Regorafenib for hepatocellular carcinoma progressing on sorafenib: just another starting point

Regorafenib for hepatocellular carcinoma progressing on sorafenib: just another starting point

Andrea Mancuso1,2

1Department of Internal Medicine, ARNAS Civico, Palermo, Italy; 2Hepatology and Gastroenterology, Niguarda Ca’ Granda Hospital, Milan, Italy

Correspondence to: Andrea Mancuso, MD. Department of Internal Medicine, ARNAS Civico, Palermo, Italy. Email:

Provenance: This is a Guest Editorial commissioned by Section Editor Xingshun Qi (Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang, China).

Comment on: Ulrich NH, Burgstaller JM, Held U, et al. The Influence of Single-level Versus Multilevel Decompression on the Outcome in Multisegmental Lumbar Spinal Stenosis: Analysis of the Lumbar Spinal Outcome Study (LSOS) Data. Clin Spine Surg 2017. [Epub ahead of print].

Received: 09 February 2017; Accepted: 15 February 2017; Published: 03 March 2017.

doi: 10.21037/amj.2017.02.08

Hepatocellular carcinoma (HCC) is the second most common cause of death from cancer worldwide and a major global health problem. The incidence of HCC increases progressively with advancing age, reaching a peak at 70 years. Moreover, there is a growing incidence of HCC worldwide (1).

Cirrhosis of whatever etiology is an important risk factor for HCC and about one-third of cirrhotic patients will finally develop HCC during their lifetime. Moreover, HCC generally arises in the context of cirrhosis. Consequently, liver transplant (LT) is nowadays the only treatment able to remove at once both the seeded-HCC and the damaged-hepatic tissue in which cancerogenesis and chronic liver disorders have together progressed (2).

Apart from LT, the only cure of both HCC and underlying liver cirrhosis, all the other treatments have to match with higher rate of HCC recurrence. The latter can be classified into curative and palliative treatments. However, these treatments, often used as a bridge for LT, are shown to be effective in terms of survival without cancelling the possibility of HCC recurrence due to the underlying liver cirrhosis. Unfortunately, in a significant amount of cases, HCC is advanced and unsuitable for LT or other curative treatments (3).

Management of advanced HCC has been challenging for physicians for years, particularly for patients who are only suitable for systemic therapy (1,3). The demonstration that sorafenib significantly prolongs survival for advanced HCC has opened new avenues of research. However, albeit having long been the only therapy able to improve the outcome of advanced HCC, due to the presence of underlying liver cirrhosis, the benefit of sorafenib is only limited to patients with adequate liver function and the gain in terms of survival is of only about 3 months (4,5). Moreover, the enthusiasm for further promising treatment has long been discouraged by the fact that almost all the potentially second line therapies after sorafenib systematically failed to improve survival in clinical trials (6-14). Some consideration is needed about the long wait of an effective second line treatment for HCC after sorafenib failure. This difficulty probably reflects the complexity of treating HCC due to the underlying liver cirrhosis, encountered not only by researchers but, also and mostly, by physicians in everyday clinical practise. In fact, despite the evidence of sorafenib efficacy for advanced HCC, the use of sorafenib has not spread, mostly due to the concern of managing both possible sorafenib adverse effects and complication of underlying cirrhosis. Consequently, the same limited spread of treatment will likely be an issue also for second line therapies.

Finally, a recent multi-center randomized double-blind placebo-controlled phase 3 trial comparing best supportive care plus regorafenib or placebo for HCC progressing on sorafenib, enclosing 567 patients (374 regorafenib versus 193 placebo), reported a significantly improved survival for regorafenib (median survival 10.6 versus 7.8 months, P<0.0001). Adverse events were reported to be similar to those described for sorafenib and did not significantly affect survival. Authors correctly concluded that regorafenib is the only systemic treatment shown to provide survival benefit in HCC progressing on sorafenib treatment. Overall, the trial was well designed ad results are convincing and relevant (15). However, as well as for those generally considered for sorafenib, the inclusion criteria limited the study to only patients with adequate liver function (Child Pugh class A). Furthermore, the study excluded patients who discontinued sorafenib because of adverse events. In fact, due to the similar range of adverse events, it is probable that patients with significant adverse events on sorafenib would not have benefit with regorafenib. Consequently, following this indication, in clinical field practise, most of HCC progressing on sorafenib would not be suitable for treatment with regorafenib because of both liver function deterioration or previous sorafenib adverse events. Furthermore, net of these stringent selection criteria, the gain of regorafenib in terms of survival seems to be of about only 3 months (15).

The results of the present trial are important, but the performance of regorafenib as second line therapy needs to be confirmed in field practise, especially in patients with other comorbidities. In fact, the experience with sorafenib raises the concern of substantial drug to drug interaction, in particular in clinical settings characterized by the need of different concomitant multiple drug exposure (16-20).

Pragmatically, the recent evidence of regorafenib efficacy for HCC progressing on sorafenib opens two different clinical scenarios. The former is a step by step consecutive strategy in which sorafenib is the first treatment option followed by regorafenib once HCC progression on sorafenib occurs. The latter is the perspective of exploring, in future clinical trials, a multidrug therapy in which regorafenib is used together with other systemic agents. Both the strategies would have the limitation linked to patients’ selection, potentially including only patients with advanced HCC in cirrhosis with adequate hepatic function and without previous history of sorafenib adverse events. Furthermore, the latter strategy should be explored with caution due to the concern of adverse events potentially correlated to drug to drug interaction, an issue already reported for sorafenib in different clinical contexts (16-20).

Unfortunately, despite the good news of the possibility of treating with regorafenib advanced HCC progressing on sorafenib, with the evidence of a further, albeit limited, improvement of survival, the way to optimize the therapy of advanced HCC still appears uphill and the current therapeutic armamentarium far from perfect.




Conflicts of Interest: The author has no conflicts of interest to declare


  1. International Agency for Research on Cancer. Available online:
  2. Mancuso A. Management of hepatocellular carcinoma: Enlightening the gray zones. World J Hepatol 2013;5:302-10. [PubMed]
  3. Mancuso A, Perricone G. Hepatocellular Carcinoma and Liver Transplantation: State of the Art. J Clin Transl Hepatol 2014;2:176-81. [PubMed]
  4. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-90. [Crossref] [PubMed]
  5. Cheng AL, Kang YK, Chen Z, 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;10:25-34. [Crossref] [PubMed]
  6. Cheng AL, Kang YK, Lin DY, et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol 2013;31:4067-75. [Crossref] [PubMed]
  7. Johnson PJ, Qin S, Park JW, 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;31:3517-24. [Crossref] [PubMed]
  8. Cainap C, Qin S, Huang WT, et al. Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol 2015;33:172-9. [Crossref] [PubMed]
  9. Zhu AX, Rosmorduc O, Evans TR, et al. SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2015;33:559-66. [Crossref] [PubMed]
  10. Abou-Alfa GK, Niedzwieski D, Knox JJ, et al. Phase III randomized study of sorafenib plus doxorubicin versus sorafenib in patients with advanced hepatocellular carcinoma (HCC): CALGB 80802 (Alliance). J Clin Oncol 2016;34:abstr 192.
  11. Llovet JM, Decaens T, Raoul JL, 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;31:3509-16. [Crossref] [PubMed]
  12. Zhu AX, Kudo M, Assenat E, et al. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA 2014;312:57-67. [Crossref] [PubMed]
  13. Zhu AX, Park JO, Ryoo BY, 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;16:859-70. [Crossref] [PubMed]
  14. Abou-Alfa GK, Qin S, Ryoo BY, et al. Phase III randomized study of second line ADI-peg 20 (A) plus best supportive care versus placebo (P) plus best supportive care in patients (pts) with advanced hepatocellular carcinoma (HCC). J Clin Oncol 2016;34:abstr 4017.
  15. Bruix J, Qin S, Merle P, 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;389:56-66. [Crossref] [PubMed]
  16. Zavaglia C, Airoldi A, Mancuso A, et al. Adverse events affect sorafenib efficacy in patients with recurrent hepatocellular carcinoma after liver transplantation: experience at a single center and review of the literature. Eur J Gastroenterol Hepatol 2013;25:180-6. [Crossref] [PubMed]
  17. Mancuso A, Airoldi A, Vigano R, et al. Fatal gastric bleeding during sorafenib treatment for hepatocellular carcinoma recurrence after liver transplantation. Dig Liver Dis 2011;43:754. [Crossref] [PubMed]
  18. Mancuso A, Zavaglia C, Bai F, et al. Letter: Sorafenib hepatotoxicity may be enhanced during treatment of advanced hepatocellular carcinoma in HIV-infected patients. Aliment Pharmacol Ther 2013;38:1414-6. [Crossref] [PubMed]
  19. Mancuso A, Perricone G. Time to resize the role of everolimus as treatment of hepatocellular carcinoma recurrence after liver transplant. Transpl Int 2015;28:502. [Crossref] [PubMed]
  20. Mancuso A, Mazzola A, Cabibbo G, et al. Survival of patients treated with sorafenib for hepatocellular carcinoma recurrence after liver transplantation: a systematic review and meta-analysis. Dig Liver Dis 2015;47:324-30. [Crossref] [PubMed]
doi: 10.21037/amj.2017.02.08
Cite this article as: Mancuso A. Regorafenib for hepatocellular carcinoma progressing on sorafenib: just another starting point. AME Med J 2017;2:31.