Loco-regional treatments of unresectable hepatocellular carcinoma: safety first

Hepatocellular carcinoma (HCC) is a severe liver cancer that complicates underlying severe liver disease.

For a long time, palliative treatment of unresectable HCC was loco-regional and based on tumor arterial hypervascularization and intra-tumor retention of Lipiodol when injected intra-arterially. In 1995, it was demonstrated that transarterial chemoembolization (TACE) reduced tumor growth and size, but did not significantly improve survival, because any benefit was offset by worsened liver function (1). Despite the failure to demonstrate improved survival, TACE remained the most commonly used palliative treatment worldwide for many years. In 2002, two RCTs demonstrated the efficacy of TACE, but only in highly selected patients (2). The good indications for TACE were limited to certain intermediate stage HCC, PS 0 (or possibly 1), with preserved liver function (Child-Pugh A without ascites), without vascular invasion, and had to be carried out in a selective manner to minimize the ischemic insult to non-tumoral tissue (3,4). In scores evaluating survival after a first TACE, the parameters linked to liver toxicity were more important than tumor response! In a recent comparison of TACE with lenvatinib, TACE but not lenvatinib was responsible for a severe decrease in the liver function (evaluating by the ALBI score) from baseline, and this acute deterioration persisted in the chronic period (5). The price to pay for the efficacy of TACE is thus liver function.

Radioembolization, also known as selective internal radiotherapy (SIRT), uses the same principle but the efficacy only comes from the irradiation of the tumor (resin or glass microspheres loaded with 90Y have a negligible embolic effect). This procedure is technically complex and demanding, but has given promising results in experienced teams. Two recent multicenter randomized trials (one in France—SARAH, the other in Asia-Pacific—SIRveNIB) compared SIRT (90Y-resin microspheres) to sorafenib in unresectable HCC (6,7). Globally, more than one-quarter of the patients in the SIRT groups failed to receive assigned therapy, mostly for technical reasons. Despite better response rates with SIRT (19% vs. 12% in SARAH and 16.5% vs. 1.7% in SIRveNIB), median overall survival (mOS) in the intention-to-treat (ITT) populations was lower in the SIRT groups compared to the sorafenib groups, and similar in the per-protocol (PP) populations (Table 1). This discrepancy between tumor response and absence of survival benefit was not related to “classic, quantifiable” (following CTCAE) toxicities; moreover, in the SARAH trial, tolerability and quality of life seemed better in the SIRT group, and in the SIRveNIB trial, analysis of time without grade 2 to 4 toxicities and time with such toxicities were in favor of SIRT. However, it can be supposed that mild, progressive and unstoppable liver toxicity caused by SIRT could gradually lead to fatal liver failure that cannot be distinguished in such patients from the “normal” evolution of the disease.

A third trial, SORAMIC, compared SIRT (resin microspheres) combined with sorafenib (216 patients; combined arm), with sorafenib (208 patients) (8). As previously, there was no difference in mOS between either arm in the ITT and PP populations (114 patients in the combined arm, 174 in the sorafenib arm) (Table 1). Regarding safety, grade 3–4 adverse events (64.8% vs. 53.3%) were more frequent, and hyperbilirubinemia and fatigue more common, in the combined arm (14.5% vs. 4.4%). In preplanned subgroup analysis of the PP population, a survival benefit was shown for SIRT + sorafenib in patients without cirrhosis, with liver disease of non-alcoholic etiology and in patients under the age of 66 years.

In order to understand this negative result, the authors monitored liver function (evaluated using the ALBI score) in some split subpopulations of interest (age: </≥65-year-old; cirrhosis: yes/no; alcoholic disease: yes/no; Child-Pugh: A5/A6; previous TACE: yes/no), each subgroup, theoretically reflecting different liver reserves, having experienced different outcomes (eventually non significant) following the treatment arm (9).

In the global PP population, there was a decline in liver function over time, whether they received SIRT + sorafenib or sorafenib alone. The decline in liver function was nevertheless more pronounced in the patients receiving SIRT + sorafenib, with the difference becoming significant at month 4.

Patients <65 years benefited from the combined treatment; in the combined arm, the decline in liver function, beginning at 4 months, was stronger and significantly more pronounced in older patients, who are believed to have more fragile liver function; in the sorafenib arm, the decline was minor and similar, regardless of age.

The baseline ALBI score was higher in patients with cirrhosis vs. those without, in both arms; in patients with cirrhosis receiving the combined treatment there was a trend toward a stronger increase in the ALBI score at 4 months, while this score remained stable if patients (with or without cirrhosis) received sorafenib.

Similar results were observed in other groups, meaning that patients with supposedly better liver reserves (no cirrhosis, non-alcoholic disease, no previous TACE and Child-Pugh A5 liver disease) and treated with SIRT + sorafenib had a less significant decline in liver function over time as shown by their ALBI score than their counterparts (cirrhosis, alcoholic, initial TACE, Child-Pugh A6) and benefited more from SIRT.

This manuscript elegantly confirms that the combination of SIRT + sorafenib may be associated with a survival benefit in certain highly selected patients with preserved liver function, as well as that the absence of benefit in others is related to a decrease in their fragile liver reserve, mainly observed 4 months after the injection. This late “radiation-induced liver disease”, not detected with our usual toxicity criteria, corresponds to progressive and irreversible worsening of liver function.

Thus, like TACE, in a palliative setting, SIRT may only be beneficial to certain highly selected patients with good liver reserves (a good baseline ALBI score), and after a single injection, degradation to the ALBI score is associated with poor prognosis related to silent and progressive liver failure (10).

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Hepatobiliary Surgery and Nutrition. The article did not undergo external peer review.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2021-30/coif). The author reports consulting fees from Valneva, honoraria for lectures from Servier and for Safety Monitoring Committee from Transgene. The author has no other conflicts of interest to declare.

Ethical Statement: The author is 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/.

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