Postoperative mortality risk assessment in colorectal cancer: development and validation of a clinical prediction model using data from the Dutch ColoRectal Audit.

BACKGROUND: As the outcome of modern colorectal cancer (CRC) surgery has significantly improved over the years, however, renewed and adequate risk stratification for mortality is important to identify high-risk patients. This population-based study was conducted to analyse postoperative outcomes in patients with CRC and to create a risk model for 30-day mortality. METHODS: Data from the Dutch Colorectal Audit were used to assess differences in postoperative outcomes (30-day mortality, hospital stay, blood transfusion, postoperative complications) in patients with CRC treated from 2009 to 2017. Time trends were analysed. Clinical variables were retrieved (including stage, age, sex, BMI, ASA grade, tumour location, timing, surgical approach) and a prediction model with multivariable regression was computed for 30-day mortality using data from 2009 to 2014. The predictive performance of the model was tested among a validation cohort of patients treated between 2015 and 2017. RESULTS: The prediction model was obtained using data from 51 484 patients and the validation cohort consisted of 32 926 patients. Trends of decreased length of postoperative hospital stay and blood transfusions were found over the years. In stage I-III, postoperative complications declined from 34.3 per cent to 29.0 per cent (P < 0.001) over time, whereas in stage IV complications increased from 35.6 per cent to 39.5 per cent (P = 0.010). Mortality decreased in stage I-III from 3.0 per cent to 1.4 per cent (P < 0.001) and in stage IV from 7.6 per cent to 2.9 per cent (P < 0.001). Eight factors, including stage, age, sex, BMI, ASA grade, tumour location, timing, and surgical approach were included in a 30-day mortality prediction model. The results on the validation cohort documented a concordance C statistic of 0.82 (95 per cent c.i. 0.80 to 0.83) for the prediction model, indicating good discriminative ability. CONCLUSION: Postoperative outcome improved in all stages of CRC surgery in the Netherlands. The developed model accurately predicts postoperative mortality risk and is clinically valuable for decision-making.

Sixty-Day Mortality of Patients With Metastatic Colorectal Cancer Randomized to Systemic Treatment vs Primary Tumor Resection Followed by Systemic Treatment: The CAIRO4 Phase 3 Randomized Clinical Trial.

Importance: The role of primary tumor resection (PTR) in synchronous patients with metastatic colorectal cancer (mCRC) who had unresectable metastases and few or absent symptoms of their primary tumor is unclear. Studying subgroups with low postoperative mortality may identify patients who potentially benefit from PTR. Objective: To determine the difference in 60-day mortality between patients randomized to systemic treatment only vs PTR followed by systemic treatment, and to explore risk factors associated with 60-day mortality. Design, Setting, and Participants: CAIRO4 is a randomized phase 3 trial initiated in 2012 in which patients with mCRC were randomized to systemic treatment only or PTR followed by systemic treatment with palliative intent. This multicenter study was conducted by the Danish and Dutch Colorectal Cancer Group in general and academic hospitals in Denmark and the Netherlands. Patients included between August 2012 and December 2019 with histologically proven colorectal cancer, unresectable metastases, and a primary tumor with few or absent symptoms were eligible. Interventions: Systemic treatment, consisting of fluoropyrimidine-based chemotherapy with bevacizumab vs PTR followed by fluoropyrimidine-based chemotherapy with bevacizumab. Main Outcomes and Measures: The aim of the current analysis was to compare 60-day mortality rates in both treatment arms. A secondary aim was the identification of risk factors for 60-day mortality in the treatment arms. These aims were not predefined in the study protocol. Results: A total of 196 patients were included in the intention-to-treat analysis (112 [57%] men; median [IQR] age, 65 [59-70] years). Sixty-day mortality was 3% (95% CI, 1%-9%) in the systemic treatment arm and 11% (95% CI, 6%-19%) in the PTR arm (P = .03). In a per-protocol analysis, 60-day mortality was 2% (95% CI, 1%-7%) vs 10% (95% CI, 5%-18%; P = .048). Patients with elevated serum levels of lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, and/or neutrophils who were randomized to PTR had a significantly higher 60-day mortality than patients without these characteristics. Conclusions and Relevance: Patients with mCRC who were randomized to PTR followed by systemic treatment had a higher 60-day mortality than patients randomized to systemic treatment. Especially patients randomized to the PTR arm with elevated serum levels of lactate dehydrogenase, neutrophils, aspartate aminotransferase, and/or alanine aminotransferase were at high risk of postoperative mortality. Final study results on overall survival have to be awaited. Trial Registration: ClinicalTrials.gov Identifier: NCT01606098.

Neoadjuvant Chemotherapy for Locally Advanced T4 Colon Cancer: A Nationwide Propensity-Score Matched Cohort Analysis.

INTRODUCTION: Neoadjuvant chemotherapy (CT) for locally advanced colon cancer (LACC) could potentially lead to tumor shrinkage, eradication of micrometastases, and prevention of tumor cell shedding during surgery. This retrospective study investigates the surgical and oncological outcomes of preoperative CT for LACC. METHODS: Using the Netherlands Cancer Registry, data of patients with stage II or III colon cancer, diagnosed between 2008 and 2016 was collected. A propensity score matching (PSM; 1:2) was performed and compared patients with clinical tumor (cT) 4 colon cancer who were treated with neoadjuvant CT to patients with cT4 colon cancer treated with adjuvant CT (Fig. 1). RESULTS: A total of 192 patients treated with neoadjuvant CT were compared to 1,954 patients that received adjuvant CT. After PSM, 149 patients in the neoadjuvant group were compared to 298 patients in the control group. No significant differences were found in baseline characteristics after PSM. After neoadjuvant CT, a significant response was observed in 13 (9%) patients with 5 (4%) patients showing a complete response. Complete resection margins (R0) were achieved in 77% in the neoadjuvant group versus 86% in the adjuvant treated group (p = 0.037). Significantly less tumor positive lymph nodes were found in the neoadjuvant group (median 0 vs. 2, p < 0.001). Major complication rates and 5-year overall survival did not differ between both groups (67-65%, p = 0.87). CONCLUSION: Neoadjuvant CT seems safe and feasible with similar long-term survival compared to patients who are treated with adjuvant CT.

Significant increase of synchronous disease in first-line metastatic colorectal cancer trials: Results of a systematic review.

BACKGROUND: Although synchronous and metachronous metastases are considered as separate entities of metastatic colorectal cancer (mCRC) with different outcomes, its proportion is reported infrequently. We compared inclusion rates and survival of synchronous versus metachronous mCRC in different types of studies investigating initial systemic therapy or surgical treatment of mCRC. METHODS: We searched PubMed and EMBASE (January 2004 - February 2016) for mCRC studies investigating first-line systemic therapy or surgical treatment of mCRC including information on synchronous versus metachronous metastases. Outcomes were the proportion of synchronous mCRC, and estimated median overall survival (OS) of the total study population. Spearman analysis (rs) was used to study correlations between outcomes and median year of study enrolment. RESULTS: We included 46 articles, reporting data from 23 phase 3 randomised controlled trials (RCTs), twenty cohort and three population-based studies (total: 25,941 patients). Seventeen different definitions for synchronous mCRC were identified. In systemic therapy RCTs, we observed an increased proportion of synchronous mCRC during recent years (rs .77, p < .001). In these trials, estimated median OS slightly improved over time (rs .48, p = .03). No significant inclusion or survival trends were observed in included cohort and population-based studies. CONCLUSIONS: In recent years, the proportion of patients with synchronous compared with metachronous mCRC enrolled in first-line systemic therapy RCTs increased. Estimated median OS of the total study population in these RCTs slightly increased over time. Many different definitions of synchronous disease were used. Uniform definitions and consistent reporting of the proportion of synchronous versus metachronous metastases could improve cross-study comparisons and interpretation of reported data in all mCRC studies.

Palliative resection of the primary tumor is associated with improved overall survival in incurable stage IV colorectal cancer: A nationwide population-based propensity-score adjusted study in the Netherlands.

As the value of palliative primary tumor resection in stage IV colorectal cancer (CRC) is still under debate, the purpose of this population-based study was to investigate if palliative primary tumor resection as the initial treatment after diagnosis was associated with improved overall survival. All patients with stage IV colorectal adenocarcinoma (2008-2011) were selected from the Netherlands Cancer Registry, and patients undergoing treatment with curative intent (i.e., metastasectomy, radiofrequency ablation and/or hyperthermic intraperitoneal chemotherapy), or best supportive care were excluded. After propensity score matching, a multivariable Cox proportional hazard model was performed to determine the association between treatment strategy and mortality. From a total group of 10,371 patients with stage IV CRC, 2,746 patients (26%) underwent an elective palliative resection of the primary tumor, whether or not followed by systemic therapy, and 3,345 patients (32%) were initially treated with palliative systemic therapy. After propensity score matching, median overall survival in these groups was 17.2 months (95% CI 16.3-18.1) and 11.5 months (95% CI 11.0-12.0), respectively. In Cox regression analysis, primary tumor resection was significantly associated with improved overall survival (hazard ratio of death = 0.44 [95% CI 0.35-0.55], p < 0.001). This large population-based study shows an overall survival benefit for patients with incurable stage IV CRC who underwent primary tumor resection as the initial treatment after diagnosis, compared to patients who started systemic therapy with the primary tumor in situ. This result is an argument in favor of resection of the primary tumor, even when patients have little to no symptoms.

The CAIRO4 study: the role of surgery of the primary tumour with few or absent symptoms in patients with synchronous unresectable metastases of colorectal cancer--a randomized phase III study of the Dutch Colorectal Cancer Group (DCCG).

BACKGROUND: There is no consensus regarding resection of the primary tumour with few or absent symptoms in patients with synchronous unresectable metastatic colorectal cancer (CRC). A potential benefit of resection of the primary tumour is to prevent complications of the primary tumour in later stages of the disease. We here propose a randomized trial in order to demonstrate that resection of the primary tumour improves overall survival. METHODS/DESIGN: The CAIRO4 study is a multicentre, randomized, phase III study of the Dutch Colorectal Cancer Group (DCCG). Patients with synchronous unresectable metastases of CRC and few or absent symptoms of the primary tumour are randomized 1:1 between systemic therapy only, and resection of the primary tumour followed by systemic therapy. Systemic therapy will consist of fluoropyrimidine-based chemotherapy in combination with bevacizumab. The primary objective of this study is to determine the clinical benefit in terms of overall survival of initial resection of the primary tumour. Secondary endpoints include progression free survival, surgical morbidity, quality of life and the number of patients requiring resection of the primary tumour in the control arm. DISCUSSION: The CAIRO4 study is a multicentre, randomized, phase III study that will assess the benefit of resection of the primary tumour in patients with synchronous metastatic CRC. TRIAL REGISTRATION: The CAIRO4 study is registered at clinicaltrials.gov (NCT01606098).