KCNQ1 and lymphovascular invasion are key features in a prognostic classifier for stage II and III colon cancer.

BACKGROUND: The risk of recurrence after resection of a stage II or III colon cancer, and therefore qualification for adjuvant chemotherapy (ACT), is traditionally based on clinicopathological parameters. However, the parameters used in clinical practice are not able to accurately identify all patients with or without minimal residual disease. Some patients considered 'low-risk' do develop recurrence (undertreatment), whilst other patients receiving ACT might not have developed recurrence at all (overtreatment). We previously analysed tumour tissue expression of 28 protein biomarkers that might improve identification of patients at risk of recurrence. In the present study we aimed to build a prognostic classifier based on these 28 biomarkers and clinicopathological parameters. METHODS: Classification and regression tree (CART) analysis was used to build a prognostic classifier based on a well described cohort of 386 patients with stage II and III colon cancer. Separate classifiers were built for patients who were or were not treated with ACT. Routine clinicopathological parameters and tumour tissue immunohistochemistry data were included, available for 28 proteins previously published. Classification trees were pruned until lowest misclassification error was obtained. Survival of the identified subgroups was analysed, and robustness of the selected CART variables was assessed by random forest analysis (1000 trees). RESULTS: In patients not treated with ACT, prognosis was estimated best based on expression of KCNQ1. Poor disease-free survival (DFS) was observed in those with loss of expression of KCNQ1 (HR = 3.38 (95% CI 2.12 - 5.40); p < 0.001). In patients treated with ACT, key prognostic factors were lymphovascular invasion (LVI) and expression of KCNQ1. Patients with LVI showed poorest DFS, whilst patients without LVI and high expression of KCNQ1 showed most favourable survival (HR = 7.50 (95% CI 3.57-15.74); p < 0.001). Patients without LVI and loss of expression of KCNQ1 had intermediate survival (HR = 3.91 (95% CI 1.76 - 8.72); p = 0.001). CONCLUSION: KCNQ1 and LVI were identified as key features in prognostic classifiers for disease-free survival in stage II and III colon cancer patients.

Estimating adjuvant treatment effects in Stage II colon cancer: Comparing the synthesis of randomized clinical trial data to real-world data.

There is an ongoing discussion regarding the impact of adjuvant chemotherapy in Stage II colon cancer. We therefore estimated adjuvant treatment effect in Stage II colon cancer using pooled disease-free survival (DFS) data from randomized clinical trials (RCT approach) and compared this to real-world data (RWD approach) estimates. First, we estimated the treatment effect in RCTs by (i) searching relevant trials reporting DFS data, (ii) generating patient-level data from reported DFS data and (iii) estimating treatment effect in the patient-level data. Second, the treatment effect was estimated in an observational cohort of 1,947 patients provided by the Netherlands Cancer Registry using three propensity score methods; matching, weighting and stratification. In the RCT approach, patient-level data of 4,489 patients (events: 853) were generated from seven trials which compared two of the following treatment arms: control, 5FU/LV or FOLFOX. A Cox model was used to estimate a hazard ratio (HR) of 0.77 (0.43;1.10) for 5FU/LV vs. control and 0.93 (0.72;1.15) for FOLFOX vs. 5FU/LV. In the RWD approach, HRs for any adjuvant treatment vs. control were 0.95 (0.50;1.80), 0.88 (0.24;3.21) and 1.05 (0.04;2.06) using matching, weighting and stratification, respectively. There was no significant difference with the estimates from the RCT approach (interaction test, p > 0.10). The RCT data suggest a clinically relevant benefit of adjuvant chemotherapy in terms of DFS, but the estimate did not reach statistical significance. Stratified analyses are required to evaluate whether treatment effect differs in specific subgroups.

Prevalence of adjustment disorder among cancer patients, and the reach, effectiveness, cost-utility and budget impact of tailored psychological treatment: study protocol of a randomized controlled trial.

BACKGROUND: Information on the prevalence of adjustment disorders among cancer patients and the value of psychological interventions in this group of patients is limited. This study investigates the prevalence of adjustment disorders among cancer patients as well as the reach, effectiveness, cost-utility and budget impact of a tailored psychological intervention. METHOD: This study consists of two parts. Part 1 is an observational study among a representative group of mixed cancer patients after cancer treatment on the prevalence of adjustment disorder as well as the uptake (i.e. reach) of psychological treatment. In Part 2, patients diagnosed with an adjustment disorder are invited to participate in a randomized controlled trial. Patients will be randomized to the intervention (access to the tailored psychological intervention) or control group (waitlist period of 6 months). The psychological intervention consists of three modules: one module containing psycho-education (3 sessions, all patients) and two additional modules (maximum of 6 sessions per module) provided as continuum, in case needed. Module 2 and 3 can consist of several evidence-based interventions (e.g. group interventions, mindfulness, eHealth) The primary outcome is psychological distress (HADS). Secondary outcomes are mental adjustment to cancer (MAC) and health-related quality of life (EORTC QLQ-C30). To assess the cost-utility and budget impact, quality of life (EQ-5D-5 L) and costs (iMCQ and iPCQ) will be measured. Measures will be completed at baseline and 3 and 6-months after randomization. DISCUSSION: This study will provide data of the prevalence of adjustment disorders and the reach, effectiveness, cost-utility and budget impact of a tailored psychological intervention. TRIAL REGISTRATION: Netherlands Trial Register identifier: NL7763. Registered on 3 June 2019.

Metachronous Peritoneal Metastases After Adjuvant Chemotherapy are Associated with Poor Outcome After Cytoreduction and HIPEC.

INTRODUCTION: Cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) improve the survival of colorectal cancer (CRC) patients with peritoneal metastases. Patient selection is key since this treatment is associated with high morbidity. Patients with peritoneal recurrence within 1 year after previous adjuvant chemotherapy are thought to benefit less from HIPEC treatment; however, no published data are available to assist in clinical decision making. This study assessed whether peritoneal recurrence within 1 year after adjuvant chemotherapy was associated with survival after HIPEC treatment. METHODS: Peritoneal recurrence within 1 year after adjuvant chemotherapy, as well as other potentially prognostic clinical and pathological variables, were tested in univariate and multivariate analysis for correlation with primary outcomes, i.e. overall survival (OS) and disease-free survival (DFS). Two prospectively collected databases from the VU University Medical Center Amsterdam and Catherina Hospital Eindhoven containing 345 CRC patients treated with the intent of HIPEC were utilized. RESULTS: High Peritoneal Cancer Index (PCI) scores were associated with worse DFS [hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.00-1.08, p = 0.040] and OS (HR 1.11, 95% CI 1.07-1.15, p < 0.001) in multivariate analysis. Furthermore, patients with peritoneal recurrence within 1 year following adjuvant chemotherapy had worse DFS (HR 2.13, 95% CI 1.26-3.61, p = 0.005) and OS (HR 2.76, 95% CI 1.45-5.27, p = 0.002) than patients who did not receive adjuvant chemotherapy or patients with peritoneal recurrence after 1 year. CONCLUSION: Peritoneal recurrence within 1 year after previous adjuvant chemotherapy, as well as high PCI scores, are associated with poor survival after cytoreduction and HIPEC. These factors should be considered in order to avoid high-morbidity treatment in patients who might not benefit from such treatment.

Loss of KCNQ1 expression in stage II and stage III colon cancer is a strong prognostic factor for disease recurrence.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer worldwide. Accurately identifying stage II CRC patients at risk for recurrence is an unmet clinical need. KCNQ1 was previously identified as a tumour suppressor gene and loss of expression was associated with poor survival in patients with CRC liver metastases. In this study the prognostic value of KCNQ1 in stage II and stage III colon cancer patients was examined. METHODS: KCNQ1 mRNA expression was assessed in 90 stage II colon cancer patients (AMC-AJCCII-90) using microarray gene expression data. Subsequently, KCNQ1 protein expression was evaluated in an independent cohort of 386 stage II and stage III colon cancer patients by immunohistochemistry of tissue microarrays. RESULTS: Low KCNQ1 mRNA expression in stage II microsatellite stable (MSS) colon cancers was associated with poor disease-free survival (DFS) (P=0.025). Loss of KCNQ1 protein expression from epithelial cells was strongly associated with poor DFS in stage II MSS (P<0.0001), stage III MSS (P=0.0001) and stage III microsatellite instable colon cancers (P=0.041). KCNQ1 seemed an independent prognostic value in addition to other high-risk parameters like angio-invasion, nodal stage and microsatellite instability-status. CONCLUSIONS: We conclude that KCNQ1 is a promising biomarker for prediction of disease recurrence and may aid stratification of patients with stage II MSS colon cancer for adjuvant chemotherapy.