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Indication for primary tumour resection (PTR) in asymptomatic metastatic colorectal cancer (mCRC) patients is unclear. Previous retrospective analyses suggest a survival benefit for patients who underwent PTR. The aim was to evaluate the prognostic value of PTR in patients with synchronous mCRC by analysis of recent large RCTs including systemic therapy with modern targeted agents. Individual patient data (IPD) of 3423 patients enrolled into 8 randomised controlled trials (RCTs) with first-line systemic therapy in the ARCAD (Aide et Recherche en Cancerologie Digestive) database were analysed. The number of patients with unresected synchronous mCRC, resected synchronous mCRC and metachronous mCRC was 710 (21%), 1705 (50%) and 1008 (29%), respectively. Adjusting for age, gender, performance status (PS) and prior chemotherapy, the unresected group had a significantly worse median overall survival (16.4 m) compared with the synchronous resected (22.2 m; hazard ratio [HR] 1.60, 95% CI 1.43-1.78) and metachronous (22.4 m; HR 1.81, 95% CI 1.58-2.07) groups. Similarly, median progression-free survival was significantly worse for the unresected group compared with the synchronous resected (HR 1.31, 95% CI 1.19-1.44) and metachronous (HR 1.47, 95% CI 1.30-1.66) groups. In a multivariate analysis, the observed associations remained significant. This largest IPD analysis of mCRC trials to date demonstrates an improved survival in synchronous mCRC patients after PTR. These results may be subject to bias since reasons for (non) resection were not available. Until results of ongoing RCTs are available, both upfront PTR followed by systemic treatment and upfront systemic treatment are considered appropriate treatment strategies. (C) 2017 Elsevier Ltd. All rights reserved

Item does not contain fulltext INTRODUCTION: Performance status (PS) is an established prognostic factor in patients with advanced cancer and is usually scored by the treating physician. The EORTC QLQ-C30 questionnaire as reported by cancer patients is a validated tool to assess quality of life (QoL). Subjectivity plays a role in both assessments, and data on a direct comparison are scarce. METHODS: We compared the prognostic value for overall survival (OS) of the WHO PS to the baseline physical function scale of the EORTC QLQ-C30 (QLQ-C30 PF) in a prospective randomised phase 3 trial in advanced colorectal cancer (ACC), the CAIRO study. Patients were divided into two groups based on the baseline QLQ-C30 PF. QLQ-C30 PF was considered 'good' if the score was more than 66.7% and 'poor' if 66.7% or less. Results were validated in a subsequent phase 3 study in ACC, the CAIRO2 study. RESULTS: The median OS for patients with a 'good' QLQ-C30 PF and a 'poor' PF in patients with WHO PS 0 was 20.3 months (n = 300) and 10.4 months (n = 44), in patients with WHO PS 1 16.8 months (n = 125) and 10.1 months (n = 63), and in patients with WHO PS 2 16.2 months (n = 11) and 9.9 months (n = 12), respectively. In a Cox regression model which included other prognostic factors, 'good' versus 'poor' QLQ-C30 PF was significantly prognostic for OS (0.57 95% confidence interval: 0.46-0.72), but not WHO PS. These results were confirmed in the CAIRO2 study. CONCLUSIONS: We demonstrate in ACC patients that PF, as assessed by patients using the EORTC QLQ-C30, is superior in terms of prognostic value to WHO PS as scored by physicians. Our data support to include the results of baseline EORTC QLQ-C30 PF instead of WHO PS as a stratification parameter in oncology trials.

Item does not contain fulltext OBJECTIVE: To evaluate and compare the overall survival (OS) in case-matched patient groups treated either with systemic therapy or surgery for colorectal liver metastases (CRLM). METHODS: Patients with CRLM, without extra-hepatic disease, treated with chemotherapy with or without targeted therapy in two phase III studies (n = 480) were selected and case-matched to patients who underwent liver resection (n = 632). Matching criteria were sex, age, established prognostic factors for survival (clinical risk score). Available computed tomography (CT)-scans of patients treated with systemic therapies were reviewed by three independent liver surgeons for resectability. Survival was compared between patients with resectable CRLM (based on CT-scan review) who were treated with systemic therapy versus patients who underwent liver resection. RESULTS: A total of 96 patients treated with systemic therapy were included. Pre-treatment CT-scans of the liver were available for review in 56 of the systemically treated patients, and metastases were unanimously considered resectable in 36 patients (64.3%) (complex resectable: n = 25; 69%). These 36 patients were case-matched with 36 patients who underwent liver resection (wedge resection or segmentectomy: n = 26; 72%). Median OS in the patient group treated with systemic therapy was 26.5 months (range 0-81 months), which was significantly lower than that in case-matched patients who underwent liver resection (median OS 56 months; range 6-116) (p = 0.027). CONCLUSIONS: In this case-matched control study, surgery provided superior OS rates compared to systemic therapy for CRLM. Resection of CRLM should always be considered, preferably in a dedicated liver centre, since not all patients that qualify for resection are identified as such.

Background In patients with colorectal liver metastases (CLM) there is limited knowledge about the occurrence of radiological heterogeneity in response to chemotherapy. Methods A retrospective analysis was performed in the CAIRO and CAIRO II studies on the incidence of intermetastatic heterogeneity in patients with CLM and its association with survival. Mixed response (MR) was defined as >30% difference in individual lesion response, with all lesions showing a similar behaviour; true mixed response (TMR) as two lesions showing progression versus response; homogeneous response (HR) as similar behaviour of all lesions. Patients were classified according to the Response Evaluation Criteria in Solid Tumours (RECIST) categories (partial response (PR), stable disease (SD), progressive disease (PD), complete response (CR)) and then subdivided into MR and TMR in order to compare survival. Results In the CAIRO and CAIRO II studies, 140 and 150 patients with liver-only disease were identified. 73/290 (25.2%) patients showed MR, and 25/290 (8.6%) patients TMR, and 192/290 (66.2%) patients HR. Overall survival (OS) at 1–4 years was significantly higher for the homogeneous partial responders category compared to other response categories. Median OS was 22.0 months for the entire population. In the partial response category, patients with MR showed significant poorer survival compared to patients with HR (median OS 23.7 versus 36.0 months, respectively, p = 0.019). Multivariate analysis identified four independent predictors for OS: serum lactate dehydrogenase (LDH) level ( p = 0.002), number of first-line chemotherapy cycles ( p = 0.001), resection of primary tumour ( p = 0.001) and response category ( p = 0.012). Conclusion Radiological heterogeneity is present in approximately 35% of patients with CLM. Partial responders according to the RECIST criteria, show a significant poorer survival if classified as heterogeneous partial responder compared to homogeneous partial responders.

Item does not contain fulltext PURPOSE: Obesity is associated with an increased risk of development and recurrence of colorectal cancer. However, the role of obesity in advanced colorectal cancer (ACC) patients is unknown. We investigated the effect of body mass index (BMI) on overall survival (OS) in ACC patients receiving systemic treatment in two large phase III studies (CAIRO and CAIRO2). PATIENTS AND METHODS: Treatment data were obtained and analysed from 796 ACC patients who were treated with chemotherapy in the CAIRO study, and from 730 ACC patients who were treated with chemotherapy plus targeted therapy in the CAIRO2 study. Baseline height and weight were used to assign patients to one of the following BMI categories: A (

Item does not contain fulltext Surgery plays an important role in the treatment of patients with limited metastatic disease of colorectal cancer (CRC). Long term survival and cure is reported in 20-50% of highly selected patients with oligometastatic disease who underwent surgery. This paper describes the role of surgery of the primary tumour in patients with unresectable stage IV colorectal cancer. Owing to the increased efficacy of chemotherapeutic regimens in stage IV colorectal cancer, complications from unresected primary tumours are relatively infrequent. The risk of emergency surgical intervention is less than 15% in patients with synchronous metastatic disease who are treated with chemotherapy. Therefore, there is a tendency among surgeons not to resect the primary tumour in case of unresectable metastases. However, it is suggested that resection of the primary tumour in case of unresectable metastatic disease might influence overall survival. All studies described in the literature (n = 24) are non-randomised and the majority is single-centre and retrospective of nature. Most studies are in favour of resection of the primary tumour in patients with symptomatic lesions. In asymptomatic patients the results are less clear, although median overall survival seems to be improved in resected patients in the majority of studies. The major drawback of all these studies is that primarily patients with a better performance status and better prognosis (less metastatic sites involved) are being operated on. Another limitation of these studies is that few if any data on the use of systemic therapy are presented, which makes it difficult to assess the relative contribution of resection on outcome. Prospective studies on this topic are warranted, and are currently being planned. CONCLUSION: Surgery of the primary tumour in patients with synchronous metastasised CRC is controversial, although data from the literature suggest that resection might be a positive prognostic factor for survival. Therefore prospective studies on the value of resection in this setting are required.

Item does not contain fulltext BACKGROUND: Peripheral sensory neurotoxicity is a frequent and potentially debilitating side effect of oxaliplatin treatment. Calcium and magnesium (Ca/Mg) infusions are frequently used to prevent this toxicity. However, concerns about a negative impact of Ca/Mg infusions on outcome have been raised. We retrospectively assessed the effect of Ca/Mg infusions on the incidence of neurotoxicity and on clinical outcome in advanced colorectal cancer (ACC) patients treated in the phase III CAIRO2 study. MATERIALS AND METHODS: Seven hundred and fifty five previously untreated ACC patients were randomised between treatment with capecitabine, oxaliplatin and bevacizumab or the same combination with the addition of cetuximab. Patients were retrospectively divided into two groups: patients in the Ca/Mg(+) group received Ca/Mg at least during their first treatment cycle, and patients in the Ca/Mg(-) group did not. RESULTS: Seven hundred and thirty two patients were evaluable for this analysis. The Ca/Mg(+) group consisted of 551 patients, the Ca/Mg(-) group consisted of 181 patients. The incidence of all grade neurotoxicity in the Ca/Mg(+) group and the Ca/Mg(-) group was 85% and 92%, respectively (p = 0.02), and the incidence of grade >/= 2 neurotoxicity was 40% and 45%, respectively (p = 0.22). The median PFS in the Ca/Mg(+) versus Ca/Mg(-) group was 10.1 versus 10.7 months (p = 0.92), the median OS was 19.8 versus 20.7 months (p = 0.10), and the response rate was 43.1% versus 50% (p = 0.11), respectively. CONCLUSIONS: In this largest retrospective analysis to date we observed that Ca/Mg infusions significantly reduced all grade oxaliplatin-related neurotoxicity. Ca/Mg infusions did not affect the clinical efficacy of treatment.

Background Patient characteristics and stratification factors are important factors influencing trial outcomes. Uniform reporting on these parameters would facilitate cross-study comparisons and extrapolation of trial results to clinical practice. In 2007, standardisation on patient characteristics reporting and stratification in metastatic colorectal cancer (mCRC) trials was proposed. We investigated the reporting of prognostic factors and implementation of this proposal in mCRC trials published from 2005 to 2016. Methods We searched PubMed and Embase (January 2005 – June 2016) for first-line phase 3 mCRC trials. Patient characteristics reporting and use of stratification factors were extracted and analysed for adherence to the proposal from 2007. Results Sixty-seven trials (35,315 patients) were identified, reporting 48 different patient characteristics (median: 9 [range: 5–18] per study). Age, gender, performance status (PS), primary tumour site and adjuvant chemotherapy were frequently reported (87%–100%), in contrast to laboratory values, such as alkaline phosphatase, lactate dehydrogenase and white blood cell count (10%–25%). We identified 29 different stratification factors (median: 3 [range: 1–9] per study). The most common strata were PS and treatment centre (>60%). A median of 8/12 (range: 4–11) of the proposed parameters was reported. Although the percentage of studies reporting each factor slightly increased over time, there was no significant correlation between publication year and adherence to the proposal from 2007. Conclusions We observed persistent heterogeneity in the reporting of patient characteristics and use of stratification factors in first-line mCRC trials. The proposal from 2007 has not led to increased uniformity of patient characteristics reporting and use of stratification over time. There is an urgent need to address this issue to improve the interpretation of trial results.

Contains fulltext : 80535.pdf (Publisher’s version ) (Closed access) We have tested several biomarkers [dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT), thymidine phosphorylase (TP), thymidylate synthase (TS) and excision cross-complementing gene (ERCC1)] for their prognostic and predictive value in relation to the outcome of chemotherapy in tumour tissues of 556 advanced colorectal cancer (ACC) patients who were randomised between sequential treatment and combination treatment in the CApecitabine, IRinotecan, Oxaliplatin (CAIRO) study. DPD expression showed a statistically significant predictive value for combination treatment with capecitabine plus irinotecan with low versus high values resulting in an improved median progression-free survival (PFS) and median overall survival (OS) of 8.9 (95% confidence interval (CI) 8.3-9.9) versus 7.2 months (95% CI 6.5-8.1, p=0.006), and 21.5 months (95% CI 17.9-26.5) versus 16.9 months (95% CI 13.0-19.1, p=0.04), respectively. In the overall patient population a high OPRT expression in stromal cells was a favourable prognostic parameter for OS, with 21.5 months (95% CI 17.9-27.3) versus 17.2 months (95% CI 15.1-18.6, p=0.036), respectively. A similar effect was observed for PFS. In a multivariate analysis that included known prognostic factors these results remained significant and also showed that a high OPRT expression in tumour cells was an unfavourable prognostic parameter for PFS and OS. In conclusion, in this largest study on capecitabine with or without irinotecan to date we found a predictive value of DPD expression. Our results on the prognostic value of OPRT expression warrant further studies on the role of stromal cells in the outcome of treatments. The divergent results of ours and previous studies underscore the complexity of these biomarkers and currently prevent the routine use of these markers in daily clinical practice.