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).

Accurate staging of non-metastatic colon cancer with CT: the importance of training and practice for experienced radiologists and analysis of incorrectly staged cases.

PURPOSE: To investigate whether locoregional staging of colon cancer by experienced radiologists can be improved by training and feedback to minimize the risk of over-staging into the context of patient selection for neoadjuvant therapy and to identify potential pitfalls of CT staging by characterizing pathologic traits of tumors that remain challenging for radiologists. METHODS: Forty-five cases of stage I-III colon cancer were included in this retrospective study. Five experienced radiologists evaluated the CTs; 5 baseline scans followed by 4 sequential batches of 10 scans. All radiologists were trained after baseline scoring and 2 radiologists received feedback. The learning curve, diagnostic performance, reader confidence, and reading time were evaluated with pathologic staging as reference. Pathology reports and H&E slides of challenging cases were reviewed to identify potential pitfalls. RESULTS: Diagnostic performance in distinguishing T1-2 vs. T3-4 improved significantly after training and with increasing number of reviewed cases. Inaccurate staging was more frequently related to under-staging rather than over-staging. Risk of over-staging was minimized to 7% in batch 3-4. N-staging remained unreliable with an overall accuracy of 61%. Pathologic review identified two tumor characteristics causing under-staging for T-stage in 5/7 cases: (1) very limited invasive part beyond the muscularis propria and (2) mucinous composition of the invading part. CONCLUSION: The high accuracy and specificity of T-staging reached in our study indicate that sufficient training and practice of experienced radiologists can ensure high validity for CT staging in colon cancer to safely use neoadjuvant therapy without significant risk of over-treatment, while N-staging remained unreliable.

Daily practice in guideline adherence to adjuvant chemotherapy in stage III colon cancer and predictors of outcome.

INTRODUCTION: Although guidelines recommend adjuvant chemotherapy for stage III colon cancer patients, many patients do not receive adjuvant chemotherapy. The aim of this study was to identify reasons for guideline non-adherence and assess the effect on patient outcomes in a multicenter cohort of stage III colon cancer patients who received surgery plus adjuvant chemotherapy or surgery alone. METHODS: Patients who underwent surgery between 2007 and 2017 were included. Reasons for non-adherence were determined. Propensity score analyses with inverse probability weighting were performed to adjust for confounding factors. Cox proportional hazards regression and risk stratified analyses were performed to assess the association of guideline adherence and other potential predictors with recurrence free survival (RFS). RESULTS: Data of 575 patients were included of whom 61% received adjuvant chemotherapy. In 87 of 222 patients (39%) who did not receive adjuvant chemotherapy, no reason was documented. Only age was predictive for receiving chemotherapy. Patients who received adjuvant chemotherapy had longer RFS (HR 0.42, 95%CI 0.29-0.62, p < 0.001). High T- and N-stage were associated with poorer RFS HR 2.0 (95%CI 1.58-2.71, p < 0.001) and HR 2.19 (95%CI 1.60-2.99, p < 0.001) respectively. Risk groups were identified with distinct prognosis and treatment effect and a nomogram is presented to visualize individualized RFS differences. CONCLUSION: This study shows considerable variation in guideline adherence to adjuvant chemotherapy and poor documentation on reasons for non-adherence. Optimizing adherence and gaining insight in reasons for non-adherence is advocated as this can lead to significant RFS benefit, especially in patients with high T-and N-stage tumors.