Definition of Conversion Therapy and Neoadjuvant Therapy for Hepatocellular Carcinoma: A Consensus Guideline from the Japan Liver Cancer Association

Abstract

With the advent of novel systemic therapies that provide high response rates, such as lenvatinib, atezolizumab-bevacizumab, durvalumab-tremelimumab, and nivolumab-ipilimumab, treatment strategies for patients with advanced hepatocellular carcinoma (HCC) have markedly evolved, and discussions on conversion therapy – which, broadly speaking, combines these systemic therapies with locoregional modalities – have become commonplace. However, the term “conversion therapy” has not yet been clearly defined, making it difficult to compare treatment outcomes among studies. To address this issue, the Japan Liver Cancer Association established a consensus-based “Working Group on the Definition of Conversion” as an official project of the association. The working group comprised experts in hepatobiliary surgery, hepatology, and radiology, with a rapporteur responsible for drafting and revising the definitions. The group proposed standardized definitions for “conversion surgery,” “neoadjuvant therapy,” and “ablation as conversion therapy,” while recommending that transcatheter arterial chemoembolization should not be classified as conversion therapy due to its limited curative potential. The definitions also introduced two key concepts: functional conversion (based on the hepatic functional reserve) and oncological conversion (based on the tumor status). Adoption of these definitions is expected to facilitate appropriate evaluation of pretreatments and outcomes of conversion therapy. Ultimately, these efforts are expected to contribute to refining clinical decision-making, providing a common framework for guideline development and future clinical studies, and improving the outcomes of multidisciplinary treatments for advanced HCC; however, further validation is required.

Introduction

In recent years, the treatment strategies for advanced hepatocellular carcinoma (HCC) have been rapidly evolving with the advent of highly effective systemic therapies. Multiple phase III trials have demonstrated substantial objective response rates and survival benefits with agents such as lenvatinib, atezolizumab-bevacizumab, durvalumab-tremelimumab, and nivolumab-ipilimumab [1–4]. Furthermore, high response rates have also been reported for approaches that combine systemic therapy with transcatheter arterial chemoembolization (TACE) or hepatic arterial infusion chemotherapy [5, 6], and multidisciplinary treatment strategies combining systemic treatment with surgery, ablation, or TACE (often referred to as “conversion therapy”) have come to be widely adopted. Although many long-term survivors have been reported [7, 8], conversion therapy has not yet been clearly defined, posing challenges for comparing treatment outcomes. To address these issues, the Japan Liver Cancer Association established the “Working Group on the Definition of Conversion” as an official project of the association, and the working group held discussions. This paper presents the proposed definitions, the underlying issues that prompted their development, and the discussions held by the working group.

Consensus Process

This section describes the multidisciplinary, consensus-based process used to develop the proposed definitions. The expert panel comprised four hepatobiliary surgeons (K.H., E.H., A.T., and M.T.), three hepatologists (R.T., K.N., and Y.M.), one radiologist (T.M.), one rapporteur (A.I.), and one observer (M.S.), all affiliated with the Japan Liver Cancer Association. From October 2023, through three web conferences, the panel identified the key issues and developed a draft proposal for “the definition of conversion.” The working group followed a consensus-building process in which members independently proposed issues, exchanged opinions during the meetings, and revised the draft iteratively until agreement was reached. During this process, the draft was also reviewed by the Board of Directors and the Committee for the General Rules for the Clinical and Pathological Study of Primary Liver Cancer. After the revisions, the panel presented the proposed “definition of conversion” at the 60th Annual Meeting of the Japan Liver Cancer Association on July 13, 2024. The proposed “definition of conversion” presented in this article also incorporates revisions made based on discussions held at the aforementioned annual meeting. A Japanese-language version of these definitions has been published in the journal Kanzo [9] and is also available on the website of the Japan Liver Cancer Association [10]. The present manuscript is an expanded and fully restructured English version prepared for international dissemination.

Proposed Conceptual Framework

Definition of Conversion Surgery

Conversion surgery is defined as curative resection (macroscopic R0 resection) performed for HCC that is initially (at diagnosis) deemed as unresectable (UR) (not amenable to complete tumor removal), but becomes resectable after nonsurgical treatment. In this definition, surgery is only applicable to surgical resection and not to liver transplantation. The judgment of technical resectability is left to the discretion of each institution. When considering the types of conversion surgery, two factors must be taken into account: functional conversion and oncological conversion.

Functional Conversion: Conversion Related to the Hepatic Functional Reserve

Functional conversion is defined as a situation where cases initially deemed UR due to insufficient hepatic functional reserve – resulting from either poor intrinsic liver function or inadequate future liver remnant volume – become eligible for curative resection after nonsurgical treatments. Cases where tumor shrinkage caused by systemic therapy enables preservation of the major vasculature and/or reduces the extent of liver resection needed are considered as examples of functional conversion. In this definition, no specific criteria have been established for determining resectability in terms of the hepatic functional reserve, and the judgment of resectability is left to each institution.

Cases in which curative resection becomes feasible solely through procedures intended to increase the future liver remnant volume – such as portal vein embolization, associating liver partition and portal vein embolization for staged hepatectomy (ALPPS), or hepatic vein embolization – are not classified under functional conversion. These cases represent a distinct cohort from that in which functional conversion is achieved through tumor-targeted nonsurgical therapies, such as systemic therapy, and including them as cases of functional conversion could cause confusion when analyzing/comparing treatment outcomes. However, functional conversion includes cases where these procedures to increase future liver remnant volume, such as portal vein embolization, are combined with tumor-targeted nonsurgical therapies (e.g., systemic therapy) to sufficiently improve the hepatic functional reserve for surgery.

Oncological Conversion: Conversion Related to Oncological Factors

Oncological conversion is defined as a situation where cases initially predicted to show a poor postoperative prognosis receive nonsurgical therapy, resulting in a state where the risk of recurrence is reduced and surgical resection becomes appropriate. Even if the oncological status, as defined by the BR-HCC Expert Consensus (e.g., borderline resectable 1 [BR1] or BR2) [11], remains unchanged after the nonsurgical treatment, cases in which disease control is achieved and curative resection is performed afterward are classified under cases of oncological conversion. Examples include cases where stable disease is maintained for a certain period under systemic therapy or cases where the oncological status does not change, but a decrease in tumor size and/or tumor marker levels is achieved.

Types of Conversion Surgery

As shown in Figure 1, conversion surgery can be classified according to changes in the oncological status and hepatic functional status. To clarify what type of conversion surgery is performed in each case, it is necessary to describe the changes in both the oncological status and hepatic functional status. In addition, the reasons why curative resection was judged as being unachievable before the nonsurgical treatment should also be specified. These reasons may include insufficient future liver remnant volume, presence of distant metastasis, tumor invasion of adjacent organs, or a combination of these factors. In cases where both oncological and hepatic functional factors contribute to initial unresectability and subsequently improve after treatment, such cases may be classified as both functional and oncological conversions, with both factors explicitly documented.

Fig. 1.

Types of conversion surgery. R, resectable; UR, unresectable.

For example, if the oncological status changes from BR1 to resectable (R) and the functional status changes from UR to R, the documentation should state conversion surgery (oncologically BR1 to R, functionally UR to R); reason for unresectability before treatment: insufficient future liver remnant volume. A clear description of the pretreatment status, as above, makes it possible to compare conversion rates and evaluate the effectiveness of pretreatments. In addition, specifying the type of conversion surgery would enable a reliable comparison of the outcomes.

Definition of Neoadjuvant Therapy

Neoadjuvant therapy is defined as treatment given to patients who are deemed as being eligible for curative resection at diagnosis, and both the treatment plan and date of surgery are set a priori. Neoadjuvant therapy is defined as preoperative therapy aimed at further improving the postoperative outcomes in cases which are deemed as resectable at diagnosis and are classified as BR1 or BR2. Conversely, cases where surgical resection was initially considered unsuitable from an oncological perspective or infeasible due to limited hepatic functional reserve but became suitable for curative resection after nonsurgical treatment are classified as conversion surgery. The specific criteria distinguishing oncological conversion from neoadjuvant therapy should be discussed and established through future expert consensus.

For example, among patients who are considered resectable from a hepatic functional standpoint, based on both liver function and the extent of liver resection, tumors classified as BR1 may be managed with planned systemic therapy followed by resection, which could be interpreted as neoadjuvant therapy. In contrast, BR2 tumors, for which the benefit of upfront resection remains uncertain, may be considered oncologically UR at baseline; if such tumors subsequently become eligible for resection after systemic therapy, this may be interpreted as oncological conversion. However, this proposed classification remains hypothetical and requires further validation.

Definition of Ablation as a Conversion Therapy

Ablation as conversion therapy is defined as curative ablation performed in cases initially deemed as being unsuitable for curative ablation but rendered amenable to curative ablation following systemic therapy. For example, in patients with multiple HCCs, if ablation is performed only for lesions that respond poorly to systemic therapy – without achieving curative ablation of all detectable tumors – such cases cannot be regarded as undergoing conversion therapy.

Considerations Regarding TACE

Although conversion therapy is fundamentally defined as treatment aimed at achieving a curative outcome, TACE is excluded from this category because its therapeutic efficacy is difficult to predict. Even when TACE is performed with curative intent and followed by surgical resection, histopathological examination of the resected specimens often reveals residual viable lesions. Therefore, the curative potential of TACE is considered as being inferior to that of resection or ablation. However, the exclusion of TACE from the definition of conversion therapy in the present consensus should not be interpreted as a denial of its therapeutic value, particularly in clinical situations where other curative options are limited or not feasible.

Discussion

The most significant issue in a discussion of conversion surgery for HCC is the absence of a clear definition of “UR HCC.” Determining surgical resectability in HCC requires consideration of multiple factors, including the tumor size, number, and location; presence/absence of vascular invasion or extrahepatic metastasis; and hepatic functional reserve. Furthermore, due to variations in the surgical technical standards among institutions, defining UR HCC is more complex than defining unresectability in other malignancies. Although several definitions of UR HCC have been proposed in the past [12, 13], no consensus has been achieved. To address this issue, a working group on borderline resectable HCC was established as a joint project between the Japan Liver Cancer Association and the Japanese Society of Hepato-Biliary-Pancreatic Surgery. An expert consensus on the definition of borderline resectable HCC was developed and published on November 2, 2023 (Fig. 2) [11]. In this consensus, resectability was classified from an oncological perspective, focusing on technically and functionally resectable cases. When defining conversion surgery, it is necessary to consider technical and hepatic functional resectability, with reference to this expert consensus from an oncological perspective. Given the substantial interinstitutional variability in surgical expertise and in the assessment of hepatic functional reserve, strict criteria for resectability were intentionally not defined in the present consensus.

Fig. 2.

Oncological resectability criteria for HCC (modified from reference 11). *Localized extrahepatic spread is as follows: solitary nodal involvement at no. 3, 8, or 12 lymph nodes, localized peritoneal dissemination, unilateral adrenal metastasis, or oligometastasis to the lung.

Another issue is whether all surgeries performed after nonsurgical treatment should be regarded as conversion surgery. Ideally, only those surgeries performed after disease control has been achieved through prior therapy should be classified as conversion surgery. However, the specific conditions under which surgery qualifies as conversion surgery are not yet clearly defined.

Although case reports and case series describing conversion surgery for HCC have been published, very few explicitly define the concept. Previous studies referring to conversion surgery have not provided specific criteria [14–17]. Recently, alternative conceptual frameworks for conversion therapy in HCC have also been proposed. For example, Vitale et al. [18] emphasized a treatment-oriented classification that stratifies patients according to therapeutic hierarchy and intent. In contrast, the present definition focuses on the process by which initially UR cases become eligible for curative treatment, explicitly incorporating both oncological and hepatic functional aspects. These differences reflect complementary perspectives and highlight the need for further investigation to determine their respective clinical applicability.

To address these issues related to the definition of conversion surgery, the “Working Group on the Definition of Conversion” developed a definition that incorporates both oncological and hepatic functional aspects, thereby classifying conversion surgery into two types. Table 1 summarizes the differences between the previously used concept and the present definition. Establishing a definition of conversion surgery would be expected to enable appropriate evaluation of the effectiveness of pretreatments aimed at conversion and facilitate comparison of surgical outcomes. In addition, while formulating the definition of conversion surgery, it became necessary to establish a definition for neoadjuvant therapy as well. Therefore, this definition was established as distinct from the definition of conversion surgery.

Table 1.

Comparison between previously used concept and the present definition

​	Previously used concept	Present definition
Conversion surgery
Oncological assessment	No standardized framework for evaluating tumor-related resectability	Uses the BR-HCC classification to define oncological status
Assessment of the hepatic functional reserve	Considered, but seldom defined explicitly	Introduces the concept of functional conversion
Distinction from neoadjuvant therapy	Definitions sometimes overlapped	Conversion therapy and neoadjuvant therapy are distinct treatment strategies
Conversion therapy
Target modalities	Often broadly included systemic therapy followed by surgery; some definitions also included ablation or TACE	Limited to curative-intent treatments (surgery or ablation). TACE performed after systemic therapy is not considered as conversion therapy
Requirement of curative intent for definition	Not consistently required	Curative intent is a fundamental requirement

TACE, transcatheter arterial chemoembolization.

In recent years, conversion to treatments other than surgery has also been actively discussed. However, it remains a problem that treatment outcomes cannot be appropriately compared unless a clear definition is established for each therapeutic modality. Therefore, it is necessary to determine under what initial and subsequent tumor conditions, and with what type of treatment, such therapy should be regarded as conversion therapy. In treatments such as TACE and ablation, it was confirmed that the term “conversion therapy” had sometimes been applied even to treatments that were not intended to be curative. In contrast, in other malignancies, the term “conversion surgery” is generally used to describe surgery with curative intent. Therefore, to facilitate meaningful comparisons of treatment outcomes across different modalities and institutions, the “Working Group on the Definition of Conversion” concluded that the term “conversion therapy” should be limited to treatments performed with curative intent, even when referring to nonsurgical therapies. With regard to TACE, although it is not uniformly deemed as being non-curative, given the relatively low probability of achieving cure with TACE as compared with resection or ablation, the term “conversion therapy” cannot be applied to TACE. Table 1 also shows the differences between the previously used concept and the present definition of conversion therapy.

In this paper, we have outlined the definitions of conversion therapy proposed by the “Working Group on the Definition of Conversion,” the key issues related to conversion therapy for HCC, and the efforts of the working group. It is expected that the application of these definitions may help clarify, in the future, the efficacy of individual pretreatments, conversion rates, outcomes of conversion surgery, and ablation performed as conversion therapy. Moreover, it is anticipated that the efficacy of neoadjuvant therapy may be evaluated independently, without being confounded by conversion therapy. As these outcomes become clearer, important clinical questions may be addressed, such as what types of patients should undergo conversion surgery or ablation as conversion therapy? Are there situations where TACE or radiation therapy should take priority over surgical resection or ablation performed as conversion therapies? Which subsets of patients are likely to benefit the most from neoadjuvant therapy? We hope that addressing these questions may provide meaningful insights and ultimately contribute to improving treatment outcomes for patients with advanced HCC. However, further validation of these concepts is required.

Statement of Ethics

This work represents a consensus-based guideline proposal and did not involve human participants, patient-level data, or identifiable personal information. Therefore, ethical approval and informed consent were not required.

Conflict of Interest Statement

The following disclosures apply in relation to this manuscript. Ryosuke Tateishi has received lecture fees from AstraZeneca K.K. Etsuro Hatano has received lecture fees from Eisai Co., Ltd., Chugai Pharmaceutical, and AstraZeneca K.K. Kiyoshi Hasegawa has received research funding from Mochida Pharmaceutical Co., Ltd., Shimadzu Corporation, FUJIFILM Corporation, and FUJIFILM Healthcare Corporation; Mitsuo Shimada has received research funding from Chugai Pharmaceutical Co., Ltd., Rohto Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., and Tsumura & Co. Takamichi Murakami has received educational donations from Guerbet Japan K.K., Siemens Healthcare K.K., Philips Japan, Ltd., and Nemoto Kyorindo Co., Ltd.; Mitsuo Shimada has received educational donations from AbbVie GK, Chugai Pharmaceutical Co., Ltd., and Taiho Pharmaceutical Co., Ltd. Takamichi Murakami is affiliated with an endowed department supported by GE Healthcare Japan Corporation and Canon Medical Systems Corporation. All other authors declare no conflicts of interest. Prof. Kiyoshi Hasegawa, Prof. Ryosuke Tateishi, Prof. Etsuro Hatano, and Prof. Kazuhiro Nouso were members of the journal’s Editorial Board at the time of submission.

Funding Sources

This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author Contributions

Conceptualization and study design: K.H., R.T., E.H., A.T., M.T., K.N., Y.M., and T.M. Consensus process and discussion: all authors. Drafting of the manuscript: A.I. Critical revision of the manuscript: K.H., R.T., E.H., A.T., M.T., K.N., Y.M., T.M., and M.S. Supervision: K.H. All authors approved the final version of the manuscript.

Funding Statement

This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data Availability Statement

No datasets were generated or analyzed during the current study. All relevant information is contained within the article. Further inquiries can be directed to the corresponding author.