In the meantime, conventional TACE is the standard treatment option for patients with intermediate stage HCC.1 TARE is not included in the BCLC staging system guidelines. On the contrary, TARE is frequently used in western countries and has increasing indications. The ongoing randomized controlled trials are supposed to “build a basis“ of the role of TARE in the management of HCC. Unfortunately, the overall survival is comparable between conventional TACE and TARE.57 However, TARE showed longer time-to-progression, better quality of life, and less hospitalization time in comparison to conventional TACE.58 One of the common complications of TARE is radiation-induced ulcer which is refractory to treatment and radiation-induced cholecystitis and pneumonitis.59

Upward and downward stage migration and multimodal treatment strategies

Surgical treatment for intermediate stage HCC

Indeed, hepatic resection for single tumors >5 cm has been in discussion for many years since the BCLC guidelines. This was supported with data reported from 173 patients with BCLC B stage with resectable HCC outside Milan criteria.60 They reported 51.5% 3-year survival rate vs 18.1% after TACE. Hsu et al reported the better 5-year survival rate in intermediate stage HCC patients undergoing resection vs TACE (43% vs 15%, P<0.001).61 In line with these findings, Liang et al, in 2017, conducted a meta-analysis that included 2,619 Asian patients with intermediate stage HCC from nine studies where they compared TACE to surgical resection. Noteworthy, they concluded that surgical resection showed better overall survival than TACE in Asian patients with intermediate stage HCC. However, no significant difference was noticed in the pooled OR in post-operative complications and 30-day mortality between both groups. Also, they recommended validation of these findings in Western patients.


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A lot of strategies have been developed for liver transplantation beyond Milan criteria. This includes several downstaging strategies. These strategies aim to super select patients who could have favorable intermediate stage lesions and are more likely to have better outcome after liver transplantation. Surprisingly, patients with HCC within the University of California San Francisco (UCSF) downstaging criteria have achieved 92.1% 4-year survival post-transplantation.62 Of note, Kamo et al conducted a study on 56 patients with intermediate stage HCC who underwent liver transplantation. They reported 1-, 3-, and 5-year overall survival and recurrence rates of liver transplantation for intermediate stage HCC of 88%/64%/58% and 22%/34%/44%, respectively.63

Locoregional ablative therapies in intermediate stage HCC

Likewise, percutaneous treatments are recommended for patients in early stages. However, clinical practice studies have proposed treatment migration from TACE to ablative percutaneous therapies. D’Avola et al, in a cohort that included 101 treatment-naïve BCLC B patients, 55 received TACE and 35 received curative therapies including radiofrequency ablation (RFA). They reported significantly better survival in patients who received curative therapies including RFA (71 vs 24 months, p<0.001).64 In a very recent meta-analysis by Yang et al, which included eleven studies, they compared the impact of combined TACE and RFA to TACE only regimen in patients with intermediate stage HCC with diameter >5 cm. They reported that the combined therapy group (TACE plus RFA) showed higher 2-year survival rate than TACE only group (RR =1.675, 95%CI: 1.233–2.275, P=0.001). Also, they concluded that combined therapy is beneficial for patients with intermediate stage HCC and tumor size >5 cm diameter. Also, Morimoto et al investigated 37 patients with intermediate HCC and concluded that combined RFA and TACE decreased local tumor progression.65Of note, Veltri et al followed-up survival in 51 patients who had RFA after TACE, they showed a survival rate of 89.7% at 1-year follow-up.66

It is still problematic to declare curative therapies as an option for intermediate stage HCC, and we are still in need of a fixed algorithm to help proper allocation of therapies such as surgical and percutaneous therapeutic options for this class of patients. The main task right now, for research studies, is to propose strategies that would enable proper patient selection for these radical treatments.2

Systemic therapy in intermediate stage HCC

Noteworthy, multimodal treatments as combining curative measures as resection or RFA with TACE. In addition to adding systemic therapies which seems quite reasonable as TACE causes local hypoxia that upregulates HIF and VEGF. Thus, it is reasonable to add multikinase inhibitors such as sorafenib, that downregulates VEGF, to the regimen.21,67,68 Li et al, in 2018, reported in their meta-analysis that combination therapy was better than TACE alone in terms of time to progression, but not in terms of overall survival as there was no significant difference.69 Also, another randomized controlled trial reported that concurrent sorafenib and TACE did not improve progression-free survival in patients with unresectable HCC in 20 different hospitals in the UK.70 In contrast, a meta-analysis by Li et al, which included 27 studies, concluded that Asian patients with unresectable HCC may benefit from combined TACE and sorafenib therapy in terms of disease control rate and time to progression.69Also, Pawlik et al reported that the safety of combined DEB-TACE and sorafenib was similar to the safety of sorafenib alone, as most side effects were related to sorafenib dosing.71 We believe that this multimodal strategy still needs more fine-tuning and validation for better treatment outcomes.

Other combined treatment options

Yoon et al investigated the efficacy and safety of TACE plus external beam radiotherapy (RT) vs sorafenib in 90 patients with liver-confined HCC lesions and macroscopic vascular invasion. They showed that the combined TAC and RT group had a significantly higher radiologic response rate than the sorafenib group at 24 weeks (15 [33.3%] vs 1 [2.2%]; P<0.001). Also, they had a significantly longer median time to progression (31.0 vs 11.7 weeks; P<0.001), and significantly longer overall survival (55.0 vs 43.0 weeks; P=0.04). Noteworthy, curative surgical resection was performed in five patients (11.1%) in the TACE-RT group due to tumor downstaging. Notably, no patients in the TACE-RT group stopped treatment due to liver decompensation.

High intensity focused ultrasound (HIFU) was investigated in combination with TACE vs TACE alone in intermediate stage HCC patients. The combined TACE and HIFU group showed better overall survival and tumor-free survival.72

Locoregional treatments such as TACE, TARE, and ablative therapies increase tumor immunogenicity by releasing huge amounts of tumor-associated antigens and induction of inflammation. Indeed, combined immunotherapy (immune check-point inhibitors) and TACE would be a promising combination.73,74 In a recent human study, anti-CTLA-4 antibody tremelimumab in combination with TACE (BCLC B) or thermal ablation (BCLC C) showed better overall survival and promising time-to-progression of the disease.75

CONCLUSION

To sum-up, intermediate stage HCC still needs precise tailoring of staging systems that would help proper treatment allocation. Studies investigating combined therapies in various sub-groups of this stage are highly recommended. We should consider differences in cohorts and liver disease etiology in different guidelines. Further, an optimum TACE-specific score should include parameters as in mHAP III score in addition to vascular invasion, age, gender, and etiology. Finally, first TACE response according to mRECIST criteria would be a significant addition to a score that would guide either the process of retreatment with TACE or early shift to targeted therapies. The availability of different treatment options requires prospective comparative randomized controlled studies to tailor better treatment algorithms that encompass the new strategies and fit the patient’s stage.

Disclosure

Imam Waked reports personal fees from Gilead, Novartis, Abbvie, Merck Sharp & Dohme, Pharco, Eva Pharma, and Inspire Pharma, outside the submitted work. The authors report no other conflicts of interest in this work.


Omar Elshaarawy, Asmaa Gomaa, Hazem Omar, Eman Rewisha, Imam Waked

Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebeen El-Kom, Egypt


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Source: Journal of Hepatocellular Carcinoma.
Originally published July 11, 2019.