Combining loco-regional treatments in early hepatocellular carcinoma: new achievements overcoming old limitations

Hepatocellular carcinoma (HCC) is the most common primary liver tumor and one of the few malignant diseases that is still increasing around the world. Countless patients are stricken by HCC worldwide, and the tumor incidence is notably linked to the prevalence of other liver diseases such as hepatitis B, hepatitis C, alcohol abuse, non-alcoholic steatohepatitis and any other disease that can cause liver cirrhosis. In the Western countries, it is estimated that more than one million people die due to HCC each year (1). The impact of HCC has led to the development of numerous treatment modalities and algorithms in order to provide better strategies to the patients. However, curative treatments are only proposed for a restricted group of cases that had the tumor diagnosed in the early stage, before the emergence of any type of local or systemic complications (2,3).

Current recommendations regarding curative strategies comprise tumor ablation [such as radiofrequency ablation (RFA)] and surgical procedures (such as liver resection or transplantation) (2,3). As a rule, the increasing number of HCC cases and the shortage of liver donations make resections and ablations a growing necessity. Consequently, the use of these procedures has been encouraging for more and more patients, including those waiting for liver transplantation (LT). Thus, if a given patient with HCC is supposed to spend more than 6 months on the LT list, the current recommendation is to perform a local treatment as a bridge therapy, such as partial resection, transarterial chemoembolization (TACE) or RFA (4). The strategy of using loco-regional procedures for HCC treatment has also been a reason to exceed the parameters stated by the guidelines by offering a curative treatment even when the tumor cannot be included within the limits proposed for a surgical treatment. For instance, many studies have accomplished good results by combining treatment modalities that could never be used together for a given patient, because they are recommended for different tumor stages.

This is the case when TACE, a procedure applied for patients with intermediate tumors, is combined with treatment modalities used for advanced or early tumors. Many articles have been written about the success rates achieved by combined treatments for patients with intermediate and/or advanced tumor stages, because the amount of patients with such conditions has been higher than the number of cases with early stage HCC (5-9). However, the spreading of surveillance programs around the world has been increasing the number of tumors diagnosed in the early stage. As a result, many trials have combined two treatment modalities for patients with small tumors, which are very useful because these tumors have a better prognosis and can be submitted to curative therapies, even when surgical procedures cannot be offered.

In an interesting work, Vasnani et al. compared two modalities of tumor ablation performed after TACE (10). The subjects were submitted to RFA from 2005 to 2009, and microwave ablation (MWA) from 2009 to 2015. One day before the ablation therapy, all the patients were submitted to a drug-eluting bead TACE (DEB-TACE). The results obtained were assessed by multi-phase computed tomography (CT) before and at three-month intervals for the first year, and then at six-month intervals until LT. To assess local response, the authors applied the European Association for the Study of the Liver (EASL) criteria (11). After LT, all the explanted livers were evaluated to calculate the percentage of tumor coagulation. A remarkable finding is that even patients with three or more tumors obtained good results, particularly in the RFA group. Comparing their results with trials using only RFA, the authors showed a striking achievement by combining DEB-TACE with RFA or MWA.

Although the article aimed to compare the results obtained by the two strategies, other findings must be highlighted. First, the authors showed that the ablation techniques performed after DEB-TACE achieved outstanding radiological results, with most subjects attaining complete response. Second, they had excellent histopathological results regardless of the ablation technique. The mean tumor coagulation was around 90% in the explanted livers, showing a strong agreement between radiological and histopathological results. The correlation between the EASL criteria and the tumors examined in the explanted livers was also registered in a similar study performed by Gordic et al. (12), which was somewhat different from the one published by Vasnani et al. For instance, this latter study included some patients with advanced cirrhosis and used MRI instead of CT, because the aim was to compare the performance of various MRI-based response criteria. Even so, the agreement between the EASL criteria and the tumors evaluated in the explanted livers was similar.

Combining loco-regional therapies is a promising strategy to work around the shortage of organ donations, thereby avoiding the tumor growth while LT is not available. It can also be a means for treating tumor recurrence or new lesions after a putatively curative treatment such as resection. At best, it can achieve tumor coagulation of 100%, which can be viewed as a temporary curative procedure. However, the risk of recurrence and/or the occurrence of new lesions must be always kept in mind. Worth mentioning, in all these settings the loco-regional therapies are still limited to patients submitted to strict surveillance programs to diagnose tumors in the early stage. The study performed by Vasnani et al. included only two patients with intermediate-stage HCC (3% of the DEB-TACE/MWA group). Unfortunately, the results of TACE and RFA procedures for intermediate stage HCC are very different (13-17).

In spite of the methods applied, HCC treatment is highly dependent on specific patients’ conditions. For instance, patients with HCC graded as B1 or B2 according to the subclassification of the intermediate stage (18) are more likely to achieve better survival rates after RFA, even without TACE, but this outcome is not attained by those with tumors graded as B3 or B4 (13). In the future, other strategies can also be combined to accomplish better results, such as adjuvant therapy. Since RFA and TACE induce transient devascularization followed by neo-angiogenic stimuli (19), some authors have investigated whether using additional drugs for patients submitted to loco-regional procedures would be valuable (19-21). Some studies achieved good results while other seemed disappointing, but this matter still requires a deep analysis after many more clinical trials. For now, the message of Vasnani and collaborators is that treating HCC can attain outstanding successful rates by combining early diagnosis with the best treatment strategy according to each patient’s condition.

Acknowledgments

Funding: The authors would like to acknowledge the financial support received from São Paulo Research Foundation, FAPESP Grant no. 2016/07117-9.

Footnote

Provenance and Peer Review: This article was commissioned and reviewed by the Section Editor Xingshun Qi (Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang, China).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2017.10.01). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Dimitroulis D, Damaskos C, Valsami S, et al. From diagnosis to treatment of hepatocellular carcinoma: An epidemic problem for both developed and developing world. World J Gastroenterol 2017;23:5282-94. [Crossref] [PubMed]
2. Llovet JM, Brú C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 1999;19:329-38. [Crossref] [PubMed]
3. Hsu CY, Liu PH, Hsia CY, et al. Nomogram of the Barcelona Clinic Liver Cancer system for individual prognostic prediction in hepatocellular carcinoma. Liver Int 2016;36:1498-506. [Crossref] [PubMed]
4. Llovet JM, Ducreux M, Lencioni R, et al. EASL-EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol 2012;56:908-43. [Crossref] [PubMed]
5. Romeiro FG, Ietsugu Md. Combined strategies for hepatocellular carcinoma treatment: a new hope. AME Med J 2017;2:89. [Crossref]
6. Varghese J, Kedarisetty C, Venkataraman J, et al. Combination of TACE and Sorafenib Improves Outcomes in BCLC Stages B/C of Hepatocellular Carcinoma: A Single Centre Experience. Ann Hepatol 2017;16:247-54. [Crossref] [PubMed]
7. Romeiro FG, Sigahi LY, Alvarez M, et al. Sorafenib after arterial chemoembolization in child-pugh A and B cirrhotic patients with intermediate hepatocellular carcinoma: a retrospective analysis. J Cancer Ther 2015;6:286-92. [Crossref]
8. Zhang L, Hu P, Chen X, et al. Transarterial chemoembolization (TACE) plus sorafenib versus TACE for intermediate or advanced stage hepatocellular carcinoma: a meta-analysis. PLoS One 2014;9:e100305 [Crossref] [PubMed]
9. Fu QH, Zhang Q, Bai XL, et al. Sorafenib enhances effects of transarterial chemoembolization for hepatocellular carcinoma: a systematic review and meta-analysis. J Cancer Res Clin Oncol 2014;140:1429-40. [Crossref] [PubMed]
10. Vasnani R, Ginsburg M, Ahmed O, et al. Radiofrequency and microwave ablation in combination with transarterial chemoembolization induce equivalent histopathologic coagulation necrosis in hepatocellular carcinoma patients bridged to liver transplantation. Hepatobiliary Surg Nutr 2016;5:225-33. [Crossref] [PubMed]
11. Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 2001;35:421-30. [Crossref] [PubMed]
12. Gordic S, Corcuera-Solano I, Stueck A, et al. Evaluation of HCC Response to Locoregional Therapy: Validation of MRI-Based Response Criteria versus Explant Pathology. J Hepatol 2017; [Epub ahead of print]. [Crossref] [PubMed]
13. Nouso K, Kariyama K, Nakamura S, et al. Application of radiofrequency ablation for the treatment of intermediate-stage hepatocellular carcinoma. J Gastroenterol Hepatol 2017;32:695-700. [Crossref] [PubMed]
14. Chen QW, Ying HF, Gao S, et al. Radiofrequency ablation plus chemoembolization versus radiofrequency ablation alone for hepatocellular carcinoma: A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol 2016;40:309-14. [Crossref] [PubMed]
15. Wang Y, Deng T, Zeng L, et al. Efficacy and safety of radiofrequency ablation and transcatheter arterial chemoembolization for treatment of hepatocellular carcinoma: A meta-analysis. Hepatol Res 2016;46:58-71. [Crossref] [PubMed]
16. Azuma S, Asahina Y, Nishimura-Sakurai Y, et al. Efficacy of additional radiofrequency ablation after transcatheter arterial chemoembolization for intermediate hepatocellular carcinoma. Hepatol Res 2016;46:312-9. [Crossref] [PubMed]
17. Xu RC, Liu HC, Li JL, et al. Long-term outcome of transcatheter arterial chemoembolization after radiofrequency ablation as a combined therapy for Chinese patients with hepatocellular carcinoma. Curr Med Res Opin 2015;31:1553-60. [Crossref] [PubMed]
18. Kudo M, Arizumi T, Ueshima K, et al. Subclassification of BCLC B Stage Hepatocellular Carcinoma and Treatment Strategies: Proposal of Modified Bolondi's Subclassification (Kinki Criteria). Dig Dis 2015;33:751-8. [Crossref] [PubMed]
19. Ranieri G, Marech I, Lorusso V, et al. Molecular targeting agents associated with transarterial chemoembolization or radiofrequency ablation in hepatocarcinoma treatment. World J Gastroenterol 2014;20:486-97. [Crossref] [PubMed]
20. Boas FE, Ziv E, Yarmohammadi H, et al. Adjuvant Medications That Improve Survival after Locoregional Therapy. J Vasc Interv Radiol 2017;28:971-7.e4. [Crossref] [PubMed]
21. Lee PC, Yeh CM, Hu YW, et al. Antiplatelet Therapy is Associated with a Better Prognosis for Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma after Liver Resection. Ann Surg Oncol 2016;23:874-83. [Crossref] [PubMed]