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  • Original Article
  • OPEN ACCESS

Efficacy and Safety of Second-line Treatments in Patients with Advanced Hepatocellular Carcinoma after Sorafenib Failure: A Meta-analysis

  • Limin An1,# ,
  • Haotian Liao1,# and
  • Kefei Yuan1,2,* 
 Author information
Journal of Clinical and Translational Hepatology 2021;9(6):868-877

DOI: 10.14218/JCTH.2021.00054

Abstract

Background and Aims

In the last decade, several second-line therapies followed by sorafenib in patients with advanced hepatocellular carcinoma (HCC) have been reported. But the outcomes were different from each other. This meta-analysis aimed to evaluate the efficacy and safety of the second-line therapies followed by sorafenib in patients with advanced HCC.

Methods

Embase (1974 to October 2019) and Ovid MEDLINE (1946 to October 2019) were searched for randomized clinical trials on second-line therapies followed by sorafenib in patients with advanced HCC. The quality of each study was assessed by the modified Jadad scale. Statistical analysis was carried out by RevMan5.3 software. Efficacy and safety were analyzed. Efficacy included overall survival (OS), disease control rate, time to progression, and progression-free survival.

Results

Eight studies involving 3,173 patients were eligible. No difference in OS was found between the second-line treatment group and the control group (HR=0.87, 95% CI: 0.74–1.01, p=0.06). Disease control rate (relative risk (RR)=1.36, 95% CI: 1.16–1.60, p=0.0002), time to progression (HR=0.64, 95% CI: 0.51–0.81, p=0.0002) and progression-free survival (HR=0.60, 95% CI: 0.46–0.77, p<0.0001) were significantly improved by the second-line therapies. There was a slight difference in adverse events of any grade (RR=1.07, 95% CI: 1.00–1.14, p=0.03) between the two groups.

Conclusions

These second-line therapies followed by sorafenib may potentially improve the prognosis in patients with advanced HCC. Compared with other second-line therapies, regorafenib seemed to be more effective.

Keywords

Hepatocellular carcinoma, Therapeutics, Sorafenib, Systematic review, Meta-analysis

Introduction

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and remains a worldwide disease burden.1,2 The tyrosine kinase inhibitor (TKI) sorafenib has become the standard first-line therapy for patients with advanced HCC who are not candidates for locoregional therapy. Moreover, it has shown survival benefits over placebo.3,4 However, for most patients, the benefits of sorafenib are not sustainable and the disease eventually progresses.5 Furthermore, many patients will experience dose reduction and treatment discontinuation due to the high rate of adverse events (AEs).6–8 It has been reported that 40–56% of patients were potentially amenable to second-line clinical trials due to resistance to sorafenib.9 In the last decade, several second-line therapies, such as cabozantinib,10 pembrolizumab11 and ADI-PEG,12 have been reported. However, the outcomes were different from each other. Therefore, there is still no standard second-line treatment followed for sorafenib.13,14

Therefore, this meta-analysis of randomized controlled trials (RCTs) was conducted to evaluate the efficacy and safety of the second-line therapies followed by sorafenib.

Methods

Search strategy

This systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines (http://www.prisma-statement.org/ ).15 A comprehensive search of studies was performed in Embase (1974 to October 2019) and Ovid MEDLINE (1946 to October 2019). The search terms were: hepatocellular carcinoma, liver cancer, HCC, nexavar, BAY 43-9006, BAY 43 9006, BAY 439006, sorafenib N-oxide, sorafenib N oxide, BAY-673472, BAY 673472, BAY 545-9085, BAY 545 9085, BAY 5459085, BAY-545-9085, BAY5459085, and sorafenib tosylate. We also manually searched the reference lists of the identified studies for related articles. Two authors (LA and HL) independently screened titles and abstracts. We obtained full texts for further assessment if the publications potentially met the inclusion criteria. Any disagreement between the two authors would be solved by consulting the third author (KY).

Inclusion and exclusion criteria

The eligibility criteria for this study were as follows: 1. Only patients (age >18 years) with advanced HCC-confirmed progression during or after sorafenib treatment or sorafenib resistance were included in these trials. 2. RCTs that compared the second-line treatment with placebo or best supportive care were included. 3. Any of the following data was reported in the articles: overall survival (OS) (defined as the time from the date of randomization to that of death of any cause), disease control rate (DCR) (defined as the percentage of patients who achieved complete, partial response or stable disease), time to progression (TTP) (defined as the time from the date of randomization to that of first observation of disease progression), progression-free survival (PFS) (defined as the time from date of randomization to that of first observation of recurrence or death due to any cause) or AEs (such as decreased appetite, edema peripheral and diarrhea).

Animal studies, reviews, letters, editorials, commentaries, abstracts, unpublished studies, case reports, duplicate studies, and studies without full articles were excluded. Also, we excluded studies that involved some patients who received other therapies instead of sorafenib as the first-line treatment.

Data extraction

The extracted data included: general information, such as year of publication, sample size, and geographical region; population characteristics, including Eastern Cooperative Oncology Group (ECOG) performance status, Barcelona Clinic Liver Cancer (BCLC) stage, Child-Pugh score, α-fetoprotein (AFP), characteristics of the previous sorafenib therapy and the reasons for discontinuation of sorafenib; characteristics of the second-line treatment; primary outcome: median OS, hazard ratios (HRs) and their 95% confidence intervals (CIs) and log-rank p values; Secondary outcomes: median PFS and median TTP with HRs and their 95% CIs and log-rank p values, number of patients who achieved disease control and number and type of adverse events.

Two authors (LA and HL) independently extracted the data using a standardized data collection form. Any disagreement was solved by discussion with the third author (KY) and a consensus was finally achieved.

Quality assessment

The quality of each study was assessed by the modified Jadad scale.16 Six items were included in the modified Jadad scale, the full score of which was 8 points. A higher score indicates better quality.16 For each question, we awarded one point for an affirmative response or zero points for a negative response. These six items were: (i) was the study described as randomized? “yes or no”; award a bonus point if the method of randomization is appropriate (score 2) (e.g., computer-generated), deduct one point if the method of randomization is inappropriate (score 1); (ii) was the study described as double-blind? “yes or no”; award a bonus point if the method of double-blinding is appropriate (score 2) (e.g., identical placebo), deduct one point if the method of double-blinding is inappropriate (score 1); (iii) was there a description of withdrawals and dropouts? “yes (score 1) or no (score 0)”; (iv) was there a clear description of the inclusion/exclusion criteria? “yes (score 1) or no (score 0)”; (v) was the method used to assess adverse effects described? “yes (score 1) or no (score 0)”; (vi) were the methods of statistical analysis described? “yes (score 1) or no (score 0)”.16

Two authors (LA and HL) performed the assessments independently. They resolved disagreements by discussion with the third author (KY).

Statistical analysis

Meta-analysis was performed with Cochrane Collaboration’s Review Manager (version 5.3). Continuous variables were assessed by calculating HRs with their 95% CIs. Results were showed by forest plots. Treatment effects were expressed as relative risks (RRs) with 95% CIs for discontinuous outcomes and HRs for continuous outcomes. It was considered statistically significant when p was <0.05. Heterogeneity of the studies was measured by the I2 statistic.17 If I2 <50%, it represented homogeneity and we would use the fixed-effects model.18 Otherwise, we would use the random-effects model.18 Subgroup analysis and sensitivity analysis would be performed if heterogeneity existed.

Results

Study selection

A total of 906 studies were identified. The results of literary searches are presented in Figure 1. After adjusting for duplicates, 676 remained. By reviewing abstracts, 661 studies were excluded because these studies clearly did not meet the eligibility criteria. Subsequently, the full text of the remaining 15 citations was examined in more detail. Five studies were excluded because sorafenib was not included in the first-line therapy for some patients and two studies were excluded because the data were insufficient. As a result, eight studies were included in the meta-analysis.19–26

PRISMA flow diagram.
Fig. 1  PRISMA flow diagram.

PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Study characteristics and quality assessment

Eight studies were included in the meta-analysis, which were all randomized controlled multicenter trials. In total, 3,173 patients were involved. There were 2,018 patients in the second-line treatment group and 1,155 patient in the control group. For the modified Jadad scale (Table 1), two studies19,21 received 7 points and five studies20,22–25 received 8 points, indicating that they were of high quality. Only one study26 received a Jadad score of 5 because it was not double-blinded and the methods of statistical analyses were not described. Most patients (66–100%) discontinued sorafenib because of progression. The majority of patients were of BCLC B or C stage (93–100%) and most of them had Child-Pugh class A or B severity of disease (95–100%). The ECOG performance status for most patients was 0 or 1. The results of the study characteristics are shown in Table 2.19–26

Table 1

Modified Jadad scale for randomized controlled trials included in the meta-analysis

Study (Year)RandomizationBlindingDescription of withdrawals and dropoutsInclusion/exc1usion criteriaAEsStatistical analysisOverall
Llovet (2013)192111117
Zhu (2014)202211118
Zhu (2015)212111117
Bruix (2017)222211118
Kudo (2017)232211118
Rimassa (2018)242211118
Zhu (2019)252211118
Moehler (2019)262011105

AEs, adverse events.

Table 2

Characteristics of studies included in the meta-analysis

Study (Year)RegionGroupSample sizeBest supportive careSecond-line treatment characteristicsReason for discontinuation of sorafenibECOG scoreBCLC performance statusChild-Pugh classAFP, ng/mL
Llovet (2013)19Europe, Asia, AmericasBrivanib263Y661 mg/ day [201–802]Radiographic or symptomatic progression=86%; Intolerance=13%0=57%; 1=39%; 2=4%A=3%; B=9%; C=87%; D=1%A=92%; B=7%; C=1%Median (range)=204 [1.2–13.6×105]
Placebo132Y800 mg/ day [324–819]Radiographic or symptomatic progression=88%; Intolerance=12%0=61%; 1=35%; 2=4%A=1%; B=14%; C=85%; D=0%A=91%; B=9%; C=0%Median (range)=100 [1.0–5.1×105]
Zhu (2014)20Europe, Asia, Americas, OceaniaEverolimus362Y7.5 mg/dayRadiographic progression=81.2%; Intolerance=18.5%; Other=0.3%0=59.1%; 1=35.6%; 2=5.2%B=13.5%; C=86.5%A=97.8%; B=2.2%<200=49.4%; ≥200=47.2%; Missing=3.3%
Placebo184YRadiographic progression=79.9%; Intolerance=20.1%; Other=0%0=56.5%; 1=40.2%; 2=3.3%B=14.1%; C=85.9%A=98.9%; B=1.1%<200=47.8%; ≥200=47.8%; Missing=4.3%
Zhu (2015)21Europe, Asia, Americas, OceaniaRamucirumab283Y8 mg/kg intravenously over 1 h every 2 weeksRadiographic progression=87%; Toxicity=13%0=56%; 1=44%B=12%; C=88%A=98%<400=57%; ≥400=42%; Missing=1%; Median (range)=174 (0–853,200)
Placebo282YRadiographic progression=85%; Toxicity=15%0=54%; 1=46%B=12%; C=88%A=98%<400=53%; ≥400=46%; Missing=1%; Median (range)= 330 (0–628,390)
Bruix (2017)22Europe, Asia, Americas, OceaniaRegorafenib379Y160 mg/day for the first three weeks of each 4-week cycleRadiographic progression0=65%; 1=35%A<1%; B=14%; C=86%A=98%; B=1%; (Missing one person)≥400=43%
Placebo194Y0=67%; 1=33%A=0; B=11%; C=89%A=97%; B=3%≥400=45%
Kudo (2017)2357 sites in JapanS-1222NADose: 80 mg/m2; Cycle: twice daily in the first cycle for 28 days. Then, patients underwent a minimum 14-day drug-free period followed by a second cycle.Disease progression=66%; AE=34%0=85%; 1=15%A=3%; B=31%; C=66%A=81%; B=19%<400=59%; ≥400=41%
Placebo111Disease progression=69%; AE=31%0=81%; 1=19%A<1%; B=32%; C=67%A=81%; B=19%<400=56%; ≥400=44%
Rimassa (2018)24Europe, Americas, OceaniaTivantinib226NA120 mg twice dailyRadiographic progression=82%; Intolerance=17%0=62%; 1=38%A=7%; B=12%; C=81%A=95%>200=43%; Median (range)=149 (2–347,837)
Placebo114Radiographic progression=78%; Intolerance=21%0=58%; 1=42%A=6%; B=15%; C=79%A=95%>200=42%; Median (range)=509 (2–440,008)
Zhu (2019)25Europe, Asia, Americas, OceaniaRamucirumab197YIntravenous ramucirumab (8 mg/kg) or placebo for 1 h every 14 daysProgressive disease=84%; Intolerance=16%0=57%; 1=43%;B=17%; C=83%A=100%≥400=100%; Median (range)=3,920 (1,175–20,000)
Placebo95YProgressive disease=80%; Intolerance=20%0=58%; 1=42%;B=21%; C=79%A=100%≥400=100%; Median (range)=2,741 (1,178–11,681)
Moehler (2019)26Europe, Asia, North AmericaPexa-Vec86YDoses of 109 plaque forming units intravenously on day 1 followed by up to 5 intratumoral treatments at day 8 and weeks 3, 6, 12 and 18.Intolerance=13%; Radiographic progression=87%2=95%; 2=5%B=13%; C=87%A=88%; B=12%200=62%; Median (range)=863 (2–1,802,066);
Best Supportive Care43Y_Intolerance=12%; Radiographic progression=88%2=100%; 2=0%B=21%; C=79%A=86%; B=14%>200=50%; Median (range)=398 (1–516,204)

AE, adverse event; BCLC, The Barcelona Clinic Liver Cancer; ECOG, Eastern Cooperative Oncology Group; NA, Not described in the study; Pexa-Vec, Pexastimogene devacirepvec.

Efficacy

DCR

Five studies20,21,23–25 used RECIST (Response Evaluation Criteria in Solid Tumors), two studies19,26 used modified RECIST (mRECIST) and one study22 used both RECIST and mRECIST to assess tumor response (Table 3). DCR was reported in all the studies,19–25 ranging from 13% to 65% in the second-line treatment group and 19% to 50% in the control group (Table 3). The random-effects meta-analysis showed that the RR for DCR was 1.36 (95% CI: 1.16–1.60, p=0.0002) with high heterogeneity (I2=71%, p=0.001), suggesting that DCR may be significantly improved in the second-line treatment group (Fig. 2A). However, among these therapies, only tivantinib24 and pexastimogene devacirepvec (Pexa-Vec)26 might be unable to increase DCR. Sensitivity analysis did not change the heterogeneity significantly.

Table 3

OS, TTP, PFS, and DCR in the included studies

Study (Year)Response CriteriaGroupMedian OS in monthsMedian TTP in monthsMedian PFS in monthsDCR
Llovet (2013)19mRECISTBrivanib9.44.2NA61%
Placebo8.22.7NA40%
Zhu (2014)20RECIST version 1.0Everolimus7.6 (95% CI: 6.7–8.7)3.0 (95% CI: 2.8–4.0)NA56.1% (95% CI: 50.8–61.3%)
Placebo7.3 (95% CI: 6.3–8.7)2.6 (95% CI: 1.5–2.8)NA45.1% (95% CI: 37.8–52.6%)
Zhu (2015)21RECIST version 1.1Ramucirumab9.2 (95% CI: 8.1–10.6)3.5 (95% CI: 2.8–4.5)2.8 (95% CI: 2.7–3.9)56% (95% CI: 50·4–61·8%)
Placebo7.6 (95% CI: 6.0–9.3)2.6 (95% CI: 1.6–2.8)2.1 (95% CI: 1.6–2.7)46% (95% CI: 40·0–51·6%)
Bruix (2017)22mRECIST and RECIST version 1.1Regorafenib10.6 (95% CI: 9.1–12.1)3.2 (95% CI: 2.9–4.2)3.1 (95% CI: 2.8–4.2)65%
Placebo7.8 (95% CI: 6.3–8.8)1.5 (95% CI: 1.4–1.6)1.5 (95% CI: 1.4–1.6)36%
Kudo (2017)23RECIST version 1.1S-111.1 (95% CI: 9.7–13.1)2.6 (95% CI: 2.6–2.8)2.6 (95% CI: 2.6–2.8)43% (95% CI: 37–50%)
Placebo11.2 (95% CI: 9.2–12.8)1.4 (95% CI: 1.3–2·3)1.4 (95% CI: 1.3–2.3)24% (95% CI: 17–33%)
Rimassa (2018)24RECIST version 1.1Tivantinib8.4 (95% CI: 6.8–10.0)2.4 (95% CI: 1.9–3.6)2.1 (95% CI: 1.9–3.0)50%
Placebo9.1 (95% CI: 7.3–10.4)3.0 (95% CI: 1·9–3·7)2.0 (95% CI: 1.9–3.6)50%
Zhu (2019)25RECIST version 1.1Ramucirumab8.5 (95% CI: 7.0–10.6)3.0 (95% CI: 2.8–4.2)2.8 (95% CI: 2.8–4.1)59·9% (95% CI: 53·1–66·7%)
Placebo7.3 (95% CI: 5.4–9.1)1.6 (95% CI: 1.5–2.7)1.6 (95% CI: 1.5–2.7)38·9% (95% CI: 29·1–48·8%)
Moehler (2019)26mRECISTPexa-Vec4.21.8 (95% CI: 1.5–2.8)NA13% (95% CI: 7–22%)
Best Supportive Care4.42.8 (95% CI: 1.5 to not unable to evaluate due to censoring)NA19% (95% CI: 8–33%)

CI, confidence interval; DCR, disease control rate; mRECIST, modified Response Evaluation Criteria in Solid Tumors; NA, Not described in the study; OS, overall survival; PFS, progression-free survival; Pexa-Vec, pexastimogene devacirepvec; RECIST, Response Evaluation Criteria in Solid Tumors; TTP, time to progression.

Efficacy.
Fig. 2  Efficacy.

(A) DCR. (B) OS. (C) TTP. (D) PFS. DCR, disease control rate; OS, overall survival; PFS, progression-free survival; TTP, time to progression; CI, confidence interval.

OS

In the included eight studies,19–26 median OS in the second-line treatment group ranged from 4.2 to 11.1 months, while in the control group it ranged from 4.4 to 11.2 months (Table 3). Seven studies20–26 provided HRs and 95% CIs of OS. The random-effects meta-analysis showed no difference in OS between two groups (HR=0.87, 95% CI: 0.74–1.01, p=0.06) with high heterogeneity (I2=62%, p=0.02) (Fig. 2B). However, ramucirumab in patients with increased AFP concentrations (HR=0.71, 95% CI: 0.53–0.95)25 and regorafenib (HR=0.63, 95% CI: 0.50–0.79)22 appeared to significantly prolong OS, indicating that they might be superior to other second-line treatments.

Sensitivity analysis by omitting Bruix 201722 reduced the heterogeneity significantly (I2=28%, p=0.22) with the HR of 0.92 (95% CI: 0.81–1.03, p=0.16), which might be the reason for the high heterogeneity.

TTP

All the studies19–26 provided available data on TTP. Median TTP ranged from 1.8 to 4.2 months in the second-line treatment group and 1.4 to 3 months in the controlled group (Table 3). We used the random-effects model for when heterogeneity was high (I2=85%, p<0.00001), and sensitivity analysis made no difference to it. It showed that TTP was significantly improved in the second-line treatment group (HR=0.64, 95% CI: 0.51–0.81, p=0.0002) (Fig. 2C). What’s more, regorafenib in Bruix 201722 (HR=0.44, 95% CI: 0.36–0.54) and ramucirumab in Zhu 201925 (HR=0.43, 95% CI: 0.31–0.58) seemed to have an advantage over the other therapies in TTP.

PFS

Five studies21–25 presented data of PFS. Median PFS reported in these five studies ranged from 2.1 to 3.1 months in the second-line treatment group and 1.4 to 2.1 months in the placebo group (Table 3). The HR for PFS was 0.60 (95% CI: 0.46–0.77, p<0.0001) by the random-effects model, with a high heterogeneity (I2=83%, p<0.0001) (Fig. 2D), indicating that the second-line treatment, especially regorafenib (HR=0.46, 95% CI: 0.37–0.57)22 and ramucirumab (HR=0.45, 95% CI: 0.34–0.60),25 might improve PFS. Sensitivity analysis did not change the heterogeneity significantly.

Safety

The most frequently reported AEs are shown in Table 4.19–26 There was a slight difference in AEs of any grade (RR=1.07, 95% CI: 1.00–1.14, p=0.03) between the two groups.19,20,22–24,26 The rate of decreased appetite (RR=1.58, 95% CI: 1.15–2.16, p=0.005),19–21,23–26 edema peripheral (RR=1.91, 95% CI: 1.59–2.29, p<0.00001),20,21,23–26 diarrhea (RR=1.73, 95% CI: 1.33–2.24, p<0.0001),19–26 pyrexia (RR=2.64, 95% CI: 2.04–3.40, p<0.00001),20–23,25,26 fatigue (RR=1.43, 95% CI: 1.14–1.80, p=0.002),19–26 nausea (RR=1.37, 95% CI: 1.15–1.64, p=0.0004),19–26 and vomiting (RR=1.61, 95% CI: 1.07–2.42, p=0.02)20–23,25,26 appeared to be higher in the second-line treatment group. No difference was found in abdominal pain (RR=0.99, 95% CI: 0.85–1.15, p=0.90),19–26 ascites (RR=1.33, 95% CI: 0.95–1.86, p=0.10),20–26 or constipation20–23,25,26 (RR=1.06, 95% CI: 0.75–1.50, p=0.74).

Table 4

Comparison of AEs between the second-line treatment group and control group

AETotal no. events/patients (%) in the second-line treatment groupTotal no. events/patients (%) in the controlled groupRR (95% CI), pI2, p
Adverse events of any grade19,20,22–24,261,345/1,527 (88.1)631/756 (83.5)1.07 (1.00–1.14), 0.0380%, 0.0002
Decreased appetite19–21,23–26445/1,627 (27.4)156/934 (16.7)1.58 (1.15–2.16), 0.00568%, 0.005
Edema peripheral20,21,23–26390/1,366 (28.6)126/803 (15.7)1.91 (1.59–2.29), 0.000010%, 0.64
Diarrhoea19–26515/2,001 (25.7)154/1,127 (13.7)1.73 (1.33–2.24), 0.000155%, 0.03
Pyrexia20–23,25,26328/1,515 (21.7)69/882 (7.8)2.64 (2.04–3.40), 0.0000148%, 0.09
Fatigue19–26583/2,001 (29.1)232/1,127 (20.6)1.43 (1.14–1.80), 0.00259%, 0.02
Abdominal pain19–26391/2,001 (19.5)220/1,127 (19.5)0.99 (0.85–1.15), 0.9026%, 0.22
Nausea19–26382/2,001 (19.1)158/1,127 (14.0)1.37 (1.15–1.64), 0.000439%, 0.12
Ascites20–26335/1,740 (19.3)151/996 (15.2)1.33 (0.95–1.86), 0.1070%, 0.002
Vomiting20–23,25,26237/1,776 (13.3)93/1,013 (9.2)1.61 (1.07–2.42), 0.0259%, 0.02
Constipation20–23,25,26209/1,515 (13.8)112/882 (12.7)1.06 (0.75–1.50), 0.7456%, 0.05

AE, adverse event.

For efficacy and safety, subgroup analysis of sample size failed to reduce the high heterogeneity and it was hard to carry out other subgroup analyses. The results of sensitivity analysis and subgroup analysis are shown in Supplementary Tables 1 and 2, respectively.

Discussion

This meta-analysis comprehensively analyzed the efficacy and safety of the second-line treatment after sorafenib failure in patients with advanced HCC. From the result, we found that DCR, TTP, and PFS were significantly improved by the second-line treatments of patients with advanced HCC after sorafenib failure. However, similar to a relevant meta-analysis,27 no statistical difference in OS was observed between the two groups. It might indicate that DCR, TTP, and PFS do not accurately correlate with OS in advanced HCC.13,28,29 Brivanib (BRISK-PS),19 S-1 (S-CUBE),23 tivantinib (METIV-HCC),24 everolimus (EVOLVE-1),20 ramucirumab (REACH),21 and Pexa-Vec26 did not meet the primary endpoint (i.e. OS). The poor outcome of OS improvement may due to the following reasons: high molecular heterogeneity of HCC;27 patients enrolled with favorable prognosis;19,23 and, imbalanced stratification. However, compared with REACH, ramucirumab in REACH-2 significantly improved OS,25 which might have been caused by the poor prognosis and more aggressive tumor features in patients with increased AFP.30 In our study, we found that regorafenib seemed to be the most effective second-line treatment after sorafenib failure, which not only showed significant improvements in OS but also seemed to have more advantages in DCR, TTP and PFS.22 Regorafenib has also been recommended by the USA’s National Comprehensive Cancer Network (NCCN) for patients with Child-Pugh liver function class A who have disease progression on or after sorafenib.31 Therefore, it may be possible for regorafenib to be considered as the standard second-line treatment. However, more studies are needed to prove its safety and improvement in efficacy. Compared with the controlled groups, second-line treatments may lead to a higher rate of AEs.

Unlike the previous studies, we analyzed not only OS but also other outcomes, including DCR, TTP, and PFS comprehensively, at the overall level. Another advantage of this meta-analysis was that all the studies included were multicenter RCTs and the quality of them was satisfactory in general. However, there were a few limitations of this meta-analysis. (1) The heterogeneity level was high in this study. Several possible hypotheses may be proposed to explain it; first, the different antitumor mechanisms of each drug may lead to various results of both efficacy and safety. For example, Brivanib works as a TKI of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) receptor,32,33 while tivantinib is a TKI targeting the MET receptor.34,35 Second, the high heterogeneity may be attributed to different baseline characteristics among these studies, such as different AFP levels and ECOG performance status. Third, the usage of different criteria for tumor progression evaluation may also result in high heterogeneity because there are some inconsistencies in defining new lesions between RECIST 1.1 and mRECIST.28 Subgroup analysis of sample size and Child-Pugh liver function classification failed to reduce the heterogeneity and it was hard to carry out other subgroup analyses. Moreover, sensitivity analysis did not reduce the heterogeneity of many results, such as DCR, TTP and PFS. (2) Only a small number of studies were included, which might affect the reliability of this study. (3) Some statistical analysis methods were limited, such as assessing heterogeneity by evaluating I2.

In view of the poor improvement in OS, future exploration of more effective therapies for patients with HCC after sorafenib failure is urgently needed. Also, further studies to prove the good outcomes of regorafenib and to explore its biological mechanisms are necessary. Furthermore, when conducting clinical trials of the second-line treatments, a more detailed patient stratification, such as the stratification of biomarkers, should be considered in the aim of predicting treatment efficacy and helping select additional therapies.36

Conclusions

Our findings indicate that the second-line treatments significantly improved DCR, TTP, and PFS for patients with advanced HCC who progressed during or after sorafenib or were intolerant to the drug. However, improvement in OS was not observed and the second-line treatments led to a higher rate of adverse events. Regorafenib may be possibly considered as the standard second-line treatment. However, further studies to prove its good outcomes are necessary. In the future, more effective therapies and more specific patient stratification are needed to improve survival.

Supporting information

Supplementary Table 1

Results of sensitivity analysis.

(DOCX)

Click here for additional data file.

Supplementary Table 2

Results of subgroup analysis.

(DOCX)

Click here for additional data file.

Abbreviations

AE: 

adverse event

AFP: 

α-fetoprotein

BCLC: 

Barcelona Clinic Liver Cancer

CI: 

confidence interval

DCR: 

disease control rate

ECOG: 

Eastern Cooperative Oncology Group

FGF: 

fibroblast growth factor

HCC: 

hepatocellular carcinoma

HR: 

hazard ratio

mRECIST: 

modified Response Evaluation Criteria in Solid Tumors

NCCN: 

National Comprehensive Cancer Network

OS: 

overall survival

Pexa-Vec: 

pexastimogene devacirepvec

PFS: 

progression-free survival

PRISMA: 

Preferred Reporting Items for Systematic Reviews and Meta-analyses

RCT: 

randomized clinical trial

RECIST: 

Response Evaluation Criteria in Solid Tumors

RR: 

relative risk

TKI: 

tyrosine kinase inhibitor

TTP: 

time to progression

VEGF: 

vascular endothelial growth factor

Declarations

Data sharing statement

No additional data are available.

Funding

The authors thank the following foundations for the support: the National Key Technologies R&D Program under Grant No. 2018YFC1106800 to KF Yuan, the Natural Science Foundation of China under Grant Nos. 81972747, 81872004, 81800564, 81770615, 81700555 and 81672882 to KF Yuan, the Science and Technology Support Program of Sichuan Province under Grant Nos. 2019YFQ0001, 2018SZ0115 and 2017SZ0003 to KF Yuan, the Science and Technology Program of Tibet Autonomous Region under Grant No. XZ201801-GB-02 to KF Yuan, and the 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University under Grant No. ZYJC18008 to KF Yuan.

Conflict of interest

The authors have no conflict of interests related to this publication.

Authors’ contributions

Contributed to concept, searched literature, collected the data (LA, HL, KY), analyzed the data, wrote the manuscript (LA, HL), revised the manuscript (KY), all authors read and approved the final manuscript.

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018;68(1):7-30 View Article PubMed/NCBI
  2. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136(5):E359-386 View Article PubMed/NCBI
  3. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359(4):378-390 View Article PubMed/NCBI
  4. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. 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 Oncol 2009;10(1):25-34 View Article PubMed/NCBI
  5. Bruix J, Tak WY, Gasbarrini A, Santoro A, Colombo M, Lim HY, et al. Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: multicentre, open-label, phase II safety study. Eur J Cancer 2013;49(16):3412-3419 View Article PubMed/NCBI
  6. Lencioni R, Kudo M, Ye SL, Bronowicki JP, Chen XP, Dagher L, et al. GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib): second interim analysis. Int J Clin Pract 2014;68(5):609-617 View Article PubMed/NCBI
  7. Iavarone M, Cabibbo G, Piscaglia F, Zavaglia C, Grieco A, Villa E, et al. Field-practice study of sorafenib therapy for hepatocellular carcinoma: a prospective multicenter study in Italy. Hepatology 2011;54(6):2055-2063 View Article PubMed/NCBI
  8. Ponziani FR, Bhoori S, Germini A, Bongini M, Flores M, Sposito C, et al. Inducing tolerability of adverse events increases sorafenib exposure and optimizes patient’s outcome in advanced hepatocellular carcinoma. Liver Int 2016;36(7):1033-1042 View Article PubMed/NCBI
  9. Trevisani F, Brandi G, Garuti F, Barbera MA, Tortora R, Casadei Gardini A, et al. Metronomic capecitabine as second-line treatment for hepatocellular carcinoma after sorafenib discontinuation. J Cancer Res Clin Oncol 2018;144(2):403-414 View Article PubMed/NCBI
  10. Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 2018;379(1):54-63 View Article PubMed/NCBI
  11. Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol 2018;19(7):940-952 View Article PubMed/NCBI
  12. Abou-Alfa GK, Qin S, Ryoo BY, Lu SN, Yen CJ, Feng YH, et al. Phase III randomized study of second line ADI-PEG 20 plus best supportive care versus placebo plus best supportive care in patients with advanced hepatocellular carcinoma. Ann Oncol 2018;29(6):1402-1408 View Article PubMed/NCBI
  13. Marino D, Zichi C, Audisio M, Sperti E, Di Maio M. Second-line treatment options in hepatocellular carcinoma. Drugs Context 2019;8:212577 View Article PubMed/NCBI
  14. Clouth J, Liepa AM, Moeser G, Friedel H, Bernzen M, Trojan J, et al. Hepatocellular carcinoma after prior sorafenib treatment: incidence, healthcare utilisation and costs from German statutory health insurance claims data. Health Econ Rev 2018;8(1):18 View Article PubMed/NCBI
  15. Panic N, Leoncini E, de Belvis G, Ricciardi W, Boccia S. Evaluation of the endorsement of the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement on the quality of published systematic review and meta-analyses. PLoS One 2013;8(12):e83138 View Article PubMed/NCBI
  16. Oremus M, Wolfson C, Perrault A, Demers L, Momoli F, Moride Y. Interrater reliability of the modified Jadad quality scale for systematic reviews of Alzheimer’s disease drug trials. Dement Geriatr Cogn Disord 2001;12(3):232-236 View Article PubMed/NCBI
  17. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327(7414):557-560 View Article PubMed/NCBI
  18. Kavvoura FK, Ioannidis JP. Methods for meta-analysis in genetic association studies: a review of their potential and pitfalls. Hum Genet 2008;123(1):1-14 View Article PubMed/NCBI
  19. Llovet JM, Decaens T, Raoul JL, Boucher E, Kudo M, Chang C, et al. 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 Oncol 2013;31(28):3509-3516 View Article PubMed/NCBI
  20. Zhu AX, Kudo M, Assenat E, Cattan S, Kang YK, Lim HY, et al. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA 2014;312(1):57-67 View Article PubMed/NCBI
  21. Zhu AX, Park JO, Ryoo BY, Yen CJ, Poon R, Pastorelli D, et al. 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 Oncol 2015;16(7):859-870 View Article PubMed/NCBI
  22. Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;389(10064):56-66 View Article PubMed/NCBI
  23. Kudo M, Moriguchi M, Numata K, Hidaka H, Tanaka H, Ikeda M, et al. S-1 versus placebo in patients with sorafenib-refractory advanced hepatocellular carcinoma (S-CUBE): a randomised, double-blind, multicentre, phase 3 trial. Lancet Gastroenterol Hepatol 2017;2(6):407-417 View Article PubMed/NCBI
  24. Rimassa L, Assenat E, Peck-Radosavljevic M, Pracht M, Zagonel V, Mathurin P, et al. Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study. Lancet Oncol 2018;19(5):682-693 View Article PubMed/NCBI
  25. Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019;20(2):282-296 View Article PubMed/NCBI
  26. Moehler M, Heo J, Lee HC, Tak WY, Chao Y, Paik SW, et al. Vaccinia-based oncolytic immunotherapy Pexastimogene Devacirepvec in patients with advanced hepatocellular carcinoma after sorafenib failure: a randomized multicenter Phase IIb trial (TRAVERSE). Oncoimmunology 2019;8(8):1615817 View Article PubMed/NCBI
  27. Kim JH, Kim BJ, Jang HJ, Lee J. Molecular targeted agents as second-line treatment for hepatocellular carcinoma: a meta-analysis and review. Oncotarget 2017;8(60):102321-102327 View Article PubMed/NCBI
  28. Piñero F, Silva M, Iavarone M. Sequencing of systemic treatment for hepatocellular carcinoma: Second line competitors. World J Gastroenterol 2020;26(16):1888-1900 View Article PubMed/NCBI
  29. Bakouny Z, Assi T, El Rassy E, Nasr F. Second-line treatments of advanced hepatocellular carcinoma: systematic review and network meta-analysis of randomized controlled trials. J Clin Gastroenterol 2019;53(4):251-261 View Article PubMed/NCBI
  30. Yamashita T, Forgues M, Wang W, Kim JW, Ye Q, Jia H, et al. EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res 2008;68(5):1451-1461 View Article PubMed/NCBI
  31. Benson AB, D’Angelica MI, Abbott DE, Abrams TA, Alberts SR, Anaya DA, et al. Guidelines insights: hepatobiliary cancers, version 2.2019. J Natl Compr Canc Netw 2019;17(4):302-310 View Article PubMed/NCBI
  32. Cai ZW, Zhang Y, Borzilleri RM, Qian L, Barbosa S, Wei D, et al. Discovery of brivanib alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate), a novel prodrug of dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 kinase inhibitor (BMS-540215). J Med Chem 2008;51(6):1976-1980 View Article PubMed/NCBI
  33. Johnson PJ, Qin S, Park JW, Poon RT, Raoul JL, Philip PA, et 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 Oncol 2013;31(28):3517-3524 View Article PubMed/NCBI
  34. Munshi N, Jeay S, Li Y, Chen CR, France DS, Ashwell MA, et al. ARQ 197, a novel and selective inhibitor of the human c-Met receptor tyrosine kinase with antitumor activity. Mol Cancer Ther 2010;9(6):1544-1553 View Article PubMed/NCBI
  35. Yap TA, Olmos D, Brunetto AT, Tunariu N, Barriuso J, Riisnaes R, et al. Phase I trial of a selective c-MET inhibitor ARQ 197 incorporating proof of mechanism pharmacodynamic studies. J Clin Oncol 2011;29(10):1271-1279 View Article PubMed/NCBI
  36. Rimassa L, Abbadessa G, Personeni N, Porta C, Borbath I, Daniele B, et al. Tumor and circulating biomarkers in patients with second-line hepatocellular carcinoma from the randomized phase II study with tivantinib. Oncotarget 2016;7(45):72622-72633 View Article PubMed/NCBI

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  • Journal of Clinical and Translational Hepatology
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  • eISSN 2310-8819

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