Association of Sustained Response Duration With Survival After Conventional Transarterial Chemoembolization in Patients With Hepatocellular Carcinoma

Yaojun Zhang,Li Xu,Zhenwei Peng,Mengping Zhang,Jiaping Li,Jie Mei,Rongping Guo,Xiaojun Lin,Minshan Chen

doi:10.1001/jamanetworkopen.2018.3213

Abstract

Defining early reliable surrogate end points for survival in patients with hepatocellular carcinoma (HCC) after conventional transarterial chemoembolization (cTACE) is of great value. To evaluate the association between sustained response duration (SRD) and overall survival (OS) after cTACE for intermediate HCC. This multicenter cohort study enrolled 2403 consecutive patients in China with naive intermediate HCC between June 1, 2000, and December 31, 2008, as the primary cohort, and 331 consecutive patients with intermediate naive HCC between January 1, 2011, to June 30, 2012, as the validation cohort. All patients received cTACE as an initial treatment. Initial response and best response were defined as the radiological response after first cTACE or best radiological response after 2 or more sessions of cTACE, respectively. Responders were those who experienced complete response or partial response. Sustained response duration was defined as the time between the date when complete response, partial response, or stable disease was achieved and the date progressive disease occurred after cTACE. Response was evaluated by modified Response Evaluation Criteria in Solid Tumors. Information about patients in the study was collected from January 1, 2018, to March 31, 2018, and analysis of these data was performed in April 2018. Overall survival. A total of 2734 total patients (2499 of 2734 [91.4%] male; median [range] age, 56.5 [18-75] years) were included in the analysis. In the primary cohort, SRD of 6 months or more was found to have the strongest association with 5-year OS after cTACE among different durations of sustained response. Patients with SRD of 6 months or more (387 of 430 male; median [range] age, 57 [18-75] years) had the longest median (range) OS (67.7 [64.8-72.1] months), followed by initial responders (760 of 874 male; median [range] age, 56 [18-75] years; median [range] OS, 55.8 [55.0-57.7] months) and best responders (939 of 1032 male; median [range] age, 57 [18-75] years; median [range] OS, 53.2 [52.2-54.6] months). Response duration of 6 months or more was found to be an independent prognostic factor for OS (hazard ratio, 0.145; 95% CI, 0.124-0.170; P < .001). The significance of SRD as a factor associated with OS was confirmed in the validation cohort. Sustained response duration of 6 months or more was associated with OS and may serve as an early surrogate end point after cTACE for intermediate HCC.

Highlights

Sustained response duration of 6 months or more was associated with overall survival (OS) and may serve as an early surrogate end point after Conventional transarterial chemoembolization (cTACE) for intermediate Hepatocellular carcinoma (HCC)
Meaning Sustained response duration of 6 months or more was associated with OS and may serve as an early surrogate end point after conventional transarterial chemoembolization for intermediate hepatocellular carcinoma
Optimal Predictable sustained response duration (SRD) Length Category for OS By using the time-dependent area under the receiver operating characteristic curve (AUROC), SRD of 6 months or more was found to have the strongest association with 5-year OS after cTACE among the different durations of response

Summary

Introduction

Hepatocellular carcinoma (HCC) is a global, continuously growing public health problem. Conventional transarterial chemoembolization (cTACE) has been widely recognized as the mainstay of therapy for intermediate HCC according to the Barcelona Clinic Liver Cancer staging system.1-5According to modified Response Evaluation Criteria in Solid Tumors (mRECIST), radiological response is the most common criterion used to evaluate efficacy of cTACE on the basis of tumor viability. Generally, necrosis response is postulated to be an early surrogate for therapeutic benefit after treatment. According to mRECIST, complete response (CR) after initial cTACE is considered to be a predictor for favorable outcome. radiological CR after cTACE does not always match histological complete tumor necrosis. Existence of residual viable tumor cells that are just stunned and can later recover, causing relapse, has been hypothesized. In addition, the embolic nature of cTACE causing hypoxia can result in upregulation of vascular endothelial growth factor. Upregulation of vascular endothelial growth factor or cytokines can increase tumor angiogenesis or tumor cell proliferation, contributing to treatment failure. These facts imply that mRECIST might exaggerate or overestimate the efficacy of cTACE based on early image response. Upregulation of vascular endothelial growth factor or cytokines can increase tumor angiogenesis or tumor cell proliferation, contributing to treatment failure.7 These facts imply that mRECIST might exaggerate or overestimate the efficacy of cTACE based on early image response. Sustained CR has been demonstrated to be associated with favorable outcome after local therapy, such as radiofrequency ablation.13 This implies that maintaining the status of response, rather than achieving the robust response itself, may be more clinically important for survival after cTACE. We know of no studies exploring the role of sustained response duration (SRD), defined as the time between the date when CR, PR, or stable disease is achieved and the date progressive disease occurs in predicting clinical prognosis of HCC after cTACE.

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Conclusion