| BackgroundAccording to the cancer statistics published by the National Central Cancer Registry of China in 2015,primary liver cancer is of high incidence in our country,which annual morbidity and mortality rates ranked fourth among all malignant tumors.Before the age of 60 years in men,liver cancer is the most commonly diagnosed cancer and the leading cause of death.Liver cancer often develops in a very insidious manner: symptoms and signs are absent or subtle.Coupled with the rapid progress of hepatocellular carcinoma(HCC),75% of patients are diagnosed as a advanced stage with portal vein tumor thrombus or distant metastasis and have no opportunity to get cutative surgery.According to the guidelines of Barcelona Clinic Liver Cancer(BCLC)staging system,sorafenib is the only proven,current standard first-line therapy for HCC patients who have advanced stage(BCLC-C).However,most patients emerge disease progression with primary or secondary resistance to the drug.However,currently,there are no standard second-line treatments for these patients.In addition,the determinants of survival and prognosis in patients with BCLC-C HCC after sorafenib failure have not been well analyzed.At the same time,the current second-line therapies are diverse,however,its potential efficacy is unclear.ObjectiveTo analyze the determinants of survival and prognosis in patients with BCLC-C HCC after sorafenib failure.To evaluate the potential efficacy of second-line therapies in BCLC stage C patients refractory or intolerant to sorafenib.MethodsAll patients diagnosed with HCC receiving sorafenib treatment during the period from 2008 to 2016 in Shandong Cancer Hospital were analyzed retrospectively.Cases were retained only if they met the following criteria: BCLC stage C with macroscopic vascular invasion or extrahepatic metastasis,an Eastern Cooperative Oncology Group(ECOG)performance status score of ≤2,and Child–Pugh class A.Overall survival(OS)was defined as the time from starting sorafenib treatment to death from any cause.Progression-free survival(PFS)was defined as the time from starting sorafenib treatment to disease progression.Postprogression survival(PPS)was defined as the time from disease progression to death.The following variables were recorded for analysis at the time of receiving sorafenib treatment and disease progression: general clinical features,causes of treatment failure,and the patterns of tumor progression.Second-line therapies in patients after sorafenib failure were divided into 3 groups according to the different treatment modalities: group A,local therapies targeting intrahepatic lesions;group B,systemic therapies(chemoradiotherapy)alone;group C,best supportive care alone.Analysis of prognostic factors for PFS,PPS,and OS was performed using the univariate analysis and multivariate analysis.Potential efficacy of second-line therapies in patients after sorafenib failure was estimated by the Kaplan–Meier method and compared by the log-rank test.P<0.05 was considered statistically significant.ResultsA total of 136 patients were enrolled in this study.The patients were 121(89.0%)males and 15(11.0%)females.The mean age was 54.1 ± 9.1 years.Median follow-up was 8.7 months(range,1.0-38.5 months).At the end of follow-up,disease progression(PD)occurred in 107(78.7%)patients.Before PD,twenty-three(16.9%)patients deteriorated liver functions.Additionally,serious adverse drug reaction occurred in 6(4.4%)patients and 114(83.8%)deaths occurred.The median PFS,PPS,and OS were 3.4,2.8,and 7.0 months,respectively.In terms of outcomes according to initial tumor status,patients with extrahepatic metastasis only had better survival and prognosis than those with portal vein invasion.Performance status(ECOG),aspartate aminotransferase(AST)levels at the time of initial receiving sorafenib treatment and dose reduction of sorafenib were independent influencing factors for PFS.The HR(95%CI)were 1.781(1.123–2.825),1.694(1.208–2.746),and 0.386(0.276–0.738),respectively.Deteriorated performance status(ECOG),deteriorated liver functions(Child-Pugh),tumor status(BCLC),total bilirubin levels,time to diease progression,and the patterns of tumor progression at the time of disease progression were independent influencing factors for PPS.The HR(95%CI)were 7.582(3.664–15.121),6.342(3.148–9.378),2.428(1.392–4.234),2.228(1.227–3.856),5.886(2.774–11.575),1.712(1.092–2.824),respectively.Baseline performance status(ECOG),tumor size,alpha-fetoprotein(AFP),causes of treatment failure,and the time to diease progression were independent influencing factors for PPS.The HR(95%CI)were 1.878(1.228–2.986),1.445(1.013–2.641),1.763(1.123–2.877),2.224(1.162–3.626),5.523(2.746–9.316),respectively.At the time of diease progression,patients who maintained well performance status(ECOG ≤2)and liver functions(Child–Pugh class A or B)continuned to receive second-line treatments.There were 23(27.1%),28(32.9%),and 34(40.0%)patients classified as group A(those who received local therapies targeting intrahepatic lesions),B(those who received only systemic therapy),and C(those who received best supportive care alone),respectively.Median PPS for patients in groups A,B,and C were 5.0,2.6,and 2.5 months,respectively.Survival after sorafenib treatment of group A was significantly longer compared with that of group C(p<0.001).In terms of conventional second-line treatments after sorafenib failure,those local therapies targeting intrahepatic lesions,such as palliative transarterial chemoembolization,hepatic arterial infusion chemotherapy,radiofrequency ablation,or local radiotherapy may be useful for extending PPS and OS.ConclusionsCurrently,there are no standard second-line treatments for the patients with BCLC-C HCC after sorafenib failure.Performance status,liver functions,time to diease progression,and the patterns of tumor progression are important determinants of survival and prognosis after sorafenib failure in patients with BCLC-C HCC.The current second-line therapies remain emphasize the conventional treatments,such as local therapies targeting intrahepatic lesions,systemic therapies(chemoradiotherapy),and best supportive care.Based on the above reserach,we recommend local therapies targeting intrahepatic lesions for those patients,which may be useful to prolong PPS and OS. |
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