Integration of the cancer-related inflammatory response as a stratifying biomarker of survival in hepatocellular carcinoma treated with sorafenib

// Jessica A. Howell 1, 2, 3, * , David J. Pinato 1, * , Ramya Ramaswami 1 , Tadaaki Arizumi 4 , Carlotta Ferrari 5 , Antonello Gibbin 5 , Michela E. Burlone 5 , Giulia Guaschino 5 , Pierluigi Toniutto 6 , James Black 1 , Laura Sellers 1 , Masatoshi Kudo 4 , Mario Pirisi 5 and Rohini Sharma 1 1 Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK 2 Centre for Population Health, Burnet Institute, Melbourne, Australia 3 Department of Medicine, University of Melbourne, Melbourne, Australia 4 Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan 5 Department of Translational Medicine, Universita degli Studi del Piemonte Orientale “A. Avogadro”, Novara, Italy 6 Department of Experimental and Clinical Medicine, University of Udine, Udine, Italy * These authors have contributed equally to the work Correspondence to: Jessica A. Howell, email: jessica.howell@svha.org.au Keywords: liver cancer, VEGF inhibitor, CLIP score, BCLC, inflammation Received: March 30, 2016      Accepted: October 13, 2016      Published: February 14, 2017 ABSTRACT Background and Aims: Response to sorafenib is highly variable in hepatocellular carcinoma (HCC). Baseline inflammatory parameters and treatment toxicities may improve survival prediction in patients on sorafenib therapy. Results: 442 patients with advanced stage HCC on sorafenib were recruited (follow-up 5096 person-months at risk). 88% had BCLC stage B or greater HCC and 72.3% had Child-Pugh A cirrhosis. On Cox multivariate regression, previously-treated HCC (HR 0.579, 95% CI 0.385-0.872, p=0.009), Cancer of Liver Italian Program (CLIP) score (HR 1.723, 95% CI 1.462-2.047, p<0.0001), baseline red cell distribution width (RDW; HR 1.234, 95% CI 1.115-1.290, p<0.0001) and neutrophil to lymphocyte ratio (NLR; HR 1.218, 95% CI 1.108-1.322, p<0.0001) were significant independent risks for shorter survival, whilst sorafenib-related diarrhoea was associated with prolonged survival (HR 0.533, 95% CI 0.373-0.763, p=0.001). The combination of RD-CLIP score (CLIP score multiplied by RDW) ≥ 70 and no treatment-related diarrhoea had good utility for predicting 3-month survival (AUC of 0.808 (95% CI 0.734-0.882), positive predictive value of 86.4% and negative predictive value of 83.3%), compared with CLIP (AUC=0.642) or BCLC score alone (AUC=0.579). RD-CLIP score ≥ 35 and no treatment-related diarrhoea had an AUC of 0.787 for predicting 12-month survival. Methods: Patients with HCC were consecutively recruited from three tertiary centres (Japan, Italy and UK) and clinical data were prospectively collected. The primary study endpoint was overall survival (OS) after commencing sorafenib. Conclusion: The novel prognostic index of CLIP score combined with inflammatory marker RDW and treatment-related diarrhoea has good accuracy for predicting overall, 3 month and 12 month survival in patients on sorafenib.