Research ArticleClinical Studies

Expanding Sorafenib Treatment for Hepatocellular Carcinoma Beyond Barcelona Clinic Liver Cancer Stage C Patients: A National Study

CHING-TSO CHEN, CHIH-HUNG HSU, ANN-LII CHENG and YU-YUN SHAO
Anticancer Research September 2022, 42 (9) 4461-4470; DOI: https://doi.org/10.21873/anticanres.15946

Abstract

Background/Aim: The reimbursement criteria of sorafenib for advanced hepatocellular carcinoma (HCC) were expanded in 2016 by Taiwan’s National Health Insurance (NHI) to include patients without macrovascular invasion or extrahepatic spread. This study explored sorafenib treatment outcomes before and after this expansion. Patients and Methods: The NHI database was searched for patients who initiated sorafenib treatment between January 1, 2013, and December 31, 2017. Clinical variables were retrieved from the Taiwan Cancer Registry database. Overall survival (OS) and time to treatment discontinuation (TTD) were calculated as the times from the first sorafenib prescription date until death and the final prescription date, respectively. Results: A total of 13,862 patients were included. The median age was 64 years, 78.1% of patients were male. Approximately a quarter of patients (25.1%) received sorafenib after the criteria expansion and exhibited significantly longer OS (median 7.9 vs. 6.6 months, p<0.001) and TTD (median 3.0 vs. 2.6 months, p=0.003) compared with patients who started before. These results were verified in patients with available data regarding clinical prognostic factors (n=9,378, 67.7% of the entire study population). In the multivariate analysis, sorafenib prescription after criteria expansion remained an independent predictor of longer OS [hazard ratio (HR)=0.87, p<0.001] and TTD (HR=0.93, p=0.004). In the subgroup analysis, these trends were consistently observed across different patient subgroups. Conclusion: Patients with HCC who received sorafenib treatment after the reimbursement criteria expansion exhibited longer OS and TTD.

Key Words:

Despite improvement in hepatitis treatment, hepatocellular carcinoma (HCC) remains one of the most common and deadly cancers worldwide (1). Early-stage HCC can be resected or ablated, and intermediate-stage HCC is mainly treated using transarterial chemoembolization (TACE). Advanced HCC, defined as HCC unsuitable for locoregional therapy, is mainly treated with systemic therapy and tends to exhibit poor prognosis (2-5). Sorafenib, a multikinase inhibitor, has been proven to enhance survival of patients with advanced HCC in two phase III studies and became a standard first-line therapy for advanced HCC (6, 7).

Patients with advanced HCC are highly heterogenous in disease extent, hepatitis etiology, and liver function reserve (8). Advanced HCC includes Barcelona Clinic Liver Cancer (BCLC) stage C diseases with extrahepatic spread (EHS) or macrovascular invasion (MVI) and BCLC stage B diseases, which are unsuitable or refractory to locoregional therapies. In the subgroup analyses of the aforementioned two phase III trials comparing sorafenib with a placebo, survival benefits were more prominent in patients without EHS or MVI (9, 10).

BCLC stage C disease is clearly defined, but designating BCLC stage B disease as unsuitable or refractory for locoregional therapy involves a clinical decision that can dramatically vary depending on geographical region. In the two phase III studies that compared sorafenib with a placebo, the Asia-Pacific study enrolled fewer patients with BCLC stage B disease than the SHARP study, which mainly enrolled patients in Europe and America (9, 10). This may reflect the differences in the criteria for feasibilities of locoregional therapy and the timings of conversion to systemic treatment between these regions.

Taiwan is an endemic area for viral hepatitis, and hence, HCC. Sorafenib prescriptions for BCLC stage C HCC have been reimbursed by the National Health Insurance (NHI) of Taiwan since August 1, 2012 (11). Since November 1, 2016, the reimbursement has been expanded to include patients with BCLC stage B disease refractory to locoregional therapies. Such a policy change resulted in two eras of sorafenib treatment for HCC in Taiwan. Thus, this study was designed to compare prescription patterns and treatment outcomes of sorafenib before and after the reimbursement criteria change.

Patients and Methods

Data source. The NHI program in Taiwan is a mandatory single-payer system covering 97% to 98% of the population according to previous literature (12). We retrieved NHI data from the Health and Welfare Data Science Center, Ministry of Health and Welfare, Taiwan. Death events were extracted from the National Death Registry database. Study participant data were collected and analyzed anonymously. This study was approved by the Research Ethics Committee of National Taiwan University Hospital.

Study population and sorafenib treatment. All inpatient or outpatient clinical visits were reviewed to identify patients who were prescribed sorafenib for the first time between January 1, 2013, and December 31, 2017. We cross-linked these patients by their identification numbers to the Taiwan Cancer Registry database for detailed information regarding initial HCC diagnosis. Patients with missing sex data or aged less than 20 years were excluded.

Under the initial sorafenib reimbursement criteria of NHI, patients with Child–Pugh A liver reserve and HCC that had EHS or MVI were covered (11). Physicians were required to apply for the use of sorafenib with imaging and laboratory evidence demonstrating that these requirements were fulfilled. The application required renewal every 2 months with dynamic imaging evidence showing no disease progression under sorafenib treatment. Since November 1, 2016, the criteria have been expanded to include patients whose liver tumors remained viable after three TACE procedures, even if the disease exhibited no EHS or MVI.

Statistical methods. Statistical analyses were performed using SAS (version 9.4; SAS Institute, Cary, NC, USA). For comparisons between the two sorafenib prescription periods (before and after the expansion of reimbursement criteria), the chi-square test and independent t test were used for categorical and continuous variables, respectively. Overall survival (OS) was calculated as the time from the first sorafenib prescription date until death. Time to treatment discontinuation (TTD) was measured from the first sorafenib prescription date to the last sorafenib prescription date or death. The last follow-up date for death events was December 31, 2018. The OS and TTD of patients were estimated using the Kaplan–Meier method and compared using the log-rank test between various groups of interest. The Cox proportional hazards model was utilized in the multivariate analysis to examine the effects of variables on OS and TTD. Two-sided p-values of ≤0.05 were considered statistically significant.

Results

Treatment patterns. A total of 13,862 patients were included in the study (Figure 1). The median age was 64 years, 78.1% were men, and almost 60% received sorafenib treatment in medical centers (Table I). Less than half (48.4%) of patients initially received the standard sorafenib dose; among them, nearly 60% required dose reduction. In patients who started sorafenib treatment with a reduced dose, 27.9% of them could eventually escalate to the standard dose. The median dose intensity of sorafenib was 533.3 mg/day. During the treatment course of sorafenib, 23.9% of patients received locoregional therapies, including TACE (88.6%), radiofrequency ablation (17.3%), and surgery (4.4%).

Figure 1.
Figure 1.

Patient flow diagram.

View this table:
Table I.

Baseline patient demographic and disease characteristics.

Approximately a quarter of patients commenced sorafenib treatment (n=3,484, 25.1%) after the criteria expansion. Compared with the patients who started before (n=10,378, 74.9%), those who started after the expansion were more likely to be younger than 65 years (p<0.001) and to receive TACE during the course of sorafenib treatment (p<0.001; Table I). The percentage of patients who received standard initial sorafenib dose (49.7% and 44.6%, respectively; p<0.001) and the sorafenib dose intensity (median, 534.5 and 517.6 mg/day, respectively; p<0.001) both decreased after the criteria expansion (Table I).

Treatment outcomes. As of December 31, 2018, 12,149 patients (87.6%) had died, and 13,419 patients (96.8%) had discontinued sorafenib treatment. The median follow-up time was 6.8 months. The median OS and median TTD of the entire population were 6.8 (95%CI=6.7-7.0) and 2.8 (95%CI=2.7-2.8) months, respectively. Patients who commenced sorafenib treatment after the reimbursement criteria expansion, compared with patients who started before, exhibited significantly longer OS (median 7.9 vs. 6.6 months, p<0.001; Figure 2A) and TTD (median 3.0 vs. 2.6 months, p=0.003; Figure 2B).

Figure 2.
Figure 2.

Kaplan–Meier plots showing (A) overall survival (OS) and (B) time to treatment discontinuation (TTD) of patients who received sorafenib treatment before and after the expansion of reimbursement criteria. p-Values were conducted using the log-rank test.

To confirm whether sorafenib prescription after the reimbursement criteria expansion was an independent predictor for OS and TTD, we adjusted other potential prognostic markers such as hepatitis virus infection and time from initial HCC diagnosis. Among the 13,862 patients, 9,378 patients (67.7%) had available data regarding these prognostic markers. In this selected population, the previously found associations between the reimbursement criteria expansion and age, TACE during sorafenib treatment, the percentage of patients who received standard initial sorafenib dose, and the sorafenib dose intensity remained (Table II). Additionally, patients who started sorafenib treatment after the criteria expansion, compared with patients who started before, exhibited longer times from HCC diagnosis to sorafenib prescription and were more likely to have BCLC stage B disease and initial serum alpha-fetoprotein (AFP) level <400 ng/ml (Table II).

View this table:
Table II.

Baseline demographic and disease characteristics of selected patients with available clinical prognostic factors.

In this selected population, patients who started sorafenib treatment after the criteria expansion, compared with patients who started before, still exhibited significant longer OS (median 7.5 vs. 6.1 months, p<0.001; Figure 3A) and TTD (median 3.0 vs. 2.5 months, p<0.001; Figure 3B). Subgroup analysis showed that these OS and TTD survival benefits consistently favored sorafenib treatment after criteria expansion (Figure 4A and B).

Figure 3.
Figure 3.

Kaplan–Meier plots showing (A) overall survival (OS) and (B) time to treatment discontinuation (TTD) of patients who received sorafenib treatment before and after the expansion of reimbursement criteria. Only patients with available prognostic factors data are included. p-Values were conducted using the log-rank test.

Figure 4.
Figure 4.

Forrest plot showing subgroup analysis of (A) overall survival (OS) and (B) time to treatment discontinuation (TTD) of patients who received sorafenib treatment before and after the expansion of reimbursement criteria.

In the multivariate analysis adjusting for age, sex, time from initial HCC diagnosis to sorafenib treatment, initial BCLC stage, initial serum AFP level, hospital level, viral hepatitis etiology, and initial standard sorafenib dose, receiving sorafenib treatment after the reimbursement criteria expansion remained an independent predictor for longer OS [hazard ratio (HR)=0.87, 95%CI=0.82-0.92, p<0.001] and TTD (HR=0.93, 95%CI=0.89-0.98, p=0.004; Table III).

View this table:
Table III.

Factors associated with overall survival and time to treatment discontinuation.

Discussion

This study compared the prescription pattern and treatment outcomes of patients who received sorafenib prescription for advanced HCC under two different sets of reimbursement criteria. Our data provided an unbiased view of the national Taiwanese population receiving sorafenib and revealed that the reimbursement criteria expansion beyond BCLC stage C was associated with longer TTD and OS. This association remained after adjustment of multiple prognostic factors. One of the possible explanations for our findings was that sorafenib provided higher efficacies in patients refractory to TACE but without MVI or EHS than patients with MVI or EHS. The subgroup analyses in the two phase III clinical trials comparing sorafenib with a placebo both revealed that sorafenib offered greater survival benefits in such patients (9, 10). However, findings regarding OS in our study may be confounded by lead-time bias because patients without MVI and EHS might have continued TACE before the reimbursement criteria expansion, and OS would only be calculated after sorafenib was prescribed later. Nevertheless, two retrospective studies suggested that in patients with BCLC stage B disease refractory to TACE, conversion to sorafenib treatment was associated with longer OS compared with continuing TACE (13, 14).

Lead-time bias could not explain the longer TTD after the reimbursement criteria expansion. A retrospective study in patients with BCLC stage B HCC refractory to TACE reported a longer time to progression to advanced disease if sorafenib treatment was initiated earlier (14). Combining the literature data and our results, we still favor that initiating sorafenib treatment at an earlier disease stage is associated with better treatment efficacy to be a reasonable explanation of our findings. Sorafenib treatment had also been tested at second-line setting for patients with treated advanced HCC and was proved to possessed attenuated anti-tumor activity (15).

The other possibility is treatment pattern shift among BCLC C patients. From the OPTIMIS study (16), an observational study of patients who received TACE for HCC, many patients with BCLC C disease still chose to undergo TACE first. Delaying the initiation of systemic therapy by repeated TACE can lead to impaired liver function reserve (16, 17), which reduces the feasibility of further systemic therapy. After the treatment options for advanced HCC expanded (18, 19), possibly more patients with BCLC C disease initiated systemic therapy directly.

In the global registry study GIDEON, approximately 30% of patients initiated sorafenib treatment at a dose lower than the standard (20). We observed that sorafenib was prescribed at a reduced initial dose in more than half of patients, and even more so after the reimbursement criteria expansion. This illustrates that physicians in Taiwan have been relatively conservative in prescribing sorafenib. Although no randomized studies have confirmed the efficacy of starting sorafenib with a lower dose, such an approach has been evaluated for regorafenib, a multikinase inhibitor with a similar profile of molecular targets and adverse reactions, in patients with refractory metastatic colorectal cancer (21). We revealed that among patients who initiated treatment with a low sorafenib dose, 28% of them escalated to the standard dose. This implies that many physicians in Taiwan preferred to titrate the sorafenib dose actively according to the adverse reactions.

As sorafenib was the mainstream treatment for patients with advanced HCC, some experts applied locoregional therapy to these patients as well (22-24). Furthermore, applying locoregional therapy during sorafenib treatment was also a common strategy, which was demonstrated with favorable outcomes compared with sorafenib treatment alone (25-28). We also found that a considerable 21% of patients received TACE during sorafenib treatment. A randomized-controlled phase III study compared combining TACE and sorafenib treatment for patients with advanced HCC against sorafenib alone; the results indicated the group receiving the combined intervention exhibited a higher disease control rate and longer progression-free survival, but without significant OS improvement (29). The combined treatment also increased the risk of adverse events resulting from TACE and warranted careful patient selection (29). Many guidelines in Asia endorse judicious TACE in patients with minor portal vein thrombosis (5, 30-33).

This study had some limitations. Patients in two eras were imbalanced in demographics and initial sorafenib dose. This is not surprising since the criteria were expanded to include patients without MVI or EHS, but also led to inevitable biases. Nevertheless, the survival benefits of expansion of sorafenib reimbursement were observed across different patient subgroups in subgroup analysis. In multivariate analysis, we found that after adjusting all these clinical variables, receiving sorafenib after the criteria expansion remained an independent predictor of favorable OS and TTD. To examine whether sorafenib efficacy is truly better in patients without MVI or EHS, a direct comparison of such patients with patients with MVI or EHS would be more ideal. However, such an approach is not feasible using the NHI database. Second-line therapies for advanced HCC emerged since 2017 (34-38). Patients who received sorafenib treatment after the reimbursement criteria expansion might have been more likely to receive subsequent therapies. However, no second-line therapies were reimbursed by the NHI in Taiwan until 2019, long after the last follow-up day of our study. The influence of clinical trials may also be limited because this is a nationwide study. Besides the aforementioned possible explanations of our findings, physicians might be more familiar with sorafenib administration and the management of side effects in the later period of this study, which may confound the survival outcomes between two eras.

In conclusion, we demonstrated that HCC patients who received sorafenib treatment after the broadening of reimbursement criteria exhibited longer OS and TTD. Whether it resulted directly from sorafenib treatment efficacies in patients without MVI or EHS remained to be explored. Initiating systemic therapy sooner in patients unsuitable or refractory to locoregional therapy for HCC is a reasonable strategy and supported by the results of this study.

Acknowledgements

The Authors would like to acknowledge the service provided by the RCF5 Lab. of the Department of Medical Research at National Taiwan University Hospital, Taiwan, R.O.C.

Footnotes

  • Authors’ Contributions

    All Authors contributed to the study conception and design. Material preparation and data analysis were performed by Ching-Tso Chen and Yu-Yun Shao. The first draft of the manuscript was written by Ching-Tso Chen and all Authors commented on previous versions of the manuscript. All Authors approved the final manuscript.

  • Conflicts of Interest

    The Authors declare no conflicts of interest in relation to this study.

  • Funding

    This study was supported by grants from the Ministry of Science and Technology, Taiwan (MOST-103-2314-B-002-181-MY2, MOST-105-2314-B-002-194, MOST-106-2314-B-002-213, MOST-108-2314-B-002-072-MY3, and MOST 111-2314-B-002-120), National Taiwan University Hospital (CTC202001), and Ministry of Health and Welfare (MOHW109-TDU-B-211-114002).

  • Received July 7, 2022.
  • Revision received July 23, 2022.
  • Accepted July 25, 2022.

References

  1. ↵
    1. Sung H,
    2. Ferlay J,
    3. Siegel RL,
    4. Laversanne M,
    5. Soerjomataram I,
    6. Jemal A and
    7. Bray F
    : Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71(3): 209-249, 2021. PMID: 33538338. DOI: 10.3322/caac.21660
    OpenUrlCrossRefPubMed
  2. ↵
    1. Forner A,
    2. Reig ME,
    3. de Lope CR and
    4. Bruix J
    : Current strategy for staging and treatment: the BCLC update and future prospects. Semin Liver Dis 30(1): 61-74, 2010. PMID: 20175034. DOI: 10.1055/s-0030-1247133
    OpenUrlCrossRefPubMed
    1. Shao YY,
    2. Lu LC,
    3. Lin ZZ,
    4. Hsu C,
    5. Shen YC,
    6. Hsu CH and
    7. Cheng AL
    : Prognosis of advanced hepatocellular carcinoma patients enrolled in clinical trials can be classified by current staging systems. Br J Cancer 107(10): 1672-1677, 2012. PMID: 23059748. DOI: 10.1038/bjc.2012.466
    OpenUrlCrossRefPubMed
    1. Shao YY,
    2. Wu CH,
    3. Lu LC,
    4. Chan SY,
    5. Ma YY,
    6. Yen FC,
    7. Hsu CH and
    8. Cheng AL
    : Prognosis of patients with advanced hepatocellular carcinoma who failed first-line systemic therapy. J Hepatol 60(2): 313-318, 2014. PMID: 24036008. DOI: 10.1016/j.jhep.2013.08.027
    OpenUrlCrossRefPubMed
  5. ↵
    1. Shao YY,
    2. Wang SY,
    3. Lin SM, Diagnosis Group and Systemic Therapy Group
    : Management consensus guideline for hepatocellular carcinoma: 2020 update on surveillance, diagnosis, and systemic treatment by the Taiwan Liver Cancer Association and the Gastroenterological Society of Taiwan. J Formos Med Assoc 120(4): 1051-1060, 2021. PMID: 33199101. DOI: 10.1016/j.jfma.2020.10.031
    OpenUrlCrossRefPubMed
  6. ↵
    1. Llovet JM,
    2. Ricci S,
    3. Mazzaferro V,
    4. Hilgard P,
    5. Gane E,
    6. Blanc JF,
    7. de Oliveira AC,
    8. Santoro A,
    9. Raoul JL,
    10. Forner A,
    11. Schwartz M,
    12. Porta C,
    13. Zeuzem S,
    14. Bolondi L,
    15. Greten TF,
    16. Galle PR,
    17. Seitz JF,
    18. Borbath I,
    19. Häussinger D,
    20. Giannaris T,
    21. Shan M,
    22. Moscovici M,
    23. Voliotis D,
    24. Bruix J and SHARP Investigators Study Group
    : Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359(4): 378-390, 2008. PMID: 18650514. DOI: 10.1056/NEJMoa0708857
    OpenUrlCrossRefPubMed
  7. ↵
    1. Cheng AL,
    2. Kang YK,
    3. Chen Z,
    4. Tsao CJ,
    5. Qin S,
    6. Kim JS,
    7. Luo R,
    8. Feng J,
    9. Ye S,
    10. Yang TS,
    11. Xu J,
    12. Sun Y,
    13. Liang H,
    14. Liu J,
    15. Wang J,
    16. Tak WY,
    17. Pan H,
    18. Burock K,
    19. Zou J,
    20. Voliotis D and
    21. 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 Oncol 10(1): 25-34, 2009. PMID: 19095497. DOI: 10.1016/S1470-2045(08)70285-7
    OpenUrlCrossRefPubMed
  8. ↵
    1. Liu TH,
    2. Shao YY,
    3. Lu LC,
    4. Shen YC,
    5. Hsu C,
    6. Lin ZZ,
    7. Hsu CH and
    8. Cheng AL
    : Considerations of heterogeneity in clinical trials for hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol 13(7): 615-621, 2019. PMID: 31132887. DOI: 10.1080/17474124.2019.1621165
    OpenUrlCrossRefPubMed
  9. ↵
    1. Bruix J,
    2. Raoul JL,
    3. Sherman M,
    4. Mazzaferro V,
    5. Bolondi L,
    6. Craxi A,
    7. Galle PR,
    8. Santoro A,
    9. Beaugrand M,
    10. Sangiovanni A,
    11. Porta C,
    12. Gerken G,
    13. Marrero JA,
    14. Nadel A,
    15. Shan M,
    16. Moscovici M,
    17. Voliotis D and
    18. Llovet JM
    : Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol 57(4): 821-829, 2012. PMID: 22727733. DOI: 10.1016/j.jhep.2012.06.014
    OpenUrlCrossRefPubMed
  10. ↵
    1. Cheng AL,
    2. Guan Z,
    3. Chen Z,
    4. Tsao CJ,
    5. Qin S,
    6. Kim JS,
    7. Yang TS,
    8. Tak WY,
    9. Pan H,
    10. Yu S,
    11. Xu J,
    12. Fang F,
    13. Zou J,
    14. Lentini G,
    15. Voliotis D and
    16. Kang YK
    : Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to baseline status: subset analyses of the phase III Sorafenib Asia-Pacific trial. Eur J Cancer 48(10): 1452-1465, 2012. PMID: 22240282. DOI: 10.1016/j.ejca.2011.12.006
    OpenUrlCrossRefPubMed
  11. ↵
    1. Lu LC,
    2. Chen PJ,
    3. Yeh YC,
    4. Hsu CH,
    5. Chen HM,
    6. Lai MS,
    7. Shao YY and
    8. Cheng AL
    : Prescription patterns of sorafenib and outcomes of patients with advanced hepatocellular carcinoma: a national population study. Anticancer Res 37(5): 2593-2599, 2017. PMID: 28476832. DOI: 10.21873/anticanres.11604
    OpenUrlAbstract/FREE Full Text
  12. ↵
    1. Fang K,
    2. Shia BC and
    3. Ma S
    : Health insurance coverage, medical expenditure and coping strategy: evidence from Taiwan. BMC Health Serv Res 12: 442, 2012. PMID: 23206690. DOI: 10.1186/1472-6963-12-442
    OpenUrlCrossRefPubMed
  13. ↵
    1. Arizumi T,
    2. Ueshima K,
    3. Minami T,
    4. Kono M,
    5. Chishina H,
    6. Takita M,
    7. Kitai S,
    8. Inoue T,
    9. Yada N,
    10. Hagiwara S,
    11. Minami Y,
    12. Sakurai T,
    13. Nishida N and
    14. Kudo M
    : Effectiveness of sorafenib in patients with transcatheter arterial chemoembolization (TACE) refractory and intermediate-stage hepatocellular carcinoma. Liver Cancer 4(4): 253-262, 2015. PMID: 26734579. DOI: 10.1159/000367743
    OpenUrlCrossRefPubMed
  14. ↵
    1. Ogasawara S,
    2. Chiba T,
    3. Ooka Y,
    4. Kanogawa N,
    5. Motoyama T,
    6. Suzuki E,
    7. Tawada A,
    8. Kanai F,
    9. Yoshikawa M and
    10. Yokosuka O
    : Efficacy of sorafenib in intermediate-stage hepatocellular carcinoma patients refractory to transarterial chemoembolization. Oncology 87(6): 330-341, 2014. PMID: 25227534. DOI: 10.1159/000365993
    OpenUrlCrossRefPubMed
  15. ↵
    1. Maesaka K,
    2. Sakamori R,
    3. Yamada R,
    4. Tahata Y,
    5. Ohkawa K,
    6. Oshita M,
    7. Tamura S,
    8. Hagiwara H,
    9. Mita E,
    10. Yakushijin T,
    11. Inada M,
    12. Kodama T,
    13. Hikita H,
    14. Tatsumi T and
    15. Takehara T
    : Efficacy of ramucirumab versus sorafenib as subsequent treatment for hepatocellular carcinoma. Anticancer Res 41(4): 2187-2192, 2021. PMID: 33813432. DOI: 10.21873/anticanres.14993
    OpenUrlAbstract/FREE Full Text
  16. ↵
    1. Peck-Radosavljevic M,
    2. Kudo M,
    3. Raoul J-L,
    4. Lee HC,
    5. Decaens T,
    6. Heo J,
    7. Lin S-M,
    8. Shan H,
    9. Yang Y,
    10. Bayh I,
    11. Nakajima K and
    12. Cheng A-L
    : Outcomes of patients (pts) with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE): Global OPTIMIS final analysis. Journal of Clinical Oncology 36(15_suppl): 4018-4018, 2019. DOI: 10.1200/JCO.2018.36.15_suppl.4018
    OpenUrlCrossRef
  17. ↵
    1. Choi J,
    2. Lee D,
    3. Shim JH,
    4. Kim KM,
    5. Lim YS,
    6. Lee YS and
    7. Lee HC
    : Evaluation of transarterial chemoembolization refractoriness in patients with hepatocellular carcinoma. PLoS One 15(3): e0229696, 2020. PMID: 32130270. DOI: 10.1371/journal.pone.0229696
    OpenUrlCrossRefPubMed
  18. ↵
    1. Finn RS,
    2. Qin S,
    3. Ikeda M,
    4. Galle PR,
    5. Ducreux M,
    6. Kim TY,
    7. Kudo M,
    8. Breder V,
    9. Merle P,
    10. Kaseb AO,
    11. Li D,
    12. Verret W,
    13. Xu DZ,
    14. Hernandez S,
    15. Liu J,
    16. Huang C,
    17. Mulla S,
    18. Wang Y,
    19. Lim HY,
    20. Zhu AX,
    21. Cheng AL and IMbrave150 Investigators
    : Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 382(20): 1894-1905, 2020. PMID: 32402160. DOI: 10.1056/NEJMoa1915745
    OpenUrlCrossRefPubMed
  19. ↵
    1. Liu TH,
    2. Shao YY and
    3. Hsu CH
    : It takes two to tango: breakthrough advanced hepatocellular carcinoma treatment that combines anti-angiogenesis and immune checkpoint blockade. J Formos Med Assoc 120(1 Pt 1): 1-4, 2021. PMID: 32660891. DOI: 10.1016/j.jfma.2020.07.009
    OpenUrlCrossRefPubMed
  20. ↵
    1. Marrero JA,
    2. Kudo M,
    3. Venook AP,
    4. Ye SL,
    5. Bronowicki JP,
    6. Chen XP,
    7. Dagher L,
    8. Furuse J,
    9. Geschwind JH,
    10. de Guevara LL,
    11. Papandreou C,
    12. Takayama T,
    13. Sanyal AJ,
    14. Yoon SK,
    15. Nakajima K,
    16. Lehr R,
    17. Heldner S and
    18. Lencioni R
    : Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: The GIDEON study. J Hepatol 65(6): 1140-1147, 2016. PMID: 27469901. DOI: 10.1016/j.jhep.2016.07.020
    OpenUrlCrossRefPubMed
  21. ↵
    1. Bekaii-Saab TS,
    2. Ou FS,
    3. Ahn DH,
    4. Boland PM,
    5. Ciombor KK,
    6. Heying EN,
    7. Dockter TJ,
    8. Jacobs NL,
    9. Pasche BC,
    10. Cleary JM,
    11. Meyers JP,
    12. Desnoyers RJ,
    13. McCune JS,
    14. Pedersen K,
    15. Barzi A,
    16. Chiorean EG,
    17. Sloan J,
    18. Lacouture ME,
    19. Lenz HJ and
    20. Grothey A
    : Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study. Lancet Oncol 20(8): 1070-1082, 2019. PMID: 31262657. DOI: 10.1016/S1470-2045(19)30272-4
    OpenUrlCrossRefPubMed
  22. ↵
    1. Quirk M,
    2. Kim YH,
    3. Saab S and
    4. Lee EW
    : Management of hepatocellular carcinoma with portal vein thrombosis. World J Gastroenterol 21(12): 3462-3471, 2015. PMID: 25834310. DOI: 10.3748/wjg.v21.i12.3462
    OpenUrlCrossRefPubMed
    1. Ye JZ,
    2. Wang YY,
    3. Bai T,
    4. Chen J,
    5. Xiang BD,
    6. Wu FX and
    7. Li LQ
    : Surgical resection for hepatocellular carcinoma with portal vein tumor thrombus in the Asia-Pacific region beyond the Barcelona Clinic Liver Cancer treatment algorithms: a review and update. Oncotarget 8(54): 93258-93278, 2017. PMID: 29190996. DOI: 10.18632/oncotarget.18735
    OpenUrlCrossRefPubMed
  24. ↵
    1. Yu JI,
    2. Choi GS,
    3. Lim DH,
    4. Lee E,
    5. Joh JW,
    6. Kwon CHD,
    7. Kim JM,
    8. Kim S,
    9. Woo SY,
    10. Paik SW and
    11. Park HC
    : Treatment of naïve HCC combined with segmental or subsegmental portal vein tumor thrombosis: Liver resection versus TACE followed by radiotherapy. Anticancer Res 38(8): 4919-4925, 2018. PMID: 30061270. DOI: 10.21873/anticanres.12808
    OpenUrlAbstract/FREE Full Text
  25. ↵
    1. Ha Y,
    2. Lee D,
    3. Shim JH,
    4. Lim YS,
    5. Lee HC,
    6. Chung YH,
    7. Lee YS,
    8. Park SR,
    9. Ryu MH,
    10. Ryoo BY,
    11. Kang YK and
    12. Kim KM
    : Role of transarterial chemoembolization in relation with sorafenib for patients with advanced hepatocellular carcinoma. Oncotarget 7(45): 74303-74313, 2016. PMID: 27494871. DOI: 10.18632/oncotarget.11030
    OpenUrlCrossRefPubMed
    1. Wu FX,
    2. Chen J,
    3. Bai T,
    4. Zhu SL,
    5. Yang TB,
    6. Qi LN,
    7. Zou L,
    8. Li ZH,
    9. Ye JZ and
    10. Li LQ
    : The safety and efficacy of transarterial chemoembolization combined with sorafenib and sorafenib mono-therapy in patients with BCLC stage B/C hepatocellular carcinoma. BMC Cancer 17(1): 645, 2017. PMID: 28899349. DOI: 10.1186/s12885-017-3545-5
    OpenUrlCrossRefPubMed
    1. Liu L,
    2. Zhang Q,
    3. Geng J,
    4. Li S,
    5. Zhao S,
    6. Zhang X,
    7. Hu J and
    8. Feng D
    : Comparison of radiofrequency ablation combined with sorafenib or sorafenib alone in patients with ECOG performance score 1: identifying optimal candidates. Ann Transl Med 8(9): 583, 2020. PMID: 32566610. DOI: 10.21037/atm.2020.03.71
    OpenUrlCrossRefPubMed
  28. ↵
    1. Kaibori M,
    2. Matsushima H,
    3. Ishizaki M,
    4. Kosaka H,
    5. Matsui K,
    6. Kariya S,
    7. Yoshii K and
    8. Sekimoto M
    : The impact of sorafenib in combination with transarterial chemoembolization on the outcomes of intermediate-stage hepatocellular carcinoma. Asian Pac J Cancer Prev 22(4): 1217-1224, 2021. PMID: 33906315. DOI: 10.31557/APJCP.2021.22.4.1217
    OpenUrlCrossRefPubMed
  29. ↵
    1. Park JW,
    2. Kim YJ,
    3. Kim DY,
    4. Bae SH,
    5. Paik SW,
    6. Lee YJ,
    7. Kim HY,
    8. Lee HC,
    9. Han SY,
    10. Cheong JY,
    11. Kwon OS,
    12. Yeon JE,
    13. Kim BH and
    14. Hwang J
    : Sorafenib with or without concurrent transarterial chemoembolization in patients with advanced hepatocellular carcinoma: The phase III STAH trial. J Hepatol 70(4): 684-691, 2019. PMID: 30529387. DOI: 10.1016/j.jhep.2018.11.029
    OpenUrlCrossRefPubMed
  30. ↵
    1. Kudo M,
    2. Matsui O,
    3. Izumi N,
    4. Iijima H,
    5. Kadoya M,
    6. Imai Y,
    7. Okusaka T,
    8. Miyayama S,
    9. Tsuchiya K,
    10. Ueshima K,
    11. Hiraoka A,
    12. Ikeda M,
    13. Ogasawara S,
    14. Yamashita T,
    15. Minami T,
    16. Yamakado K and Liver Cancer Study Group of Japan
    : JSH consensus-based clinical practice guidelines for the management of hepatocellular carcinoma: 2014 update by the Liver Cancer Study Group of Japan. Liver Cancer 3(3-4): 458-468, 2014. PMID: 26280007. DOI: 10.1159/000343875
    OpenUrlCrossRefPubMed
    1. Poon RT,
    2. Cheung TT,
    3. Kwok PC,
    4. Lee AS,
    5. Li TW,
    6. Loke KL,
    7. Chan SL,
    8. Cheung MT,
    9. Lai TW,
    10. Cheung CC,
    11. Cheung FY,
    12. Loo CK,
    13. But YK,
    14. Hsu SJ,
    15. Yu SC and
    16. Yau T
    : Hong Kong consensus recommendations on the management of hepatocellular carcinoma. Liver Cancer 4(1): 51-69, 2015. PMID: 26020029. DOI: 10.1159/000367728
    OpenUrlCrossRefPubMed
    1. Omata M,
    2. Cheng AL,
    3. Kokudo N,
    4. Kudo M,
    5. Lee JM,
    6. Jia J,
    7. Tateishi R,
    8. Han KH,
    9. Chawla YK,
    10. Shiina S,
    11. Jafri W,
    12. Payawal DA,
    13. Ohki T,
    14. Ogasawara S,
    15. Chen PJ,
    16. Lesmana CRA,
    17. Lesmana LA,
    18. Gani RA,
    19. Obi S,
    20. Dokmeci AK and
    21. Sarin SK
    : Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int 11(4): 317-370, 2017. PMID: 28620797. DOI: 10.1007/s12072-017-9799-9
    OpenUrlCrossRefPubMed
  33. ↵
    1. Korean Liver Cancer Association and National Cancer Center
    : 2018 Korean Liver Cancer Association-National Cancer Center Korea Practice guidelines for the management of hepatocellular carcinoma. Gut Liver 13(3): 227-299, 2019. PMID: 31060120. DOI: 10.5009/gnl19024
    OpenUrlCrossRefPubMed
  34. ↵
    1. Abou-Alfa GK,
    2. Meyer T,
    3. Cheng AL,
    4. El-Khoueiry AB,
    5. Rimassa L,
    6. Ryoo BY,
    7. Cicin I,
    8. Merle P,
    9. Chen Y,
    10. Park JW,
    11. Blanc JF,
    12. Bolondi L,
    13. Klümpen HJ,
    14. Chan SL,
    15. Zagonel V,
    16. Pressiani T,
    17. Ryu MH,
    18. Venook AP,
    19. Hessel C,
    20. Borgman-Hagey AE,
    21. Schwab G and
    22. Kelley RK
    : Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 379(1): 54-63, 2018. PMID: 29972759. DOI: 10.1056/NEJMoa1717002
    OpenUrlCrossRefPubMed
    1. Bruix J,
    2. Qin S,
    3. Merle P,
    4. Granito A,
    5. Huang YH,
    6. Bodoky G,
    7. Pracht M,
    8. Yokosuka O,
    9. Rosmorduc O,
    10. Breder V,
    11. Gerolami R,
    12. Masi G,
    13. Ross PJ,
    14. Song T,
    15. Bronowicki JP,
    16. Ollivier-Hourmand I,
    17. Kudo M,
    18. Cheng AL,
    19. Llovet JM,
    20. Finn RS,
    21. LeBerre MA,
    22. Baumhauer A,
    23. Meinhardt G,
    24. Han G and RESORCE Investigators
    : Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 389(10064): 56-66, 2017. PMID: 27932229. DOI: 10.1016/S0140-6736(16)32453-9
    OpenUrlCrossRefPubMed
    1. Zhu AX,
    2. Kang YK,
    3. Yen CJ,
    4. Finn RS,
    5. Galle PR,
    6. Llovet JM,
    7. Assenat E,
    8. Brandi G,
    9. Pracht M,
    10. Lim HY,
    11. Rau KM,
    12. Motomura K,
    13. Ohno I,
    14. Merle P,
    15. Daniele B,
    16. Shin DB,
    17. Gerken G,
    18. Borg C,
    19. Hiriart JB,
    20. Okusaka T,
    21. Morimoto M,
    22. Hsu Y,
    23. Abada PB,
    24. Kudo M and REACH-2 study investigators
    : 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 20(2): 282-296, 2019. PMID: 30665869. DOI: 10.1016/S1470-2045(18)30937-9
    OpenUrlCrossRefPubMed
    1. El-Khoueiry AB,
    2. Sangro B,
    3. Yau T,
    4. Crocenzi TS,
    5. Kudo M,
    6. Hsu C,
    7. Kim TY,
    8. Choo SP,
    9. Trojan J,
    10. Welling TH Rd.,
    11. Meyer T,
    12. Kang YK,
    13. Yeo W,
    14. Chopra A,
    15. Anderson J,
    16. Dela Cruz C,
    17. Lang L,
    18. Neely J,
    19. Tang H,
    20. Dastani HB and
    21. Melero I
    : Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 389(10088): 2492-2502, 2017. PMID: 28434648. DOI: 10.1016/S0140-6736(17)31046-2
    OpenUrlCrossRefPubMed
  38. ↵
    1. Finn RS,
    2. Ryoo BY,
    3. Merle P,
    4. Kudo M,
    5. Bouattour M,
    6. Lim HY,
    7. Breder V,
    8. Edeline J,
    9. Chao Y,
    10. Ogasawara S,
    11. Yau T,
    12. Garrido M,
    13. Chan SL,
    14. Knox J,
    15. Daniele B,
    16. Ebbinghaus SW,
    17. Chen E,
    18. Siegel AB,
    19. Zhu AX,
    20. Cheng AL and KEYNOTE-240 investigators
    : Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, Phase III trial. J Clin Oncol 38(3): 193-202, 2020. PMID: 31790344. DOI: 10.1200/JCO.19.01307
    OpenUrlCrossRefPubMed
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Expanding Sorafenib Treatment for Hepatocellular Carcinoma Beyond Barcelona Clinic Liver Cancer Stage C Patients: A National Study
CHING-TSO CHEN, CHIH-HUNG HSU, ANN-LII CHENG, YU-YUN SHAO
Anticancer Research Sep 2022, 42 (9) 4461-4470; DOI: 10.21873/anticanres.15946
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