Prediction of post-progression survival in patients with advanced hepatocellular carcinoma treated with sorafenib by using time-dependent changes in clinical characteristics

Abstract

Aim: Sorafenib has been shown to improve time to tumor progression (TTP) and overall survival (OS) in patients with hepatocellular carcinoma (HCC); however, post-progression survival (PPS) has not been well characterized in these patients. This study aimed to evaluate the predictors of PPS by using time-dependent and dynamic changes in radiologic progression patterns, liver function, and performance status (PS) in patients with advanced HCC receiving sorafenib treatment.

Methods: We retrospectively analyzed the clinical characteristics of 128 advanced HCC patients with Child-Pugh scores ≤ 7 at the initiation of sorafenib treatment.

Results: The median TTP, OS, and PPS were 3.8, 15.6, and 9.9 months, respectively. At the time of confirmation of radiologic progressive disease (PD), a total of 46 (35.6%) patients showed impairments in their PS of ≥ +1 points over time. For the Child-Pugh score, 27 (21.1%) and 26 (10.9%) patients exhibited an impairment of ≥ +1 and ≥ +2 points, respectively. Multivariate analysis identified the following independent predictors of PPS: impairment in the PS score of ≥ +1 point [hazard ratio (HR) 1.81, 95% confidence interval (CI) 1.16-2.82], impairment in the Child-Pugh score of ≥ +2 points (HR 3.70, 95% CI 1.68-8.15), radiologic pattern of progression (target lesion growth and emergence of a new lesion) (HR 2.91, 95% CI 1.79-2.91), a TTP < 4 months (HR 1.87, 95% CI 1.21-2.91), second-line treatment after radiologic confirmation of PD (HR 0.16, 95% CI 0.08-0.32), and continuous sorafenib treatment after radiologic confirmation of PD (HR 1.76, 95% CI 1.06-3.00).

Conclusion: PPS in patients with advanced HCC can be characterized by using time-dependent dynamic changes in clinical parameters.

Keywords

Contactin-associated protein-2 / Isaac / neuromuscular hyperexcitability / neuromyotonia / voltage-gated potassium channel

References

[1] European Association for the Study of the Liver; European Organisation for Research and Treatment of Cancer.EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma..J Hepatol2012;56:908-43

[2] Bruix J.Management of hepatocellular carcinoma: an update..Hepatology2011;53:1020-2 PMCID:PMC3084991

[3] Giannini EG,Ciccarese F,Rapaccini GL,Benvegnu L,Zoli M,Chiaramonte M.Prognosis of untreated hepatocellular carcinoma..Hepatology2015;61:184-90

[4] Llovet JM,Mazzaferro V,Gane E,de Oliveira AC,Raoul JL,Schwartz M,Zeuzem S,Greten TF,Seitz JF,Haussinger D,Shan M,Voliotis D.Sorafenib in advanced hepatocellular carcinoma..N Engl J Med2008;359:378-90

[5] Cheng AL,Chen Z,Qin S,Luo R,Ye S,Xu J,Liang H,Wang J,Pan H,Zou J,Guan Z.Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial..Lancet Oncol2009;10:25-34

[6] Cheng AL,Lin DY,Kudo M,Chung HC,Xu J,Omata M,Lanzalone S,Lechuga MJ.Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial..J Clin Oncol2013;31:4067-75

[7] Johnson PJ,Park JW,Raoul JL,Hsu CH,Heo J,Lu L,Boucher E,Paik SW,Kudo M,Sobhonslidsuk A,Decaens T,Jeng LB,Ezzeddine R,Cheng AL.Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study..J Clin Oncol2013;31:3517-24

[8] Cainap C,Huang WT,Pan H,Kudo M,Chen PJ,Gorbunova V,Qian J,Ricker JL,El-Nowiem S.Linifanib versus sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial..J Clin Oncol2015;33:172-9 PMCID:PMC4279237

[9] Zhu AX,Evans TR,Santoro A,Bruix J,Thuluvath PJ,Leberre MA,Meinhardt G.SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma..J Clin Oncol2015;33:559-66

[10] Llovet JM,Raoul JL,Kudo M,Kang YK,Lim HY,Mathurin P,Lin DY,Poon RT,Blanc JF,Tak WY,Ezzeddine R,Walters I.Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study..J Clin Oncol2013;31:3509-16

[11] Zhu AX,Assenat E,Kang YK,Poon RT,Vogel A,Dorval E,Santoro A,Furuse J,Perraud K,Sellami DB.Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial..JAMA2014;312:57-67

[12] Zhu AX,Ryoo BY,Poon R,Blanc JF,Baron AD,Okusaka T,Trojan J,Chau I,Abada PB,Schwartz JD.Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial..Lancet Oncol2015;16:859-70

[13] Llovet JM,Lathia CD,Meinhardt G.Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma..Clin Cancer Res2012;18:2290-300

[14] Bruix J,Merle P,Huang YH,Pracht M,Rosmorduc O,Gerolami R,Ross PJ,Bronowicki JP,Kudo M,Llovet JM,LeBerre MA,Meinhardt G.Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial..Lancet2017;389:56-66

[15] Lencioni R.Modified RECIST (mRECIST) assessment for hepatocellular carcinoma..Semin Liver Dis2010;30:52-60

[16] Hotta K,Fujiwara Y,Hisamoto A,Tabata M.Role of survival post-progression in phase III trials of systemic chemotherapy in advanced non-small-cell lung cancer: a systematic review..PLoS One2011;6:e26646 PMCID:PMC3219633

[17] Saad ED,Buyse M.Overall survival and post-progression survival in advanced breast cancer: a review of recent randomized clinical trials..J Clin Oncol2010;28:1958-62

[18] Petrelli F.Correlation of progression-free and post-progression survival with overall survival in advanced colorectal cancer..Ann Oncol2013;24:186-92

[19] Reig M,Torres F,Rodriguez-Lope C,Llarch N,Ayuso C.Postprogression survival of patients with advanced hepatocellular carcinoma: rationale for second-line trial design..Hepatology2013;58:2023-31

[20] Lee IC,Chao Y,Li CP,Lin HC,Huang YH.Determinants of survival after sorafenib failure in patients with BCLC-C hepatocellular carcinoma in real-world practice..Medicine (Baltimore)2015;94:e688 PMCID:PMC4554055

[21] Hsu CY,Hsia CY,Su CW,Lee RC,Lee FY.Performance status in patients with hepatocellular carcinoma: determinants, prognostic impact, and ability to improve the Barcelona Clinic Liver Cancer system..Hepatology2013;57:112-9

[22] Huitzil-Melendez FD,O'Reilly EM,Gansukh B,Abou-Alfa GK.Advanced hepatocellular carcinoma: which staging systems best predict prognosis?.J Clin Oncol2010;28:2889-95 PMCID:PMC3651603

[23] Wada Y,Tateishi M,Mikagi K.The efficacy of continued sorafenib treatment after radiologic confirmation of progressive disease in patients with advanced hepatocellular carcinoma..PLoS One2016;11:e0146456 PMCID:PMC4706384

[24] Nakano M,Kuromatsu R,Satani M,Okamura S,Shimose S,Noda Y,Torimura T.Alternative treatments in advanced hepatocellular carcinoma patients with progressive disease after sorafenib treatment: a prospective multicenter cohort study..Oncotarget2016;7:64400-9 PMCID:PMC5325452

[25] Marrero JA,Venook AP,Bronowicki JP,Dagher L,Geschwind JH,Papandreou C,Sanyal AJ,Nakajima K,Heldner S.Observational registry of sorafenib use in clinical practice across child-pugh subgroups: the gideon study..J Hepatol2016;65:1140-7

[26] Kaneko S,Matsuzaki Y,Minami H,Sunaya T,Inuyama L.Safety and effectiveness of sorafenib in Japanese patients with hepatocellular carcinoma in daily medical practice: interim analysis of a prospective postmarketing all-patient surveillance study..J Gastroenterol2016;51:1011-21 PMCID:PMC5037148

[27] Kudo M,Chida N,Tak WY,Yoon JH,Kumada H,Kaneko S,Suh DJ,Okusaka T,Matsui O,Yamaguchi I,Meinhardt G.Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma..Eur J Cancer2011;47:2117-27in Japanese