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

Abstract

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.

Influence of neoadjuvant chemotherapy on resection of primary colorectal liver metastases: A propensity score analysis

“…As a matter of fact, there is little evidence on whether NC prior to surgery improves the OS of these patients and especially patients with a high risk of relapse (MSKCC >2). Furthermore, results from powerful randomized controlled trials (RCT), such as the CHARISMA trial, that address this question, are either rare or still pending …”

“…Furthermore, results from powerful randomized controlled trials (RCT), such as the CHARISMA trial, that address this question, are either rare or still pending. 10 Therefore, the aim of the present study was to investigate the role of NC in patients with primary CRLM. During the clinical course, the patient developed metachronous liver metastases and liver resection was performed within 6 months after the first operation.…”

mRNA expression profiles of colorectal liver metastases as a novel biomarker for early recurrence after partial hepatectomy

“…Identification of patients for neo‐adjuvant (preoperative) therapy is certainly possible since prognostic gene expression profiles may be detected in liquid biopsies before surgery (Mostert et al., 2013, 2015). Currently the clinical risk scores do not impact clinical management, although some retrospective reports have suggested they may be effective (Ayez et al., 2015a; Rahbari et al., 2014) (this is prospectively investigated at present in the CHARISMA trial (Ayez et al., 2015b)). There may be a synergistic effect between the clinical risk score and the molecular score of the current study.…”

“…Natural killer group 2, member D ligand ULBP2 and Ras‐GAP binding protein G3BP2 are two extrinsic stress induced proteins contributing to progression. ULBP2, whose expression is low in patients having an early recurrence and whose receptor is on the surface of natural killer (NK) cells and specific T‐cells, implies immune modulation (Ayez et al., 2015b) in recurrence. G3BP2 is known to affect matrix stiffness as does RPUSD1 (RNA pseudouridylate synthase domain containing 1) by controlling lateral growth of collagen II fibrils.…”

Treatment sequencing for simultaneous colorectal liver metastases

“…CRS is useful for providing prognostic information but is unable to exclude any particular patient from potentially curative surgery . Furthermore, though it is generally accepted that patients with high clinical risk require chemotherapy, this has not been proven in clinical trials and is still under investigation …”