Editorial: Predictive Factors and Survival Outcome of Conversion Therapy for Unresectable Hepatocellular Carcinoma Patients Receiving Atezolizumab and Bevacizumab: Comparative Analysis of Conversion, Partial Response and Complete Response Patients. Authors' Reply

Abstract

We appreciate the editorial comment [1] by Dr. Joao Gorgulho and Dr. Johann von Felden on our study. Their insights have expanded upon the conclusions of our research [2] on the impact of conversion therapy on the survival of patients with unresectable hepatocellular carcinoma (HCC) receiving combination therapy with atezolizumab and bevacizumab (Atez/Bev).

Given the increasing emergence of immunotherapy (ICI)-based regimens, it is anticipated that the number of conversion cases will rise. This raises a further clinical question: Does continuing ICI treatment prolong overall survival (OS) in HCC patients after achieving conversion therapy? In the field of colorectal liver metastasis, a meta-analysis [3] demonstrated that systemic therapy following liver resection improved recurrence-free survival (RFS) but did not extend OS. Additionally, this meta-analysis [3] also reported a minimal correlation between RFS and OS after resection of colorectal liver metastases. The Imbrave050 trial [4] showed that adjuvant Atez/Bev improved RFS but did not prolong OS in patients at high risk for HCC recurrence. However, since the patients included in this trial had not undergone any prior systemic therapy and approximately 80% were classified as Barcelona Clinic Liver Cancer stage A, these results cannot be directly extrapolated to conversion cases. While continuing Atez/Bev for patients after conversion therapy may help suppress HCC recurrence and prolong RFS, it remains uncertain whether it contributes to prolonging OS. Furthermore, adjuvant Atez/Bev treatment may impair preserved liver function and increase the risk of adverse events (AEs), including immune-related AEs. On the other hand, omitting adjuvant Atez/Bev treatment after conversion therapy raises unresolved questions, such as the recurrence rate, the pattern of disease progression (e.g., the appearance of new solitary nodules in the liver, multinodular lesions in the liver, portal vein tumour thrombosis [PVTT] or extrahepatic lesions) and the percentage of patients resuming Atez/Bev therapy. This is because, while the recurrence rate is an important concern, it is equally significant whether the recurrence involves multiple intrahepatic and/or extrahepatic lesion or is limited to a few localised lesions within the liver [5]. If the recurrence is confined to a few lesions in the liver, curative treatments such as hepatectomy or ablation therapy may be feasible. In contrast, the appearance of distant metastasis or PVTT may necessitate the resumption of systemic therapy. The pattern of recurrence—whether repeated curative treatment can be applied or systemic therapy must be resumed—is likely to affect the patient's subsequent prognosis. In this context, drug-off criteria [6] have been proposed recently, but additional studies are warranted to determine whether these criteria are useful.

Further analyses are required to investigate whether RFS can serve as an appropriate surrogate marker for OS after conversion therapy for HCC. If the benefits of continuing Atez/Bev after conversion therapy are limited, conversion therapy itself for partial response cases could offer significant advantages, as stopping Atez/Bev would help preserve liver function and reduce the incidence of AEs.

Takeshi Hatanaka: conceptualization, writing – original draft. Satoru Kakizaki: conceptualization, writing – review and editing. Atsushi Hiraoka: conceptualization, writing – review and editing. Toshifumi Tada: conceptualization, writing – review and editing. Takashi Kumada: conceptualization, writing – review and editing.

This article is linked to Hatanaka et al papers. To view these articles, visit https://doi.org/10.1111/apt.18237 and https://doi.org/10.1111/apt.18296.