Radiation segmentectomy for curative intent of unresectable very early to early stage hepatocellular carcinoma (RASER): a single-centre, single-arm study

Summary

Background

Unresectable solitary very early to early stage hepatocellular carcinoma is managed with ablation for curative intent. Radiation segmentectomy is a treatment option that delivers radioactive ⁹⁰yttrium (⁹⁰Y)-bound microspheres transarterially to a segment of liver. The aim of this study was to assess the safety and efficacy of radiation segmentectomy in patients with unresectable hepatocellular carcinoma deemed unfavourable for ablation.

Methods

RASER was a single-centre, single-arm study that included adults (>18 years) with solitary hepatocellular carcinoma with unfavourable location for ablation, without metastasis or macrovascular invasion. Eligibility criteria included measurable disease 3 cm or less in diameter, Child-Pugh score A–B7, an Eastern Cooperative Oncology Group score of 0, and adequate haematological and organ function. The primary endpoint was target tumour response measured by mRECIST. Patients were followed up with imaging and office visits for up to 24 months. The trial is registered with ClinicalTrials.gov (NCT03248375), and is completed.

Findings

Individuals were enrolled between Aug 3, 2016, and April 4, 2019, and the last patient follow-up occurred on March 31, 2021. Of the 44 individuals assessed for eligibility, 29 patients were included in the study. Initial target lesion complete response was observed in 24 (83%) of 29 patients, and partial response was observed in five (17%) of patients. All patients had an initial objective response and 26 (90%) individuals had a sustained complete response. Four (14%) patients had grade 3 leukopenia and two (7%) had grade 3 thrombocytopenia. There were two (7%) non-laboratory-related grade 3 adverse events (one arterial injury and one ascites). The most frequent (>10% patients) grade 1 or 2 adverse events were fatigue (nine [31%]); nausea, vomiting, or anorexia (seven [24%]); abdominal discomfort (six [21%]), leukopenia (nine [31%]), thrombocytopenia (four [14%]), increased alkaline phosphatase (four [14%]), increased alanine or aspartate aminotransferase (four [14%]), increased bilirubin (four [14%]), and decreased albumin (six [21%]). There was one death that was not treatment related.

Interpretation

Radiation segmentectomy was efficacious, with a low proportion of high-grade adverse events in patients with unresectable very early to early stage hepatocellular carcinoma with suboptimal location for ablation. These results suggest that radiation segmentectomy should be further investigated as a potential curative treatment option for well selected patients.

Funding

Boston Scientific.

Introduction

Unresectable solitary very early to early stage hepatocellular carcinoma is treated with ablation for lesions 3 cm or smaller, with the goal of curative intent.¹ However, tumours might not be amendable to ablation for a variety of reasons, such as unfavourable locations (appendix p 4). In these situations, ablation might underperform, with high rates of incomplete necrosis and local recurrence.2, 3 Radiation segmentectomy, defined as selective administration of an ablative dose with ⁹⁰yttrium (⁹⁰Y) microspheres to two couinaud hepatic segments or less, is another treatment option showing promising results. Radiation segmentectomy uses the preferential blood flow to the tumour to deliver radioactive microspheres to a volume of tissue while minimising damage to the non-tumoural parenchyma. Unlike ablation, radiation segmentectomy avoids a percutaneous approach and thus limits the risk of seeding, bleeding, or injury to key structures.⁴ Compared with transarterial chemoembolisation, radiation segmentectomy can provide better tumour control and complete response.5, 6, 7 In addition, radioembolisation can increase progression-free survival and achieve similar responses to transarterial chemoembolisation followed by ablation for lesions 3 cm or less.⁸ Radiological–pathological correlation has also shown complete pathological response for tumours less than 5 cm treated with radiation segmentectomy.9, 10 The LEGACY study¹¹ showed that radiation segmentectomy can provide good local tumour control and overall survival for solitary tumours up to 8 cm, adding to the body of evidence in support of the US Food and Drug Administration approval and Barcelona Clinic Liver Cancer guideline inclusion of ⁹⁰Y glass microspheres for hepatocellular carcinoma.¹² Despite favourable results, no prospective study has validated the safety and efficacy of radiation segmentectomy used in very early to early stage, unresectable hepatocellular carcinoma. This is important, as retrospective studies involving radiation segmentectomy are often limited by selection bias and non-standardised imaging and adverse event follow-up protocols. We aimed to assess outcomes and adverse events of radiation segmentectomy, when used as a treatment for unresectable, solitary very early to early stage hepatocellular carcinoma deemed unfavourable for ablation.

Research in context

Evidence before this study

We searched PubMed for articles published from Jan 1, 1991, to Jan 1, 2016, in English, focusing on publications of randomised studies and systematic reviews, but also including larger retrospective studies, for the treatment of unresectable hepatocellular carcinoma. In particular, we focused our review on very early to early stage hepatocellular carcinoma. We used search terms “hepatocellular carcinoma” and “selective internal radiation therapy” or “radioembolization” or “chemoembolization” or “ablation.” We identified no prospective studies involving radioembolisation for very early to early hepatocellular carcinoma. Several retrospective studies were found, the results of which suggested that radioembolisation can achieve good response rates as well as result in complete histopathological necrosis. We also found many articles discussing suboptimal outcomes after thermal ablation in patients with unfavourable tumour locations.

Added value of this study

To our knowledge, this is the first prospective study to assess outcomes after radiation segmentectomy in patients with very early to early stage hepatocellular carcinoma. The study showed that radiation segmentectomy, which delivers an ablative radiation dose via a transarterial route, can achieve good sustained complete response rates for tumours deemed suboptimal for ablation. Our findings support the inclusion of radioembolisation in the Barcelona Clinic Liver Cancer guidelines for early stage hepatocellular carcinoma.

Implications of all the available evidence

This study provides a strong rationale for new randomised trials comparing radiation segmentectomy to ablation. Given complete pathological necrosis of the explanted tumours, larger investigative studies on the curative potential of radiation segmentectomy are warranted.