Eric P. van der Stok

Neo-adjuvant chemotherapy followed by surgery versus surgery alone in high-risk patients with resectable colorectal liver metastases: The CHARISMA randomized multicenter clinical trial

BackgroundEfforts to improve the outcome of liver surgery by combining curative resection with chemotherapy have failed to demonstrate definite overall survival benefit. This may partly be due to the fact that these studies often involve strict inclusion criteria. Consequently, patients with a high risk profile as characterized by Fong’s Clinical Risk Score (CRS) are often underrepresented in these studies. Conceptually, this group of patients might benefit the most from chemotherapy. The present study evaluates the impact of neo-adjuvant chemotherapy in high-risk patients with primary resectable colorectal liver metastases, without extrahepatic disease. Our hypothesis is that adding neo-adjuvant chemotherapy to surgery will provide an improvement in overall survival (OS) in patients with a high-risk profile.Methods/DesignCHARISMA is a multicenter, randomized, phase III clinical trial. Patients will be randomized to either surgery alone (standard treatment, arm A) or to 6 cycles of neo-adjuvant oxaliplatin-based chemotherapy, followed by surgery (arm B). Patients must be ≥ 18 years of age with liver metastases of histologically confirmed primary colorectal carcinoma. Patients with extrahepatic metastases are excluded. Liver metastases must be deemed primarily resectable. Only patients with a CRS of 3–5 are eligible. The primary study endpoint is OS. Secondary endpoints are progression free survival (PFS), quality of life, morbidity of resection, treatment response on neo-adjuvant chemotherapy, and whether CEA levels can predict treatment response.DiscussionCHARISMA is a multicenter, randomized, phase III clinical trial that will provide an answer to the question if adding neo-adjuvant chemotherapy to surgery will improve OS in a well-defined high-risk patient group with colorectal liver metastases.Trial registrationThe CHARISMA is registered at European Union Clinical Trials Register (EudraCT), number: 2013-004952-39, and in the “Netherlands national Trial Register (NTR), number: 4893.

International consensus guidelines for scoring the histopathological growth patterns of liver metastasis

Background:Liver metastases present with distinct histopathological growth patterns (HGPs), including the desmoplastic, pushing and replacement HGPs and two rarer HGPs. The HGPs are defined owing to the distinct interface between the cancer cells and the adjacent normal liver parenchyma that is present in each pattern and can be scored from standard haematoxylin-and-eosin-stained (H&E) tissue sections. The current study provides consensus guidelines for scoring these HGPs.Methods:Guidelines for defining the HGPs were established by a large international team. To assess the validity of these guidelines, 12 independent observers scored a set of 159 liver metastases and interobserver variability was measured. In an independent cohort of 374 patients with colorectal liver metastases (CRCLM), the impact of HGPs on overall survival after hepatectomy was determined.Results:Good-to-excellent correlations (intraclass correlation coefficient >0.5) with the gold standard were obtained for the assessment of the replacement HGP and desmoplastic HGP. Overall survival was significantly superior in the desmoplastic HGP subgroup compared with the replacement or pushing HGP subgroup (P=0.006).Conclusions:The current guidelines allow for reproducible determination of liver metastasis HGPs. As HGPs impact overall survival after surgery for CRCLM, they may serve as a novel biomarker for individualised therapies.

Surveillance after curative treatment for colorectal cancer

Treatments for colorectal cancer (CRC) of all stages have evolved considerably over the past two decades, resulting in improved long-term outcomes. After curative treatment, however, 30% of patients with stage I–III and up to 65% of patients with stage IV CRC develop recurrent disease. Thus, patients are routinely offered surveillance in order to detect disease recurrence at an early, asymptomatic stage, with the intention of improving survival. Nevertheless, controversy continues to surround the optimal surveillance protocols. For patients with stage I–III CRC, more-intensive surveillance improves overall survival compared with less-intensive or no surveillance, probably owing to improved outcomes after cancer recurrence, as well as proactive treatment of other conditions detected opportunistically. The benefit of surveillance after curative treatment of stage IV CRC is more controversial, but might be justified because repeat resection can improve overall survival and 20% of these patients are eligible for such treatment with curative intent. No trials have assessed the optimal follow-up approach after curative resection of metastatic CRC, and similarly to surveillance of patients with stage I–III disease, most programmes are more intensive during the first 3 years than at later time points. Herein, we provide a comprehensive overview of surveillance strategies for patients with CRC, and discuss the future development of patient-centred programmes.

Neo-adjuvant chemotherapy followed by surgery versus surgery alone in high-risk patients with resectable colorectal liver metastases: The CHARISMA randomized multicenter clinical trial.

TPS790 Background: Colorectal carcinoma is a leading cause of cancer death worldwide, mostly as a consequence of metastatic disease. If metastases are confined to the liver, surgical resection is the only therapy providing potential for cure. Efforts to improve the outcome of hepatectomy for colorectal liver metastases (CRLM) by combining surgery with chemotherapy have failed to demonstrate overall survival (OS) benefit. This may partly be explained by the fact that previous trials on this subject involved strict inclusion criteria. Consequently, patients with a high oncological risk profile - who might benefit the most from chemotherapy – might have been underrepresented in previous trials. Several Clinical Risk Scores (CRS) have been developed predicting patients’ prognosis after resection of CRLM. The most widely used and validated CRS was described by Fong et al., which characterizes 2 risk groups (high versus low) based on 5 independent clinicopathologic prognostic variables. Each variable is assigne...

Abstract LB-291: Central obesity drives oesophageal tumor cell growth through VEGF-mediated mechanisms

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Introduction : Obesity is a risk-factor for both esophageal/colorectal adenocarcinoma. Adipose tissue is an endocrine organ secreting numerous factors, including Vascular Endothelial Growth Factor (VEGF). VEGF was identified to be up-regulated in cancer cells by affymetrix-array following co-culture with human omental adipose tissue (OAT). An understanding of the mechanisms driving obesity-related disease is needed to uncover pathways and develop new targets for therapy. In this study, we aimed to investigate the effect of OAT-derived VEGF on tumor growth and the potential of bevacizumab to block this effect. Methods : Matched subcutaneous and omental adipose tissue, serum and tumor were harvested from oesophageal/colorectal cancer patients undergoing resective surgery. VEGF was quantified in adipose conditioned media (ACM) and serum by ELISA. Proliferation of esophageal (OE33, JH-ESO) and colorectal (HCT15, SW480) cells following culture with ACM was assessed by BrdU assay. The protective effect of ACM on chemotherapy (cisplatin and 5FU) induced death was assessed. The effect of bevacizumab in attenuating these effects was also examined. VEGF and VEGF receptor 2 (KDR) expression was assessed in tumor tissue by qPCR. In a 200-patient tissue microarray, VEGF and VEGFR expression was related to clinico-pathological parameters and obesity status. Results : ACM from omental adipose tissue of obese patients significantly (p<0.05) increased proliferation in oesophageal (313%) and colorectal (424%) adenocarcinoma cell lines relative to omental adipose tissue from non-obese cancer patients (180% and 157% respectively). Interestingly, this effect was not observed in ACM from matched subcutaneous depots indicating that omental adipose tissue is more pro-tumor and metabolically active. Omental ACM from obese patients contained significantly higher levels of VEGF (p<0.05). In our patient cohort, serum VEGF was significantly elevated in centrally obese relative to normal weight cancer patients (determined by CT). There was a significant (p<0.05) higher expression of VEGF and KDR expression in esophageal tumours from centrally obese patients. The expression of KDR was higher in the leading edge of tumors from patients classified as obese, and was associated with decreased survival and increased nodal involvement. ACM from omental adipose tissue protected against 5FU-induced cell death (P<0.01), an effect which could be blocked by treatment with bevacizumab. Conclusion : VEGF from OAT increased proliferation in oesophageal/colorectal cancer cells. VEGF and KDR expression in oesophageal cancer was higher in centrally obese patients. ACM protected against chemotherapy-induced death, an effect that was mediated through VEGF. These findings suggest anti-VEGF strategies are warrented in obesity-associated malignancies, alone or in combination with conventional chemotherapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-291. doi:10.1158/1538-7445.AM2011-LB-291