V.E.P.P. Lemmens

The BRAF V600E mutation is an independent prognostic factor for survival in stage II and stage III colon cancer patients

BACKGROUND Molecular markers in colon cancer are needed for a more accurate classification and personalized treatment. We determined the effects on clinical outcome of the BRAF mutation, microsatellite instability (MSI) and KRAS mutations in stage II and stage III colon carcinoma. PATIENTS AND METHODS Stage II colon carcinoma patients (n = 106) treated with surgery only and 258 stage III patients all adjuvantly treated with 5-fluorouracil chemotherapy were included. KRAS mutations in codons 12 and 13, V600E BRAF mutation and MSI status were determined. RESULTS Older patients (P < 0.001), right-sided (P = 0.018), better differentiated (P = 0.003) and MSI tumors (P < 0.001) were significantly more frequent in stage II than stage III. In both groups, there was a positive association between mutated BRAF and MSI (P = 0.001) and BRAF mutation and right-sided tumors (P = 0.001). Mutations in BRAF and KRAS were mutually exclusive. In a multivariate survival analysis with pooled stage II and stage III data, BRAF mutation was an independent prognostic factor for overall survival (OS) and cancer-specific survival [hazards ratio (HR) = 0.45, 95% confidence interval (CI) 0.25-0.8 for OS and HR = 0.47, 95% CI 0.22-0.99]. KRAS mutation conferred a poorer disease-free survival (HR = 0.6, 95% CI 0.38-0.97). CONCLUSIONS The V600E BRAF mutation confers a worse prognosis to stage II and stage III colon cancer patients independently of disease stage and therapy.

Use of Aspirin postdiagnosis improves survival for colon cancer patients

Background:The preventive role of non-steroid anti-inflammatory drugs (NSAIDs) and aspirin, in particular, on colorectal cancer is well established. More recently, it has been suggested that aspirin may also have a therapeutic role. Aim of the present observational population-based study was to assess the therapeutic effect on overall survival of aspirin/NSAIDs as adjuvant treatment used after the diagnosis of colorectal cancer patients.Methods:Data concerning prescriptions were obtained from PHARMO record linkage systems and all patients diagnosed with colorectal cancer (1998–2007) were selected from the Eindhoven Cancer Registry (population-based cancer registry). Aspirin/NSAID use was classified as none, prediagnosis and postdiagnosis and only postdiagnosis. Patients were defined as non-user of aspirin/NSAIDs from the date of diagnosis of the colorectal cancer to the date of first use of aspirin or NSAIDs and user from first use to the end of follow-up. Poisson regression was performed with user status as time-varying exposure.Results:In total, 1176 (26%) patients were non-users, 2086 (47%) were prediagnosis and postdiagnosis users and 1219 (27%) were only postdiagnosis users (total n=4481). Compared with non-users, a survival gain was observed for aspirin users; the adjusted rate ratio (RR) was 0.77 (95% confidence interval (CI) 0.63–0.95; P=0.015). Stratified for colon and rectal, the survival gain was only present in colon cancer (adjusted RR 0.65 (95%CI 0.50–0.84; P=0.001)). For frequent users survival gain was larger (adjusted RR 0.61 (95%CI 0.46–0.81; P=0.001). In rectal cancer, aspirin use was not associated with survival (adjusted RR 1.10 (95%CI 0.79–1.54; P=0.6). The NSAIDs use was associated with decreased survival (adjusted RR 1.93 (95%CI 1.70–2.20; P<0.001).Conclusion:Aspirin use initiated or continued after diagnosis of colon cancer is associated with a lower risk of overall mortality. These findings strongly support initiation of a placebo-controlled trial that investigates the role of aspirin as adjuvant treatment in colon cancer patients.

Differences in outcomes of oesophageal and gastric cancer surgery across Europe

In several European countries, centralization of oesophagogastric cancer surgery has been realized and clinical audits initiated. The present study was designed to evaluate differences in resection rates, outcomes and annual hospital volumes between these countries, and to analyse the relationship between hospital volume and outcomes.

Population-based survival of patients with peritoneal carcinomatosis from colorectal origin in the era of increasing use of palliative chemotherapy

BACKGROUND Palliative chemotherapy improves survival in patients with metastasised colorectal cancer. However, there is a lack of data regarding the effectiveness of modern chemotherapy in patients with isolated peritoneal carcinomatosis (PC). PATIENTS AND METHODS All patients with synchronous PC of colorectal origin diagnosed in the Eindhoven Cancer Registry registration area between 1995 and 2008 were included (N = 904). We assessed the use of chemotherapy and overall survival in three time periods related to the availability of different chemotherapy regimens. RESULTS Chemotherapy use gradually increased over time. Median survival (MS) for patients with PC without other metastases diagnosed in 1995-2000 was 35 weeks [95% confidence interval (CI) 24-43] and 34 weeks (25-54) in 2005-2008. MS in patients diagnosed with PC plus other metastases was 21 weeks (15-27) in 1995-2000 and 26 weeks (18-33) in 2005-2008. In multivariable regression analysis, use of chemotherapy had a beneficial influence on survival only in 2005-2008. In the first two periods, chemotherapy treatment did not decrease the risk for death. CONCLUSION Despite increasing usage of palliative chemotherapy and availability of new agents, population-based survival of patients with PC did not improve until very recently. Response to palliative chemotherapy in PC should be evaluated separately from haematogenous metastases.

Quality assurance in rectal cancer treatment in the Netherlands: A catch up compared to colon cancer treatment

BACKGROUND In the Netherlands, the Total Mesorectal Excision (TME) surgical technique for rectal cancer was introduced together with pre-operative radiotherapy in a quality controlled manner within the framework of the TME trial (1996-1999). The aim of this study is to examine the effects of the structural changes in rectal cancer care on survival compared to colon cancer for patients treated before, during and after the TME trial. METHOD We compared overall survival of all patients with curatively resected colon (n = 15,266) and rectal cancer (n = 5839) in the regions of Comprehensive Cancer Centres South and West between 1990 and 2005, adjusting for prognostic variables. RESULTS In the pre-trial period, rectal cancer had a significant lower survival compared to colon cancer (HR 1.248, P < 0.01). However, in the post-trial period, survival after rectal cancer was similar to colon cancer (HR 0.987, n.s.). CONCLUSION Although survival improved significantly for both colon and rectal cancer in the last 15 years, the substantially worse results after rectal cancer have been eliminated. This study shows the lasting effects that structural surgical training and quality assurance can have on survival outcome.

Influence of hospital type on outcomes after oesophageal and gastric cancer surgery

Outcomes after oesophagectomy and gastrectomy vary considerably between hospitals. Possible explanations include differences in case mix, hospital volume and hospital type. The present study examined the distribution of oesophagectomies and gastrectomies between hospital types in the Netherlands, and the relationship between hospital type and outcome.

Reduction of in-hospital mortality following regionalisation of pancreatic surgery in the south-east of The Netherlands

BACKGROUND In the late nineties of the former century, surgery for pancreatic and peri-ampullary cancer in the southern part of The Netherlands was performed mainly in low-volume hospitals (<5 resections/year). Results reported by the Comprehensive Cancer Center South (CCCS) in 2005 revealed the clearly disappointing results of this practice. The former stimulated the regionalisation of pancreatic surgery by 3 collaborating surgical units into one non-academic teaching hospital in the eastern part of the CCCS-region starting from July 2005. METHODS All of the 76 patients in this regional cohort group in whom a resection of a (peri-)pancreatic tumour was performed with curative intent have been followed up prospectively. The results of surgical morbidity and in-hospital mortality were compared with the results of the CCCS cohort group which were reported previously. RESULTS Ever since the regionalisation the annual number of patients undergoing resection of a pancreatic tumour increased from 10 to 33, resulting in a total number of 76 patients. Post-operative complications, reoperation rate and in-hospital mortality decreased significantly to 34.2%, 18.4% and 2.6% respectively, as compared to 71.9%, 37.8 and 24.4% in the time period before regionalisation (p < 0.01). CONCLUSION These unique comparative prospective data derived from daily practice in a collaborative surgical region in The Netherlands (CCCS) support the need for centralisation of pancreatic surgery in order to improve standard of care in pancreatic surgery. This can be achieved by collaboration in a large regional hospital.

Textbook outcome as a composite measure in oesophagogastric cancer surgery

Quality assurance is acknowledged as a crucial factor in the assessment of oncological surgical care. The aim of this study was to develop a composite measure of multiple outcome parameters defined as ‘textbook outcome’, to assess quality of care for patients undergoing oesophagogastric cancer surgery.

Outcome of surgery for colorectal cancer in the presence of peritoneal carcinomatosis

AIM The detection of peritoneal carcinomatosis (PC) in colorectal cancer patients frequently results in a dilemma with regard to the optimal treatment strategy, especially when PC is encountered unexpectedly during surgery. The aim of this study was to evaluate outcomes of patients undergoing surgery for colorectal carcinoma in the presence of synchronous PC. METHODS Patients diagnosed with primary colorectal cancer and synchronous PC in three community hospitals were selected from the Eindhoven Cancer Registry database. Outcomes of postoperative complications, in-hospital mortality and overall survival were collected and analyzed according to the type of intervention performed. RESULTS Between 1995 and 2009, 169 colorectal cancer patients were diagnosed with synchronous PC, most of them unexpectedly during surgery (n = 130). 142 patients underwent surgery: primary tumor resection (n = 91), palliative procedure (n = 46) or exploration only (n = 5). In-hospital mortality was 41% after palliative surgery and 14% after primary tumor resection. Median survival was 12 weeks after palliative surgery or exploration as opposed to 55 weeks after primary tumor resection. CONCLUSION PC is most often encountered unexpectedly during surgery for colorectal cancer. Results of palliative procedures are very poor with a high in-hospital mortality rate and short survival. Resection of the primary tumor can be performed safely with relatively good outcomes but some patients could have benefited from an even more radical approach when the presence of PC would have been diagnosed at an earlier stage. Improvement of imaging techniques to detect PC prior to surgery is therefore urgently needed. Until this is the case, a high index of suspicion is required when subtle signs of PC are encountered.

Large variation in the utilization of liver resections in stage IV colorectal cancer patients with metastases confined to the liver

BACKGROUND Surgical resection of both the primary tumor and all metastases is considered the only chance of cure for patients with stage IV colorectal cancer. The aim of this study was to investigate change over time in the utilization of liver resections, as well as possible institutional variations. PATIENTS AND METHODS All patients diagnosed with stage IV colorectal cancer with metastases confined to the liver (n = 1617) between 2004 and 2012 were selected from the population-based Eindhoven Cancer Registry. The proportion of patients undergoing liver resection was investigated. Institutional variation in the period 2010-2012 was analyzed using logistic regression. Kaplan-Meier and Cox regression analyses were used to analyze overall survival. RESULTS The proportion of patients undergoing liver metastasectomy increased over time from 8% in 2004 to approximately 24% in 2012. There was a wide inter-hospital variation in the proportion of patients that underwent a liver resection (range: 14-34%) in the period 2010-2012. Liver resection was more often performed in younger patients and in rectal cancer patients. Median overall survival in patients undergoing liver resection was 55 months. Adjusted for potential confounders, resection of liver metastases was strongly associated with improved overall survival (HR 0.32, 95%CI 0.25-0.40). DISCUSSION This study shows that despite the excellent long-term prognosis for patients with stage IV colorectal cancer after liver resection, there is still a large institutional variation in the utilization of this potentially curative therapy.