Comparison of SBRT and SIRT With Combination IO for Locally-advanced, Unresectable HCCs (BIIRTH)

Hepatocellular carcinoma (HCC) represents a major global health threat, ranking sixth in worldwide cancer incidence and third in cancer mortalities. Southeast Asia remains endemic, with liver cancer ranking fifth and third in local cancer incidence and mortalities respectively according to the Hong Kong Cancer Registry. While resection, radiofrequency ablation (RFA) and liver transplantation represents chances of cure, only 30% of patients are eligible for curative local intervention upon presentation. Large, locally advanced HCCs represent a distinct population of aggressive clinical courses conferring poor prognoses and are often rapidly symptomatic, with limited treatment options and represent true unmet clinical needs.

1.1 Current Landscape of Locoregional Therapies for Locally Advanced HCC

A substantial population of locally advanced HCC patients die of intra-hepatic treatment failures. Intensifying local treatment strategies has been suggested to improve survival outcomes, hence optimizing locoregional therapy is of paramount importance. Transarterial chemoembolization (TACE) remains the most widely adopted local treatment modality in unresectable HCCs. Growing evidence, however, has demonstrated limited efficacy among large tumours, with reported low response rates of roughly 30% among large (≥5cm) or multinodular HCCs and poor 2-year overall survival of 0% for tumour sizes ≥8 cm.

On the other hand, radiotherapy techniques have evolved, with stereotactic body radiotherapy (SBRT) and selective internal radiotherapy (SIRT) gaining recognition in the treatment of large unresectable HCCs. SIRT has been suggested to be as effective as sorafenib in HCC patients with liver-only involvement with more favourable tumour response and side effect profile. Lately, the American Society for Radiation Oncology (ASTRO) Clinical Practice Guideline on External Beam Radiotherapy (EBRT) for Primary Liver Cancers 2021 recommended EBRT as a potential first-line therapy option in liver-confined, incurable HCCs alongside with catheter-based therapies including TACE and SIRT.

While Y90 SIRT is considered the Hospital Authority's standard in HCC patients with tumours (i) ≥8cm, or (ii) presence of portal vein invasion, or (iii) as a bridge therapy to liver transplantation, there is currently no prospective, head-to-head comparison on the choice of locoregional therapy, and growing evidence urges optimization and standardization of treatment algorithms for locally advanced, unresectable tumours.

1.1.1 SIRT Radioembolization with 90yttrium (Y90)-tagged glass or resin microspheres has been an internationally recognized and widely-practiced local treatment modality among large, unresectable HCCs. Salem et al reported comparable outcomes to TACE in terms of response rate (42%) and time-to-progression (7.9 months) for a sample of 291 patients with median tumour sizes of 7 cm with acceptable toxicities. As Hospital Authority's standard indication, Y90 SIRT is considered in HCC patients with tumours (i) ≥8cm, or (ii) presence of portal vein invasion, or (iii) as a bridge therapy to liver transplantation.

However, price and accessibility concerns have limited its application, especially among pandemic areas and/or developing countries. In addition, more vigorous screening is required to meet the eligibility criteria for SIRT. In particular, a pre-treatment Technetium-99m (99mTc) macroaggregated albumin (MAA) scan is required as initial screening, in which only patients without significant lung shunting of hepatic artery blood flow are considered eligible. While HCC patients were found to have higher median lung shunt fraction (LSF) than other metastatic liver tumours, as high as 21.4% were ineligible for Y90 due to an exceedingly high LSF.

1.1.2 TACE with SBRT SBRT liver has emerged as a promising local therapy in patients with locally advanced HCCs. While TACE alone might be suboptimal in treating large, unresectable HCCs, meta-analyses concluded an improvement in OS with combination TACE and EBRT as compared to TACE alone. Furthermore, a retrospective study of patients with unresectable HCCs and a median tumour size of 8.5cm (5.1-21cm) demonstrated a significantly better 5-year OS rate of 46.9% vs 32.9% among those who received combination TACE and SBRT versus SBRT alone.

The American Society for Radiation Oncology (ASTRO) clinical practice guideline on EBRT for primary liver cancers conditionally recommended the use of EBRT in patients with liver-confined, multifocal and/or unresectable HCCs, with or without macrovascular invasion, either alone or sequenced with other catheter-based therapies. The relatively high accessibility, less expensive RT and TACE interventional radiology facilities has represented a highly attractive treatment option.

Prior local work has been done. A substantially enhanced anti-tumour response and survival benefits with similar toxicities by means of sequential single-course of TACE followed by SBRT as compared with the TACE alone group by propensity score matched analysis was reported. Subsequently, a published 2020 study evaluating 55 consecutive patients with large (≥10 cm) HCCs of median tumour sizes 15.3cm (range, 10.0-25.7cm) receiving sequential TACE and hypofractionated image-guided radiotherapy (HIGRT) at Tuen Mun Hospital during 2007-2017 with a 1-year local in-field progression-free survival (PFS) rate of 57.4% (95% CI = 40.8%-74.0%). Notably, 27% of treatment responders achieved remarkable tumour downstaging and underwent subsequent curative resection, achieving a significantly prolonged OS of 41.2months (95% CI, 19.1-63.2 months) as compared to those without surgery. Such results are also in line with the Hong Kong consensus statements on unresectable HCC 2021 guidelines affirming the role of combination TACE and SBRT.

1.1.3 Immune Checkpoint Inhibitors (ICI) While systemic therapy is also considered a standard therapeutic option in locally advanced, unresectable HCCs, response rates were modest even in the post-immunotherapy era, ranging from 5-40%. Atezolizumab, a programmed death ligand 1 (PD-L1) inhibitor, in combination with bevacizumab, a monoclonal antibody against the vascular endothelial growth factor (VEGF), is the preferred first-line treatment option since the establishment of IMbrave150 trial. The response rate at 27.3% (95% CI, 7.4-18.0%), albeit the presence of survival benefits, urges needs for further improvement.

1.2 Emerging Combination of Locoregional and Systemic Therapy and Potential Surgical Conversion in Local Advanced HCCs

Evolving evidence suggests upfront liver-directed therapy application followed by systemic therapy combination could achieve successful tumour downstaging in locally advanced HCCs leading to curative surgeries and improved survival. The randomized, multicentre, phase 3 NRG/RTOG 1112 trial reported the addition of SBRT to sorafenib has improved OS, PFS and TTP in advanced HCC patients versus Sorafenib alone, with no significant increase in adverse events. Another recent prospective single arm, single centre, phase 2 NASIR-HCC study demonstrated rates of surgical conversion (9.5%), partial response (PR) (16.7%) and OR (41.5%; 95% CI: 26.3-57.9%), as well as median time to progression (mTTP) of 8.8months (95% CI: 7.0-10.5months) and mOS of 20.9months (95% CI: 17.7-24.1months) in 42patients with HCCs exceeding 5cm or multiple beyond the up-to-seven criteria treated with SIRT followed by nivolumab combination therapy.

Moreover, local research is emerging. The published START-FIT study in Lancet Gastroenterology and Hepatology was a prospective single arm, multi-centre phase 2 trial demonstrating initial success of the novel, sequential TACE-SBRT-immunotherapy (avelumab) approach. Promising rates of conversion (55%), complete response (CR) (42%) and objective response (OR) (66.7%; 95% CI: 48.2-82.0%), as well as favourable mPFS of 20.7months (95% CI: 14.6-26.8months) and median overall survival (mOS) of 30.3months (95% CI: 22.7-37.8months) were achieved in 33 patients with locally advanced, upfront unresectable HCCs of median sizes 15.1cm (range: 5.3-31.1cm). Toxicity profile was also favourable, hereby demonstrating the safety and efficacy of our combination TACE-SBRT and immunotherapy treatment. Since then, two propensity score matching analyses, one of which was in Liver Cancer, demonstrated a significantly improved OS rates of SBRT-immunotherapy as compared to TACE alone (2-year OS 80.4% vs. 8.3%), and SBRT alone (3-year OS 62.9% vs. 43.4%) respectively.

While sequential local-systemic therapy is expected to be synergistic, direct comparison on the different types of local therapy backbone is lacking. Determining the optimal loco-systemic treatment strategy is therefore integral to achieve potential surgical conversion and unlock major survival benefits.

With results of combination TACE and SBRT being numerically favourable as compared to that of SIRT, a comparison of sequential TACE-SBRT versus Y90 SIRT would therefore be the next logical investigation approach. We aim at conducting a prospective trial with head-to-head comparison on combinational TACE-SBRT versus Y90 SIRT as standard locoregional therapy, together with combination immunotherapy treatment among locally advanced HCCs.

This project carries substantial impact on HCC management via:

(a) establishing the role of locoregional therapy in the post-immunotherapy era, (b) shedding light on local and international guidelines of incorporating locoregional therapy to first-line treatment in locally advanced HCC patients, and (c) potentially unlocking major, durable survival benefits through the synergistic effects of optimal local-systemic therapy combination among patients with locally advanced HCCs whom prognosis is guarded and treatment option is limited.