Prognostic value of patient-reported quality of life for survival in oesophagogastric cancer: analysis from the population-based POCOP study.

BACKGROUND: Accumulating evidence of trials demonstrates that patient-reported health-related quality of life (HRQoL) at diagnosis is prognostic for overall survival (OS) in oesophagogastric cancer. However, real-world data are lacking. Moreover, differences in disease stages and tumour-specific symptoms are usually not taken into consideration. The aim of this population-based study was to assess the prognostic value of HRQoL, including tumour-specific scales, on OS in patients with potentially curable and advanced oesophagogastric cancer. METHODS: Data were derived from the Netherlands Cancer Registry and the patient reported outcome registry (POCOP). Patients included in POCOP between 2016 and 2018 were stratified for potentially curable (cT1-4aNallM0) or advanced (cT4b or cM1) disease. HRQoL was measured with the EORTC QLQ-C30 and the tumour-specific OG25 module. Cox proportional hazards models assessed the impact of HRQoL, sociodemographic and clinical factors (including treatment) on OS. RESULTS: In total, 924 patients were included. Median OS was 38.9 months in potentially curable patients (n = 795) and 10.6 months in patients with advanced disease (n = 129). Global Health Status was independently associated with OS in potentially curable patients (HR 0.89, 99%CI 0.82-0.97), together with several other HRQoL items: appetite loss, dysphagia, eating restrictions, odynophagia, and body image. In advanced disease, the Summary Score was the strongest independent prognostic factor (HR 0.75, 99%CI 0.59-0.94), followed by fatigue, pain, insomnia and role functioning. CONCLUSION: In a real-world setting, HRQoL was prognostic for OS in patients with potentially curable and advanced oesophagogastric cancer. Several HRQoL domains, including the Summary Score and several OG25 items, could be used to develop or update prognostic models.

Endoscopically removed rectal NETs: a nationwide cohort study.

PURPOSE: Rectal neuroendocrine tumours (NETs) often present as an incidental finding during colonoscopy. Complete endoscopic resection of low-grade NETs up to 10 mm is considered safe. Whether this is also safe for NETs up to 20 mm is unclear. We performed a nationwide study to determine the risk of lymph node and distant metastases in endoscopically removed NETs. METHODS: All endoscopically removed rectal NETs between 1990 and 2010 were identified using the national pathology database (PALGA). Each NET was stratified according to size, grade and resection margin. Follow-up was until February 2016. RESULTS: Between 1990 and 2010, a total of 310 NETs smaller than 20 mm were endoscopically removed. Mean size of NETs was 7.4 mm (SD 3.5). In 49% of NETs (n = 153), no grade (G) could be assessed from the pathology report, 1% was G2 (n = 3), and the remaining NETs were G1. Median follow up was 11.6 years (range 4.9-26.0). During follow-up, 30 patients underwent surgical resection. Lymph node or distant metastasis was seen in 3 patients (1%) which all had a grade 2 NET. Mean time from endoscopic resection to diagnosis of metastases was 6.1 years (95% CI 2.9-9.2). CONCLUSION: No lymph node or distant metastases were seen in endoscopically removed G1 NETs up to 20 mm during the long follow-up of this nationwide study. This adds evidence to the ENET guideline that endoscopic resection of G1 NETs up to 20 mm appears to be safe.

Improving clinical management of colon cancer through CONNECTION, a nation-wide colon cancer registry and stratification effort (CONNECTION II trial): rationale and protocol of a single arm intervention study.

BACKGROUND: It is estimated that around 15-30% of patients with early stage colon cancer benefit from adjuvant chemotherapy. We are currently not capable of upfront selection of patients who benefit from chemotherapy, which indicates the need for additional predictive markers for response to chemotherapy. It has been shown that the consensus molecular subtypes (CMSs), defined by RNA-profiling, have prognostic and/or predictive value. Due to postoperative timing of chemotherapy in current guidelines, tumor response to chemotherapy per CMS is not known, which makes the differentiation between the prognostic and predictive value impossible. Therefore, we propose to assess the tumor response per CMS in the neoadjuvant chemotherapy setting. This will provide us with clear data on the predictive value for chemotherapy response of the CMSs. METHODS: In this prospective, single arm, multicenter intervention study, 262 patients with resectable microsatellite stable cT3-4NxM0 colon cancer will be treated with two courses of neoadjuvant and two courses of adjuvant capecitabine and oxaliplatin. The primary endpoint is the pathological tumor response to neoadjuvant chemotherapy per CMS. Secondary endpoints are radiological tumor response, the prognostic value of these responses for recurrence free survival and overall survival and the differences in CMS classification of the same tumor before and after neoadjuvant chemotherapy. The study is scheduled to be performed in 8-10 Dutch hospitals. The first patient was included in February 2020. DISCUSSION: Patient selection for adjuvant chemotherapy in early stage colon cancer is far from optimal. The CMS classification is a promising new biomarker, but a solid chemotherapy response assessment per subtype is lacking. In this study we will investigate whether CMS classification can be of added value in clinical decision making by analyzing the predictive value for chemotherapy response. This study can provide the results necessary to proceed to future studies in which (neo) adjuvant chemotherapy may be withhold in patients with a specific CMS subtype, who show no benefit from chemotherapy and for whom possible new treatments can be investigated. TRIAL REGISTRATION: This study has been registered in the Netherlands Trial Register (NL8177) at 11-26-2019, https://www.trialregister.nl/trial/8177 . The study has been approved by the medical ethics committee Utrecht (MEC18/712).

Clinical value of ctDNA in upper-GI cancers: A systematic review and meta-analysis.

BACKGROUND: The recent expanding technical possibilities to detect tumor derived mutations in blood, so-called circulating tumor DNA (ctDNA), has rapidly increased the interest in liquid biopsies. This review and meta-analysis explores the clinical value of ctDNA in malignancies of the upper gastro-intestinal tract. METHODS: PubMed, Cochrane and Embase databases were searched to identify studies reporting the diagnostic, prognostic or predictive value of ctDNA in patients with esophageal, gastric and pancreatic cancer, until January 2017. The diagnostic accuracy and, using random-effect pair-wise meta-analyses, the prognostic value of ctDNA was assessed. RESULTS: A total of 34 studies met the inclusion criteria. For esophageal and gastric cancer, amplification of oncogenes in blood, such as HER2 and MYC, can be relevant for diagnostic purposes, and to predict treatment response in certain patient subpopulations. Given the limited number of studies assessing the role of ctDNA in esophageal and gastric cancer, the meta-analysis estimated the diagnostic accuracy and predictive value of ctDNA in pancreatic cancer only (n=10). The pooled sensitivity and specificity of ctDNA as a diagnostic tool in pancreatic cancer were 28% and 95%, respectively. Patients with pancreatic cancer and detectable ctDNA demonstrated a worse overall survival compared to patients with undetectable ctDNA (HR 1.92, 95% confidence interval (CI) 1.15-3.22, p=0.01). CONCLUSION: The presence of ctDNA is significantly associated with a poor prognosis in patients with pancreatic cancer. The use of ctDNA in clinical practice is promising, although standardization of sequencing techniques and further development of high-sensitive detection methods is needed.

Treatment and Outcome of Synchronous Colorectal Carcinomas: A Nationwide Study.

BACKGROUND: Synchronous colorectal carcinomas (CRC) occur in 1-8% of patients diagnosed with CRC. This study evaluated treatment patterns and patient outcomes in synchronous CRCs compared with solitary CRC patients. METHODS: All patients diagnosed with primary CRC between 2008 and 2013, who underwent elective surgery, were selected from the Netherlands Cancer Registry. Using multivariable regressions, the effects of synchronous CRC were assessed for both short-term outcomes (prolonged postoperative hospital admission, anastomotic leakage, postoperative 30-day mortality, administration of neoadjuvant or adjuvant treatment), and 5-year relative survival (RS). RESULTS: Of 41,060 CRC patients, 1969 patients (5%) had synchronous CRC. Patients with synchronous CRC were older (mean age 71 ± 10.6 vs. 69 ± 11.4 years), more often male (61 vs. 54%), and diagnosed with more advanced tumour stage (stage III-IV 54 vs. 49%) compared with solitary CRC (all p < 0.0001). In 50% of the synchronous CRCs, an extended surgery was conducted (n = 934). Synchronous CRCs with at least one stage II-III rectal tumour less likely received neoadjuvant (chemo)radiation [78 vs. 86%; adjusted OR 0.6 (0.48-0.84)], and synchronous CRCs with at least one stage III colon tumour less likely received adjuvant chemotherapy [49 vs. 63%; adjusted OR 0.7 (0.55-0.89)]. Synchronous CRCs were independently associated with decreased survival [RS 77 vs. 71%; adjusted RER 1.1 (1.01-1.23)]. CONCLUSIONS: The incidence of synchronous CRCs in the Dutch population is 5%. Synchronous CRCs were associated with decreased survival compared with solitary CRC. The results emphasize the importance of identifying synchronous tumours, preferably before surgery to provide optimal treatment.

A Nationwide Population-Based Study on the Survival of Patients with Pancreatic Neuroendocrine Tumors in The Netherlands.

BACKGROUND: Large population-based studies give insight into the prognosis and treatment outcomes of patients with pancreatic neuroendocrine tumors (pNETs). Therefore, we provide an overview of the treatment and related survival of pNET in the Netherlands. METHODS: Patients diagnosed with pNET between 2008 and 2013 from the Netherlands Cancer Registry were included. Patient, tumors and treatment characteristics were reported. Survival analyses with log-rank testing were performed to compare survival. RESULTS: In total, 611 patients were included. Median follow-up was 25.7 months, and all-cause mortality was 42%. Higher tumor grade and TNM stage were significantly associated with worse survival in both the overall and metastasized population. The effect of distant metastases on survival was more significant in lower tumor stages (T1-3 p < 0.05, T4 p = 0.074). Resection of the primary tumor was performed in 255 (42%) patients. Patients who underwent surgery had the highest 5-year survival (86%) compared to PRRT (33%), chemotherapy (21%), targeted therapy and somatostatin analogs (24%) (all p < 0.001). Patients with T1M0 tumors (n = 115) showed favorable survival after surgical resection (N = 95) compared to no therapy (N = 20, p = 0.008). Resection also improved survival significantly in patients with metastases compared to other treatments (all p > 0.05). Without surgery, PRRT showed the best survival curves in patients with distant metastases. Grade 3 tumors and surgical resection were independently associated with survival (HR 7.23 and 0.12, respectively). CONCLUSION: Surgical resection shows favorable outcome for all pNET tumors, including indolent tumors and tumors with distant metastases. Prospective trials should be initiated to confirm these results.

Treatment strategies in recurrent esophageal or junctional cancer.

Little evidence is available about survival rates in patients with recurrent disease after potentially curative surgery for esophageal or junctional cancer. Only in limited occasions, potentially curative salvage strategies are available. The aim of this study is to analyze survival rates and patterns of dissemination, and to identify independent prognostic factors in a consecutive series of patients who develop recurrent esophageal or junctional cancer. Between 1994 and 2015, patients who developed disease recurrence after neoadjuvant chemo(radio)therapy followed by radical esophagectomy for esophageal or junctional cancer were retrospectively analyzed. The Kaplan-Meier estimates were performed to calculate and compare overall survival between patients with different patterns of dissemination and to compare between different treatment strategies. Furthermore, univariate and multivariate Cox-regression analyses were performed to identify independent prognostic factors for post recurrence survival. In this study, we included 219 patients. The median overall survival of all included patients was 3.2 months (range: 0.0-101.1 months). The median overall survival in patients with exclusively locoregional recurrence (n = 23, 10.8%) was 4.9 months (range: 0.1- 55.6) and 2.9 months (range: 0.0-101.1) in patients who had distant metastases (n = 189, 89.2%), P = 0.003. Patients who received treatment aimed at complete tumor eradication (n = 28, 13.7%) had a median overall survival of 13.6 months (range: 1.1-101.1) and palliative treated patients (n = 94, 46.1%) of 4.7 months (range: 0.3-25.6), P < 0.001. In a selected group of patients survival of more than 20 months was achieved. Univariate and multivariate Cox-regression analysis showed that a higher age at the diagnosis of recurrent disease (hazard ratio: 1.087, P ≤ 0.001), an irradical resection of the primary tumor (hazard ratio: 3.355, P = < 0.001), the number of positive lymph nodes after neoadjuvant therapy (hazard ratios: ypN2 = 1.724 (P = 0.024) and ypN3 = 2.082 (P = 0.028) and the presence of a single hematogenous distant metastases (hazard ratio: 2.281, P = 0.003) or more than one hematogenous distant metastasis (hazard ratio: 2.385, P = 0.005) were associated with a shorter postrecurrence survival. The prognosis of patients who develop recurrent esophageal or junctional cancer is poor. In a selected group of patients however relatively long survival can be achieved. This offers new perspectives to improve treatment strategies and survival rates.

Optimal first-line chemotherapeutic treatment in patients with locally advanced or metastatic esophagogastric carcinoma: triplet versus doublet chemotherapy: a systematic literature review and meta-analysis.

There is a debate whether triplet or doublet chemotherapy should be used as a first-line treatment in patients with advanced or metastatic esophagogastric cancer. Therefore, here we will review the available literature to assess the efficacy and safety of triplet versus doublet chemotherapy as a first-line treatment in patients with advanced esophagogastric cancer. We searched MEDLINE, Embase, and CENTRAL (Cochrane Central Register of Controlled Trials) between 1980 and March 2015 for randomized controlled phase II and III trials comparing triplet with doublet chemotherapy and abstracts of major oncology meetings from 1990 to 2014. Twenty-one studies with a total of 3475 participants were included in the meta-analysis for overall survival. An improvement in overall survival (OS) (hazard ratio (HR) 0.90, 95% confidence interval (CI) 0.83-0.97) and progression-free survival (PFS) (HR 0.80, 95% CI 0.69-0.93) was observed in favor of triplet. In addition, the use of triplet was associated with better objective response rate (ORR) (risk ratio 1.25, 95% CI 1.09-1.44) compared to doublet. The risks of grade 3-4 thrombocytopenia (6.2 vs 3.8%), infection (10.2 vs 6.4%), and mucositis (9.7 vs 4.7%) were statistically significantly increased with triplet compared to doublet. This review shows that first-line triplet therapy is superior to doublet therapy in patients with advanced esophagogastric cancer. However, the survival benefit is limited and the risks of grade 3-4 thrombocytopenia, infection, and mucositis are increased.

Prospective Dutch colorectal cancer cohort: an infrastructure for long-term observational, prognostic, predictive and (randomized) intervention research.

BACKGROUND: Systematic evaluation and validation of new prognostic and predictive markers, technologies and interventions for colorectal cancer (CRC) is crucial for optimizing patients' outcomes. With only 5-15% of patients participating in clinical trials, generalizability of results is poor. Moreover, current trials often lack the capacity for post-hoc subgroup analyses. For this purpose, a large observational cohort study, serving as a multiple trial and biobanking facility, was set up by the Dutch Colorectal Cancer Group (DCCG). METHODS/DESIGN: The Prospective Dutch ColoRectal Cancer cohort is a prospective multidisciplinary nationwide observational cohort study in the Netherlands (yearly CRC incidence of 15 500). All CRC patients (stage I-IV) are eligible for inclusion, and longitudinal clinical data are registered. Patients give separate consent for the collection of blood and tumor tissue, filling out questionnaires, and broad randomization for studies according to the innovative cohort multiple randomized controlled trial design (cmRCT), serving as an alternative study design for the classic RCT. Objectives of the study include: 1) systematically collected long-term clinical data, patient-reported outcomes and biomaterials from daily CRC practice; and 2) to facilitate future basic, translational and clinical research including interventional and cost-effectiveness studies for both national and international research groups with short inclusion periods, even for studies with stringent inclusion criteria. RESULTS: Seven months after initiation 650 patients have been enrolled, eight centers participate, 15 centers await IRB approval and nine embedded cohort- or cmRCT-designed studies are currently recruiting patients. CONCLUSION: This cohort provides a unique multidisciplinary data, biobank, and patient-reported outcomes collection initiative, serving as an infrastructure for various kinds of research aiming to improve treatment outcomes in CRC patients. This comprehensive design may serve as an example for other tumor types.

Metformin Use During Treatment of Potentially Curable Esophageal Cancer Patients is not Associated with Better Outcomes.

BACKGROUND: Metformin use has been associated with a dose-dependent increased response to neoadjuvant chemo(radio)therapy in esophageal cancer patients. However, no association between metformin use and overall survival has been reported yet. The purpose of our study was to investigate the effect of metformin use on pathological response as well as overall and disease-free survival in patients with resectable esophageal cancer. METHODS: Between March 1994 and September 2013, all patients undergoing an esophagectomy for esophageal and gastroesophageal junction cancer after neoadjuvant chemo(radio)therapy with curative intent were included in a prospective database. A complete pathological response was defined as ypT0N0M0, Mandard 1. Kaplan-Meier curves with log-rank testing were performed for overall survival and disease-free survival. RESULTS: A total of 461 patients were included with a median follow-up of 24 months (range 1-228); 43 patients were diagnosed with diabetes mellitus type II (9.3 %) of whom 32 patients used metformin (74 %). A total of 94 (20 %) patients had a complete pathological response, which did not differ between metformin users (19 %) and non-metformin users (21 %, p = 0.99). We did not observe a statistically significant difference between metformin users and non-metformin users for median overall survival (43.6 vs. 42.8 months, p = 0.66) or for median disease-free survival (31.1 vs. 47.0 months, p = 0.68). A subgroup analysis in patients with diabetes mellitus type II showed a nonsignificant increase in median overall survival for metformin users (43.6 months) compared with non-metformin users (21.4 months, p = 0.44). For median disease-free survival, a similar nonsignificant increase was observed for metformin users (31.1 months) compared with non-metformin users (20.1 months, p = 0.31). CONCLUSIONS: The use of metformin did not result in higher pathological response rates or improved overall survival or disease-free survival compared with non-metformin use in patients receiving neoadjuvant chemo(radio)therapy for resectable esophageal cancer. In contrast to what has been postulated for other tumor types, metformin may not have a beneficial effect in esophageal cancer.

Burden of spousal caregivers of stage II and III esophageal cancer survivors 3 years after treatment with curative intent.

OBJECTIVES: The aim of this study is to examine caregiver burden of spousal caregivers of patients with esophageal cancer after curative treatment with neoadjuvant chemoradiation followed by resection and to assess factors associated with caregiver burden. METHODS: In this exploratory, cross-sectional study, spousal caregivers and patients were eligible if the caregiver was the patient's spouse and the patient had been treated with chemoradiation followed by surgery after esophageal carcinoma diagnosis. Forty-seven couples were included. Spousal caregivers completed a questionnaire, examining caregivers' burden (Self-Perceived Pressure from Informal Care (SPPIC, Dutch)), caregiver unmet needs (SCNS-P&S), anxiety and depression (Hospital Anxiety and Depression Scale (HADS)), and marital satisfaction (Maudsley Marital Questionnaire (MMQ)). Patients completed the latter two questionnaires and a cancer specific quality of life questionnaire (EORTC-QLQ C30 and OES18 (oesophageal module). Logistic regression analysis was performed to identify correlates for caregiver burden. RESULTS: The median time after esophagectomy was 38 months. Thirty-four percent of the spousal caregivers reported moderate or high burden. Spousal caregivers most frequently reported unmet needs were managing concerns about the cancer coming back (43%), dealing with others not acknowledging the impact on your life of caring for a person with cancer (38%), and balancing the needs of the person with cancer and one's own needs. A comparable proportion of spousal caregivers and patients showed symptoms of anxiety (23 vs 17%) and depression (17 vs 17%). Spousal caregivers reported significantly more dissatisfaction than patients on the marital scale (p < 0.01). Factors independently associated with higher caregiver burden were fatigue of the patient (OR = 1.66, 95% CI 1.12-2.47) and depression of the spousal caregiver (OR = 1.44, 95% CI 1.11-1.86). CONCLUSIONS: More than a third of the spousal caregivers of patients with esophageal cancer treated with curative intent report moderate or high burden 3 years after treatment. Fatigue of the patient and depression of the spousal caregiver are associated with caregiver burden. To improve clinical care, identification of spousal caregivers at risk for experiencing higher caregiver burden and implementation of specific interventions is needed.

Association between socioeconomic status, surgical treatment and mortality in patients with colorectal cancer.

BACKGROUND: High socioeconomic status is associated with better survival in colorectal cancer (CRC). This study investigated whether socioeconomic status is associated with differences in surgical treatment and mortality in patients with CRC. METHODS: Patients diagnosed with stage I-III CRC between 2005 and 2010 in the Eindhoven Cancer Registry area in the Netherlands were included. Socioeconomic status was determined at a neighbourhood level by combining the mean household income and the mean value of the housing. RESULTS: Some 4422 patients with colonic cancer and 2314 with rectal cancer were included. Patients with colonic cancer and high socioeconomic status were operated on with laparotomy (70·7 versus 77·6 per cent; P = 0·017), had laparoscopy converted to laparotomy (15·7 versus 29·5 per cent; P = 0·008) and developed anastomotic leakage or abscess (9·6 versus 12·6 per cent; P = 0·049) less frequently than patients with low socioeconomic status. These differences remained significant after adjustment for patient and tumour characteristics. In rectal cancer, patients with high socioeconomic status were more likely to undergo resection (96·3 versus 93·7 per cent; P = 0·083), but this was not significant in multivariable analysis (odds ratio (OR) 1·44, 95 per cent confidence interval 0·84 to 2·46). The difference in 30-day postoperative mortality in patients with colonic cancer and high and low socioeconomic status (3·6 versus 6·8 per cent; P < 0·001) was not significant after adjusting for age, co-morbidities, emergency surgery, and anastomotic leakage or abscess formation (OR 0·90, 0·51 to 1·57). CONCLUSION: Patients with CRC and high socioeconomic status have more favourable surgical treatment characteristics than patients with low socioeconomic status. The lower 30-day postoperative mortality found in patients with colonic cancer and high socioeconomic status is largely explained by patient and surgical factors.

Gastrointestinal symptoms in NSAID users in an 'average risk population': results of a large population-based study in randomly selected Dutch inhabitants.

AIM: Non-steroidal anti-inflammatory drug (NSAID) use is widespread and associated with gastrointestinal symptoms and complications. The aims of this study were to assess (i) gastrointestinal symptoms in users of prescribed and over-the-counter (OTC) NSAIDs and (ii) proton pump inhibitor (PPI) co-prescription rates in NSAID users at increased risk for gastrointestinal complications. METHODS: Surveys were sent to a randomly selected sample of the adult Dutch general population in December 2008. Questions included demographics, gastrointestinal symptoms, medication use and comorbidity. Main outcome measure was presence of gastrointestinal symptoms. RESULTS: A total of 18,317 surveys were returned (response rate 35%), of which 16,758 surveys were eligible for analysis. Of these, 3233 participants (19%) reported NSAID use. NSAID users more frequently reported gastrointestinal symptoms than persons not using NSAIDs (33% vs. 24%, p < 0.01). Respondents who specified on prescription NSAID use (n = 683) were older, reported more comorbidity, and experienced more gastrointestinal symptoms (41%) compared with OTC users (n = 894, 33%, p < 0.01). This difference was not statistically significant after adjustment for confounders (0.99, 95% CI 0.71-1.37). In respondents with an increased gastrointestinal risk profile, PPI co-prescription rates were 51% for on prescription users and 25% for OTC users. CONCLUSIONS: Prevalence of gastrointestinal symptoms was high in both prescribed and OTC NSAID users, emphasising the side effects of both types of NSAIDs. PPI co-prescription rates in NSAID users at risk for gastrointestinal complication were low.

Gastrointestinal symptoms in low-dose aspirin users: a comparison between plain and buffered aspirin.

BACKGROUND: Aspirin is associated with gastrointestinal side effects such as gastric ulcers, gastric bleeding and dyspepsia. High-dose effervescent calcium carbasalate (ECC), a buffered formulation of aspirin, is associated with reduced gastric toxicity compared with plain aspirin in healthy volunteers, but at lower cardiovascular doses no beneficial effects were observed. AIM: To compare the prevalence of self-reported gastrointestinal symptoms between low-dose plain aspirin and ECC. METHODS: A total of 51,869 questionnaires were sent to a representative sample of the Dutch adult general population in December 2008. Questions about demographics, gastrointestinal symptoms in general and specific symptoms, comorbidity, and medication use including bioequivalent doses of ECC (100 mg) and plain aspirin (80 mg) were stated. We investigated the prevalence of self-reported gastrointestinal symptoms on ECC compared with plain aspirin using univariate and multivariate logistic regression analyses. RESULTS: A total of 16,715 questionnaires (32 %) were returned and eligible for analysis. Of these, 911 (5 %) respondents reported the use of plain aspirin, 633 (4 %) ECC and 15,171 reported using neither form of aspirin (91 %). The prevalence of self-reported gastrointestinal symptoms in general was higher in respondents using ECC (27.5 %) compared with plain aspirin (26.3 %), but did not differ significantly with either univariate (OR 1.06, 95 %CI 0.84-1.33), or multivariate analysis (aOR 1.08, 95 %CI 0.83-1.41). Also, none of the specific types of symptoms differed between the two aspirin formulations. CONCLUSIONS: In this large cohort representative of the general Dutch population, low-dose ECC is not associated with a reduction in self-reported gastrointestinal symptoms compared with plain aspirin.

Gastroprotective strategies in chronic NSAID users: a cost-effectiveness analysis comparing single-tablet formulations with individual components.

OBJECTIVES: To evaluate the cost-effectiveness of competing gastroprotective strategies, including single-tablet formulations, in the prevention of gastrointestinal (GI) complications in patients with chronic arthritis taking nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: We performed a cost-utility analysis to compare eight gastroprotective strategies including NSAIDs, cyclooxygenase-2 inhibitors, proton pump inhibitors (PPIs), histamine-2 receptor antagonists, misoprostol, and single-tablet formulations. We derived estimates for outcomes and costs from medical literature. The primary outcome was incremental cost per quality-adjusted life-year gained. We performed sensitivity analyses to assess the effect of GI complications, compliance rates, and drug costs. RESULTS: For average-risk patients, NSAID + PPI cotherapy was most cost-effective. The NSAID/PPI single-tablet formulation became cost-effective only when its price decreased from €0.78 to €0.56 per tablet, or when PPI compliance fell below 51% in the NSAID + PPI strategy. All other strategies were more costly and less effective. The model was highly sensitive to the GI complication risk, costs of PPI and NSAID/PPI single-tablet formulation, and compliance to PPI. In patients with a threefold higher risk of GI complications, both NSAID + PPI cotherapy and single-tablet formulation were cost-effective. CONCLUSIONS: NSAID + PPI cotherapy is the most cost-effective strategy in all patients with chronic arthritis irrespective of their risk for GI complications. For patients with increased GI risk, the NSAID/PPI single-tablet formulation is also cost-effective.

Gastroprotection in low-dose aspirin users for primary and secondary prevention of ACS: results of a cost-effectiveness analysis including compliance.

PURPOSE: Low-dose aspirin (ASA) increases the risk of upper gastrointestinal (GI) complications. Proton pump inhibitors (PPIs) reduce these upper GI side effects, yet patient compliance to PPIs is low. We determined the cost-effectiveness of gastroprotective strategies in low-dose ASA users considering ASA and PPI compliance. METHODS: Using a Markov model we compared four strategies: no medication, ASA monotherapy, ASA+PPI co-therapy and a fixed combination of ASA and PPI for primary and secondary prevention of ACS. The risk of acute coronary syndrome (ACS), upper GI bleeding and dyspepsia was modeled as a function of compliance and the relative risk of developing these events while using medication. Costs, quality adjusted life years and number of ACS events were evaluated, applying a variable risk of upper GI bleeding. Probabilistic sensitivity analyses were performed. RESULTS: For our base case patients using ASA for primary prevention of ACS no medication was superior to ASA monotherapy. PPI co-therapy was cost-effective (incremental cost-effectiveness ratio [ICER] €10,314) compared to no medication. In secondary prevention, PPI co-therapy was cost-effective (ICER €563) while the fixed combination yielded an ICER < €20,000 only in a population with elevated risk for upper GI bleeding or moderate PPI compliance. PPI co-therapy had the highest probability to be cost-effective in all scenarios. PPI use lowered the overall number of ACS. CONCLUSIONS: Considering compliance, PPI co-therapy is likely to be cost-effective in patients taking low dose ASA for primary and secondary prevention of ACS, given low PPI prices. In secondary prevention, a fixed combination seems cost-effective in patients with elevated risk for upper GI bleeding or in those with moderate PPI compliance. Both strategies reduced the number of ACS compared to ASA monotherapy.

Time to reimbursement of novel anticancer drugs in Europe: a case study of seven European countries.

BACKGROUND: Time to reimbursement (TTR) of new anticancer medicines differs between countries and contributes to unequal access. We aimed to investigate TTR of new anticancer medicines and explore factors influencing the reimbursement process in seven high-income European countries. MATERIALS AND METHODS: We carried out a retrospective case study of anticancer medicines with European Union Market Access (EU-MA) and a positive Committee for Medicinal Products for Human Use opinion from 2016 until 2021 with subsequent national reimbursement approval (NRA). The National Health Technology Assessment (HTA) and reimbursement websites of Germany, France, UK, the Netherlands, Belgium, Norway and Switzerland were used to identify TTR, defined as time from EU-MA to NRA. Additionally, we investigated medication-, country-, indication- and pharma-related factors potentially influencing TTR. RESULTS: Thirty-five medicines were identified for which TTR ranged from -81 days to 2320 days (median 407 days). At data cut-off, 16 (46%) were reimbursed in all seven countries. Overall, the shortest TTR was in Germany (median 3 days, all medicines reimbursed <5 days). The time limit for reimbursement of 180 days stated by the Council of European Communities after the EU-MA (EU Transparency Directive) was met for 100% of included medicines in Germany, 51% in France, 29% in the UK and the Netherlands, 14% in Switzerland, 6% in Norway and 3% in Belgium. The TTR was significantly different between countries (P < 0.001). In multivariate analysis, factors associated with shorter TTR were higher gross domestic product (GDP), absence of a pre-assessment procedure and submission by a big pharmaceutical company. CONCLUSIONS: TTR of anticancer medicines varies significantly between seven high-income European countries and leads to inequality in access. Among explored medication-, country-, indication- and pharma-related factors we found that a high GDP, the absence of a pre-assessment procedure and submission by big pharmaceutical companies were associated with shorter TTR.

Genetic variation in alcohol dehydrogenase (ADH1A, ADH1B, ADH1C, ADH7) and aldehyde dehydrogenase (ALDH2), alcohol consumption and gastric cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

Studies that have examined the association between alcohol consumption and gastric cancer (GC) risk have been inconsistent. We conducted an investigation of 29 genetic variants in alcohol metabolism loci (alcohol dehydrogenase, ADH1 gene cluster: ADH1A, ADH1B and ADH1C; ADH7 and aldehyde dehydrogenase, ALDH2), alcohol intake and GC risk. We analyzed data from a nested case-control study (364 cases and 1272 controls) within the European Prospective Investigation into Cancer and Nutrition cohort. Single nucleotide polymorphisms (SNPs) were genotyped using a customized array. We observed a statistically significant association between a common 3'-flanking SNP near ADH1A (rs1230025) and GC risk [allelic odds ratio (OR)(A v T) = 1.30, 95% confidence interval (CI) = 1.07-1.59]. Two intronic variants, one in ADH1C (rs283411) and one in ALDH2 (rs16941667), also were associated with GC risk (OR(T v C) = 0.59; 95% CI = 0.38-0.91 and OR(T v C) = 1.34; 95% CI = 1.00-1.79, respectively). Individuals carrying variant alleles at both ADH1 (rs1230025) and ALDH2 (rs16941667) were twice as likely to develop GC (OR(A+T) = 2.0; 95% CI = 1.25-3.20) as those not carrying variant alleles. The association between rs1230025 and GC was modified by alcohol intake (<5 g/day: OR(A) = 0.89, 95% CI = 0.57-1.39; ≥5 g/day: OR(A) = 1.45, 95% CI = 1.08-1.94, P-value = 0.05). The association was also modified by ethanol intake from beer. A known functional SNP in ADH1B (rs1229984) was associated with alcohol intake (P-value = 0.04) but not GC risk. Variants in ADH7 were not associated with alcohol intake or GC risk. In conclusion, genetic variants at ADH1 and ALDH2 loci may influence GC risk, and alcohol intake may further modify the effect of ADH1 rs1230025. Additional population-based studies are needed to confirm our results.

Factors influencing the miss rate of polyps in a back-to-back colonoscopy study.

BACKGROUND AND STUDY AIMS: In patients undergoing colonoscopy, 22 % - 28 % of polyps and 20 % - 24 % of adenomas are missed. It is unclear which factors contribute to polyp miss rates, but colorectal cancer detected within 3 years after colonoscopy may originate from missed lesions. The aim of the current study was to determine patient- and polyp-related factors that influence the miss rates of polyps and adenomas during colonoscopy. PATIENTS AND METHODS: Data from 406 patients were obtained from a multicenter, randomized back-to-back colonoscopy study investigating the Third Eye Retroscope (TER) in improving polyp detection rate by visualizing hidden areas such as folds and curves. Patients were randomized to undergo standard colonoscopy followed by colonoscopy with TER, or vice versa. Miss rates were calculated for all polyps and adenomas. All lesions were categorized for size and location within the colon/rectum. Odds ratios (ORs) were computed using adjusted logistic regression models to identify factors independently associated with missed lesions. RESULTS: The miss rate was 25 % (150 /611) for all polyps and 26 % (90 /350) for adenomas. Miss rates were significantly lower (21 % vs. 29 %) in patients randomized to TER as the first procedure (P < 0.03). Taking all groups together, > 2 polyps compared with ≤ 2 polyps detected during the first colonoscopy increased the risk of missing additional polyps (adjusted OR = 2.83; 95 % confidence interval [CI] 1.22 - 6.70). Adenomas in the left colon compared with adenomas in the right colon were also more frequently missed (adjusted OR = 1.65; 95 %CI 1.06 - 2.58). CONCLUSIONS: A quarter of polyps were missed during colonoscopy. Physicians should be aware that the risk of missing a polyp is related to patient factors (presence of > 2 polyps) and polyp factors (left colon location).

Prediction scores in gastrointestinal bleeding: a systematic review and quantitative appraisal.

BACKGROUND AND STUDY AIMS: Several algorithms predicting outcomes in acute gastrointestinal bleeding have been developed over the past three decades. These algorithms differ substantially and therefore the aim of the current study was to conduct a systematic review to compare their predictive performance and methodological quality in gastrointestinal bleeding. METHODS: A PubMed literature search was performed up to 1 July 2011. All studies reporting prediction scores in gastrointestinal bleeding were included. Studies were analyzed for predictive performance, and a quality appraisal of these rules was performed for which a score range of 0 (lowest) to 29 (highest) was used. RESULTS: A total of 372 studies were identified, of which 16 were eligible for inclusion. The studies evaluated different outcomes: mortality (n = 5), rebleeding (n = 2), intervention required (n = 2), or a combination (n = 7). The predictive performance of the identified prediction scores varied between an area under the curve of 0.71 - 0.92 (if given). The mean overall quality rating was 17 (SD 4.0, range 9 - 25). Major methodological shortcomings were the absence of validation and absence of impact analyses. Eight of 16 scores (50 %) were determined "easy to use," and five scores (31 %) reported some type of action based on the results. CONCLUSION: Substantial heterogeneity in outcomes and results was seen in the 16 identified prediction scores. Moreover, the methodological quality was suboptimal in most studies. However, we suggest that clinicians should use the "best available" scores according to performance and quality, which are the Blatchford score to assess the need for intervention, and the scores of Villanueva et al. for poor outcome, Guglielmi et al. for rebleeding, and Chiu et al. for mortality risk.