant. KRAS mutational status did not differentiate in the association between aspirin use and survival. Conclusion: Low-dose aspirin use after colon cancer diagnosis was associated with improved survival in BRAF wild-type tumors only. However, the large confidence interval of the rate ratio for the use of aspirin in patients with BRAF mutation does not rule out a possible benefit. These results preclude BRAF and KRAS mutation status to be used as a marker for individualized treatment with aspirin, if aspirin becomes regular adjuvant treatment for colon cancer patients in the future

Nationwide comprehensive gastro-intestinal cancer cohorts: the 3P initiative

Background: The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients. Material and methods: All patients aged ≥18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future. Results: In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing. Conclusion: A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies can be performed in an efficient, safe, and comprehensive setting

Socioeconomic status and changing inequalities in colorectal cancer? A review of the associations with risk, treatment and outcome

BACKGROUND: Upcoming mass screening for colorectal cancer (CRC) makes a review of recent literature on the association with socioeconomic status (SES) relevant, because of marked and contradictory associations with risk, treatment and outcome. METHODS: The Pubmed database using the MeSH terms 'Neoplasms' or 'Colorectal Neoplasms' and 'Socioeconomic Factors' for articles added between 1995 and 1st October 2009 led to 62 articles. RESULTS: Low SES groups exhibited a higher incidence compared with high SES groups in the US and Canada (range risk ratio (RR) 1.0-1.5), but mostly lower in Europe (RR 0.3-0.9). Treatment, survival and mortality all showed less favourable results for people with a lower socioeconomic status: Patients with a low SES received less often (neo)adjuvant therapy (RR ranging from 0.4 to 0.99), had worse survival rates (hazard ratio (HR) 1.3-1.8) and exhibited generally the highest mortality rates up to 1.6 for colon cancer in Europe and up to 3.1 for rectal cancer. CONCLUSIONS: A quite consistent trend was observed favouring individuals with a high SES compared to those with a low SES that still remains in terms of treatment, survival and thus also mortality. We did not find evidence that the low/high SES gradients for treatment chosen and outcome are decreasing. To meet increasing inequalities in mortality from CRC in Europe for people with a low SES and to make mass screening successful, a high participation rate needs to be realised of low SES people in the soon starting screening progra

Evaluation of Guideline Adherence in Colorectal Cancer Treatment in The Netherlands: A Survey Among Medical Oncologists by the Dutch Colorectal Cancer Group

Clinical guidelines are generated to preserve high-quality evidence-based care. Data on the implementation of guidelines into clinical practice are scarce, despite that guideline adherence prevents over- and undertreatment and correlates with survival. Therefore, we investigated guideline adherence for the systemic treatment in high-risk stage II and stage III colon cancer and metastatic colorectal cancer. In all Dutch hospitals (n = 88) 1 medical oncologist involved in colorectal cancer care was approached to participate. An online survey was conducted regarding the local standard of care for adjuvant chemotherapy in high-risk stage II and stage III colon cancer and first-line treatment regimens in metastatic colorectal cancer. Frequency tables were provided for categorical variables and compared for differences in guideline adherence according to hospital type (academic/teaching/regional). The overall response rate was 70% (62 of 88). Reported guideline adherence was at least 60% of all presented settings. For high-risk stage II and stage III colon cancer, treatment strategies agreed with national guidelines in 66% and 84% of hospitals, and overtreatment patterns were identified in 28% and 13%, respectively. Targeted therapy was not routinely administered as first-line treatment in metastatic colorectal cancer (range from 63% to 71% in different settings). No differences in guideline adherence were observed among different hospital types. Guideline adherence as reported by medical oncologists in The Netherlands is suboptimal. Possible explanations include unawareness or disagreement with the guidelines, or local financial restrictions. Our results recommend additional support of guideline implementation and monitoring in clinical practice, and investigating underlying causes in case of nonadherenc

Practice Variation in the Adjuvant Treatment of Colon Cancer in the Netherlands: A Population-based Study

Background/Aim: Adjuvant chemotherapy is recommended for a subgroup of colon cancer patients based on patient and tumour characteristics. Population-based data on the adoption of the prevailing guideline recommendations including the assessment of tumour mismatch repair (MMR) status are limited, while variations in treatment strategies may influence patient outcomes. Therefore, the aim of the study was to assess practice variation in adjuvant chemotherapy administration in colon cancer patients. Patients and Methods: We examined the association between patient, demographic and tumour characteristics on the odds of being treated with adjuvant chemotherapy in a random sample of adult stage IIIII colon cancer patients from the Dutch National Cancer Registry (2008-2015) and assessed its association with survival. Results: The study population consisted of 2,044 patients of whom 18% (79 out of 450) were high-risk stage II and 65% (645 out of 997) were stage III colon cancer and received adjuvant chemotherapy. Chemotherapy administration differed between individual hospitals (high-risk stage II: 0-39%; p=0.01; stage III: 50-78%; p=0.06). Type of hospital (teaching versus academic) and the presence of a pT4 tumour were positively associated (high-risk stage II), and bowel perforation and examined regional lymph nodes (<10) were negatively associated (stage III) with adjuvant treatment. Higher age was associated with non-administration of adjuvant chemotherapy for both stages. Tumour MMR-status assessment increased from 9% to 23% (p<0.001), but 62% of high-risk stage II and 13% of stage III patients did not undergo guideline-recommended MMR-status testing. Adjuvant chemotherapy was correlated with survival for stage III (HR=0.4; 95%CI=0.3-0.5) but not for high-risk stage II patients (HR=1.2; 95%CI=0.7-2.2). Conclusion: Significant practice variation in the adjuvant treatment of colon cancer on hospital level was demonstrated, predominantly in high-risk stage II patients. The implementation of MMR testing was suboptimal. We recommend continuous monitoring of treatment patterns using population-based data, which should facilitate hospital auditing and improve guideline implementation and quality of care for colon cancer patients

Practice variation on hospital level in the systemic treatment of metastatic colorectal cancer in The Netherlands: a population-based study

Introduction: Population-based data on the implementation of guidelines for cancer patients in daily practice are scarce, while practice variation may influence patient outcomes. Therefore, we evaluated treatment patterns and associated variables in the systemic treatment of metastatic colorectal cancer (mCRC) in the Netherlands. Material and methods: We selected a random sample of adult mCRC patients diagnosed from 2008 to 2015 from the National Cancer Registry in 20 (4 academic, 8 teaching and 8 regional) Dutch hospitals. We examined the influence of patient, demographic and tumour characteristics on the odds of being treated with systemic therapy according to the current guideline and assessed its association with survival. Results: Our study population consisted of 2222 mCRC patients of whom 1307 patients received systemic therapy for mCRC. Practice variation was most obvious in the use of bevacizumab and anti-EGFR therapy in patients with (K)RAS wild-type tumours. Administration rates did not differ between hospital types but fluctuated between individual hospitals for bevacizumab (8–92%; p <.0001) and anti-EGFR therapy (10–75%; p =.05). Bevacizumab administration was inversely correlated to higher age (OR:0.2; 95%CI: 0.1–0.3) comorbidity (OR:0.6; 95%CI: 0.5–0.8) and the presence of metachronous metastases (OR:0.5; 95%CI: 0.3–0.7), but patient characteristics did not differ between hospitals with low or high bevacizumab administration rates. The hazard ratios for exposure to bevacizumab and anti-EGFR therapy were 0.8 (95%CI: 0.7–0.9) and 0.6 (95%CI: 0.5–0.8), respectively. Discussion: We identified significant inter-hospital variation in targeted therapy administration for mCRC patients, which may affect outcome. Age and comorbidity were inversely correlated with non-administration of bevacizumab but did not explain inter-hospital practice variation. Our data suggest that practice variation is based on individual strategy of hospitals rather than guideline recommendations or patient-driven decisions. Individual hospital strategies are an additional factor that may explain the observed differences between real-life data and results obtained from clinical trials

Evaluating the scientific basis of quality indicators in colorectal cancer care: A systematic review

In colorectal cancer care, many indicators for assessment and improvement of quality of care are being used. These quality indicators serve as national and international benchmarks to compare health care on hospital and patient level. However, the scientific basis of these indicators is often unclear. Therefore, the aim of this systematic review is to examine reported quality indicators used in multidisciplinary colorectal cancer care and categorise these indicators based on scientific evidence. We searched PubMed from 2005 to 2015 for original articles reporting on development, evaluation or validation of quality indicators in colorectal cancer care. Included articles were categorised in consensus-based, evidence-based and validation cohort studies. Extracted quality indicators were divided into structure, process and outcome indicators and grouped per discipline(s) involved. From 1163 studies, 41 articles were included: 12 (29%) consensus-based, 7 (17%) evidence-based and 22 (54%) validation cohort studies. In total, we identified 389 reported quality indicators: consensus-based (n = 349), evidence-based (n = 7) and validation (n = 33), respectively. Of all reported indicators, 45% (n = 186) concerned surgical items. The vast majority were process indicators (n = 315; 81%) and the remaining outcome (n = 57; 15%) or structure measurements (n = 17; 4%). Only 5 indicators were reported in the majority (≥7/12 articles) of consensus-based papers and 7 indicators were successfully validated. There is an abundance of reported colorectal cancer quality indicators, of which the majority are surgical, consensus-based process measures, which have not been validated in cohort studies. There is a need for international consensus on a limited evidence-based data set of validated quality indicators, with a focus on outcome indicator