Evolving practices, treatment decisions, and unmet needs in intermediate-stage hepatocellular carcinoma: An Asia Pacific perspective

Abstract

BACKGROUND

Until recently, the use of systemic therapies among patients with intermediate-stage hepatocellular carcinoma (iHCC) was limited. However, this has recently become a topic of interest in the treatment of patients who are also eligible for locoregional therapy (LRT). The combination of LRT with systemic therapy in patients with iHCC has been investigated in multiple clinical trials, with guidelines recently updated to reflect this.

AIM

To investigate current iHCC management and address readiness to adopt systemic therapy and LRT combinations among physicians in Asia.

METHODS

An online survey addressing the surveillance and diagnosis of hepatocellular carcinoma (HCC), the role of treatment decision makers and the multidisciplinary team in iHCC, current treatment approaches and decision-making practices in iHCC, and options for improving outcomes for patients with iHCC was developed and administered to physicians from seven Asian countries (Korea, Malaysia, Philippines, Singapore, Taiwan, Thailand, and Vietnam). One-to-one follow-up interviews were conducted with three physicians from each country to verify the survey results and further understand country-wide practices.

RESULTS

Seventy of 135 invited physicians completed the survey (response rate 51.9%). Conventional transarterial chemoembolization (C-TACE) was the preferred first-line treatment for Barcelona Clinic Liver Cancer (BCLC) stage B1-2 iHCC, while systemic therapy alone or in combination with LRT was the preferred first-line treatment for BCLC-B3 or BCLC-C HCC. Among 54 self-identified prescribers, 98.1% had experience of using a systemic therapy in combination or sequence with LRT, and systemic therapies were most commonly combined or sequenced with C-TACE. While 94.3% of respondents had access to a multidisciplinary team for the management of iHCC, gastroenterologists/hepatologists were seen as the primary treatment decision maker by 44.3% of respondents. Barriers to the adoption of systemic therapy and LRT combinations included evidence gaps and cost/reimbursement status.

CONCLUSION

This survey gives a snapshot of real-world iHCC management across Asia and provides evidence of a growing role for locoregional and systemic therapy combinations in the management of iHCC.

Key Words: Intermediate hepatocellular carcinoma; Hepatocellular carcinoma; Systemic therapy; Locoregional therapy; Survey; Physician survey

Core Tip: The integration of systemic therapy with locoregional therapy (LRT) for the treatment of intermediate-stage hepatocellular carcinoma (iHCC) is rapidly becoming an area of interest. In this physician-targeted survey, 98.1% of prescribers had experience using a systemic therapy in combination or sequence with LRT for the treatment of iHCC. Patients with Barcelona Clinic Liver Cancer stage B2 and B3 iHCC were seen as ideal candidates for such combinations; however, barriers to access included lack of evidence for combination-therapy use and cost/reimbursement status of approved treatments.

INTRODUCTION

Liver cancer is the sixth most common cancer worldwide and the third-leading cause of cancer death, accounting for 758000 deaths in 2020. The disease poses a particularly significant health challenge in Asia, with approximately 70% of both cases and deaths occurring within the region. According to the most recent World Health Organization observations, East Asia has an incidence of 14.7 per 100000 and mortality of 11.9 per 100000, while Southeast Asia has incidence and mortality of 13.5 and 13.0 per 100000, respectively[1]. Considering the high burden and often poor prognosis associated with liver cancer[2], the development of innovative treatment approaches is paramount to improving patient outcomes.

Intermediate-stage hepatocellular carcinoma (iHCC), also referred to as Barcelona Liver Cancer Clinic (BCLC) stage B hepatocellular carcinoma (HCC), is defined as HCC with more than three nodules, or HCC with up to three nodules whereby at least one is larger than 3 cm and Eastern Cooperative Oncology Group performance status is 0[3]. Traditionally, this stage is complex to manage, with treatment focusing on the use of locoregional therapies (LRTs) such as conventional transarterial chemoembolization (C-TACE), drug-eluting bead transarterial chemoembolization (DEB-TACE), and radioembolization; however, the efficacy of these therapies is limited, with only half of patients diagnosed with iHCC surviving for more than 2 years[2].

Until recently, systemic therapies were typically reserved for patients with iHCC who were refractory to or unsuitable for transarterial chemoembolization (TACE)[4]; however, they have recently become a topic of interest in the treatment of patients who are also eligible for LRTs. Whereas C-TACE alone is primarily a palliative treatment in the iHCC setting and typically has a limited therapeutic effect, the use of systemic therapies in combination or sequence with C-TACE has the potential to improve progression-free survival (PFS) and the possibility of conversion to resectability[4].

Over the past 5 years, multiple clinical trials have investigated the use of systemic therapies in combination with C-TACE. In 2022, the final readout of the TACTICS trial reported no significant survival benefits following the addition of sorafenib to LRT compared with the use of LRT alone[5]. In 2024, the phase 2 TACTICS-L trial reported a median PFS of 28.0 months among patients with unresectable HCC treated with lenvatinib + LRT[6], prompting this combination to become an acceptable treatment choice in Asia.

At the same time, the advent of immuno-oncology in HCC has rapidly changed the systemic treatment landscape across all treatment stages, and these therapies also show promise in combination with LRTs[4,7]. The LEAP-012, EMERALD-1, TALENTACE, and EMERALD-3 trials found that addition of pembrolizumab + lenvatinib, durvalumab + bevacizumab, atezolizumab + bevacizumab, or tremelimumab + durvalumab + lenvatinib to TACE resulted in significant increases in PFS among patients with iHCC, with median PFS of 14.6 months, 15.0 months, 11.3 months, and 13.0 months in each investigational arm, respectively[8-11]. While the EMERALD-1, TALENTACE, and EMERALD-3 studies are still ongoing, with immature overall survival data, the LEAP-012 study has now been closed. The LEAP-012 regimen is currently approved in China.

In February 2025, in response to these clinical trials, the European Society for Medical Oncology (ESMO) recommended the combination of TACE with pembrolizumab + lenvatinib or durvalumab + bevacizumab for the treatment of patients with unresectable BCLC-B HCC for the first time, marking a key change in established treatment strategies[12]. During the ESMO Asia 2025 congress, updates to the pan-Asian adapted ESMO clinical practice guidelines were discussed, with lenvatinib + TACE suggested as a suitable treatment option for iHCC[13].

While other studies have addressed treatment approaches in HCC in Asia[14,15], no survey has specifically assessed treatment approaches in iHCC. Considering the recent shifts in the iHCC treatment landscape towards the use of systemic therapy in combination with LRT and the heterogeneous nature of resource and treatment availability in the region, we wished to understand current iHCC treatment practices in Asia with a view to comprehending readiness to implement evolving treatment recommendations. As such, we conducted an industry-sponsored physician-targeted survey to generate a comprehensive overview of iHCC management and address the readiness to adopt systemic therapy and LRT combinations in the region.

MATERIALS AND METHODS

This study describes a physician-targeted survey conducted between April and August 2025. An online survey comprising 44 core multiple-choice questions, with additional subquestions shown conditionally to relevant respondents (Supplementary material), was developed to assess practices surrounding iHCC diagnosis and management in seven Asian countries. Specifically, the survey addressed the surveillance and diagnosis of HCC, the role of treatment decision makers and the multidisciplinary team (MDT) in iHCC, current treatment approaches and decision-making practices in iHCC, and options for improving outcomes for patients with iHCC. Questions were multiple choice and closed, with the option to select more than one answer or enter a free-text explanation of answers for some questions. Participants could opt out of answering questions that did not apply to their practice or expertise. Some questions, primarily relating to the use of and preference for systemic therapies in iHCC, were only asked to those licensed to prescribe systemic therapies in their country. Participants were asked to identify treatment choices according to HCC stage as defined by BCLC strategy criteria and BCLC-B substage, as shown in Table 1[3,16]. Participants were also asked questions regarding the timing of systemic therapy in relation to TACE, with the timings defined as follows: pre-TACE - before TACE only; peri-TACE - before and after TACE, or between TACE cycles; post-TACE - after TACE only. The survey was administered in English and not externally validated before use.

Table 1 Hepatocellular carcinoma staging as defined throughout the survey[3,16].

	BCLC stage	Definition
Early HCC	BCLC-0	Single ≤ 2 cm lesion; preserved liver function; ECOG PS 0
	BCLC-A	Single or ≤ 3 nodules, each ≤ 3 cm; preserved liver function; ECOG PS 0
Intermediate HCC	BCLC-B1	Meets extended liver transplant criteria of institution; CPS 5-7; ECOG PS 0; ‘Up to 7’ in
	BCLC-B2	Well-defined nodules, preserved portal flow, selective access; CPS 5-7; ECOG PS 0; ‘Up to 7’ out
	BCLC-B3	Diffuse, infiltrative, extensive bilobar liver involvement; CPS 7; ECOG PS 0; ‘Up to 7’ out
Advanced HCC	BCLC-C	Vascular invasion and/or extrahepatic spread; preserved liver function; ECOG PS 1-2
End-stage HCC	BCLC-D	Any tumour burden; end-stage liver function; ECOG PS 3-4

BCLC: Barcelona Clinic Liver Cancer; HCC: Hepatocellular carcinoma; ECOG PS: Eastern Cooperative Oncology Group performance status; CPS: Child-Pugh score.

The survey respondents comprised physicians treating HCC. Survey respondents were restricted to oncologists, gastroenterologists/hepatologists, interventional radiologists, and surgeons and were only eligible if they treated a minimum of 10 patients with HCC annually and had > 1 year of experience. Physicians must have been practising in public and/or private institutions in the following countries: Korea, Malaysia, the Philippines, Singapore, Taiwan, Thailand, and Vietnam. There were no further inclusion/exclusion criteria other than those listed above.

As this was a descriptive exploratory survey, a target sample size of 10 physicians per country was deemed appropriate; this sample size was not designed to generate nationally representative estimates or powered for cross-country comparison. Nonetheless, efforts were made to ensure geographical spread and representation from all specialties. Physicians were recruited using a non-probability convenience sampling approach, whereby participants were identified through accessible professional networks and invited to participate voluntarily. An independent research agency managed all outreach. The survey link was sent to potential respondents by email, with respondents completing the survey independently. As the sample size of 10 physicians per country was relatively small, follow-up interviews were conducted to verify survey results and further understand country-wide practices. Three physicians per country were invited for follow-up interviews on the basis of their availability and willingness to participate, with representatives from all specialties interviewed.

As this was a non-interventional physician survey that did not collect patient-level data or identifiable patient information, formal ethics committee or institutional review board approval was not required. All responses to the survey were voluntary and anonymous, with all participants providing informed consent prior to participation. Respondents who completed the survey and/or interview were compensated financially in accordance with fair market value for the respective regions. This survey was funded by Eisai Co Ltd. The study sponsor reviewed the survey instrument before administration; however, recruitment, administration, data analysis, interpretation, and reporting were handled by an independent third-party research organization. All authors had joint responsibility for the decision to publish the results of this survey.

Analyses were conducted on a question-by-question basis, including all available responses for each item. Denominators vary where questions were not applicable to all respondents or were restricted to licensed prescribers. No imputation was performed. Survey responses were aggregated descriptively. As this survey was not designed to enable statistically robust cross-country comparison, inferential statistics (including 95% confidence intervals) were not estimated. Similarly, the survey design and sample size were not adequate for multivariable modelling. Qualitative comments from one-to-one interviews were thematically analysed to contextualize quantitative findings, with themes including the role of national screening programmes, diagnosis routes, treatment decision making, preferred treatment choices, and the role of the MDT. The results are reported in the following section.

RESULTS

Demographics

Seventy responses were received from 135 invited physicians, giving an overall response rate of 51.9%. Characteristics are described in Table 2. Most respondents were medical oncologists (44.3%; 31/70) or hepatologists (34.3%; 24/70), with relatively small proportions of surgeons (10.0%; 7/70) and interventional radiologists (11.4%; 8/70). The primary place of work among all respondents was national or regional cancer centres (48.6%; 34/70) or large to mid-sized regional hospitals (28.6%; 20/70), with only 17.1% (12/70) of respondents working in private clinics/practices, most of whom came from the Philippines or Singapore. Respondents had 18.0 years of experience of treating HCC on average, and 54 of 70 responders (77.1%) reported that they were licensed to prescribe systemic therapies for the treatment of HCC in their country.

Table 2 Participant characteristics (n = 70), n (%).

	Overall (n = 70)	Korea (n = 10)	Malaysia (n = 10)	Philippines (n = 10)	Singapore (n = 10)	Taiwan (n = 10)	Thailand (n = 10)	Vietnam (n = 10)
Specialty
Medical oncologist	31 (44.3)	3 (30.0)	6 (60.0)	5 (50.0)	4 (40.0)	2 (20.0)	6 (60.0)	5 (50.0)
Gastroenterologist/hepatologist	24 (34.3)	6 (60.0)	-	3 (30.0)	4 (40.0)	7 (70.0)	2 (20.0)	2 (20.0)
Surgeon	7 (10.0)	-	2 (20.0)	1 (10.0)	2 (20.0)	1 (10.0)	-	1 (10.0)
Interventional radiologist	8 (11.4)	1 (10.0)	2 (20.0)	1 (10.0)	-	-	2 (20.0)	2 (20.0)
Healthcare setting
Public only	21 (30.0)	5 (50.0)	4 (40.0)	-	3 (30.0)	4 (40.0)	1 (10.0)	4 (40.0)
Private only	18 (25.7)	3 (30.0)	3 (30.0)	4 (40.0)	7 (70.0)	1 (10.0)	-	-
Both public and private	31 (44.3)	2 (20.0)	3 (30.0)	6 (60.0)	-	5 (50.0)	9 (90.0)	6 (60.0)
Primary institution
National or regional cancer centre	34 (48.6)	7 (70.0)	3 (30.0)	1 (10.0)	2 (20.0)	8 (80.0)	8 (80.0)	5 (50.0)
Large or mid-sized regional hospital	20 (28.6)	3 (30.0)	4 (40.0)	3 (30.0)	3 (30.0)	1 (10.0)	1 (10.0)	5 (50.0)
Private clinic/practice	12 (17.1)	-	2 (20.0)	4 (40.0)	5 (50.0)	1 (10.0)	-	-
Other	4 (5.7)	-	1 (10.0)	2 (20.0)	-	-	1 (10.0)	-
Role at primary institution
Junior doctor/resident	1 (1.4)	-	-	-	-	-	-	1 (10.0)
Consultant	34 (48.6)	-	9 (90.0)	9 (90.0)	6 (60.0)	-	2 (20.0)	8 (80.0)
Assistant/associate professor	22 (31.4)	4 (40.0)	2 (20.0)	2 (20.0)	1 (10.0)	3 (30.0)	8 (80.0)	2 (20.0)
Professor	16 (22.9)	5 (50.0)	1 (10.0)	1 (10.0)	2 (20.0)	6 (60.0)	1 (10.0)	-
Leadership position	29 (41.4)	4 (40.0)	3 (30.0)	5 (50.0)	2 (20.0)	5 (50.0)	3 (30.0)	7 (70.0)
Other	3 (4.3)	-	-	-	1 (10.0)	2 (20.0)	-	-
Licensed to prescribe systemic therapies for HCC	54 (77.1)	9 (90.0)	7 (70.0)	9 (90.0)	5 (50.0)	10 (100.0)	8 (80.0)	6 (60.0)
Leadership position in a medical society	17 (24.3)	3 (30.0)	2 (20.0)	3 (30.0)	2 (20.0)	2 (20.0)	2 (20.0)	3 (30.0)
Mean length of experience, years (SD)	18.0 (10.1)	16.3 (7.1)	12.9 (4.1)	15.5 (3.9)	21.4 (8.7)	24.7 (19.7)	17.8 (5.3)	17.3 (6.5)
Mean patients with HCC assessed annually, n (SD)	294.5 (604.9)	769.0 (971.0)	69.2 (80.9)	63.2 (54.2)	39.8 (39.3)	223.7 (264.7)	152.5 (164.5)	744.0 (942.6)
Mean total patients managed who have HCC, % (SD)	27.6 (26.2)	46.5 (28.1)	20.5 (23.1)	19.0 (19.2)	19.4 (22.3)	23.5 (20.0)	23.0 (24.3)	42.0 (29.3)

HCC: Hepatocellular carcinoma; SD: Standard deviation.

Diagnosis and surveillance

Results regarding the surveillance and diagnosis of HCC are detailed in Table 3. All respondents from Korea (100.0%; 10/10) identified formalized, reimbursable national screening programmes for individuals at risk of HCC, while 90.0% (9/10) of respondents from Taiwan and 70.0% (7/10) of respondents from Thailand did the same, suggesting the presence of such programmes. With the exception of the Philippines, interviewees reported that reimbursable or low-cost screening was provided to individuals at risk of HCC who met certain criteria, although formalized screening programmes were lacking. In the Philippines, no respondents noted the presence of a screening programme, and interviewees confirmed that such a programme was lacking.

Table 3 Reported availability of national screening programmes and nature of diagnosis among survey responders (n = 70), n (%).

	Overall (n = 70)	Korea (n = 10)	Malaysia (n = 10)	Philippines (n = 10)	Singapore (n = 10)	Taiwan (n = 10)	Thailand (n = 10)	Vietnam (n = 10)
Respondents identifying availability of a national screening programme	N/A1	10 (100.0)	2 (20.0)	-	3 (30.0)	9 (90.0)	7 (70.0)	3 (30.0)
Usual location of HCC diagnosis
Large national hospital	40 (57.1)	5 (50.0)	6 (60.0)	3 (30.0)	8 (80.0)	7 (70.0)	5 (50.0)	6 (60.0)
Mid-sized hospital	21 (30.0)	2 (20.0)	4 (40.0)	3 (30.0)	2 (20.0)	3 (30.0)	5 (50.0)	2 (20.0)
Rural hospital	1 (1.4)	-	-	-	-	-	-	1 (10.0)
Private practice	4 (5.7)	1 (10.0)	-	3 (30.0)	-	-	-	-
Other	4 (5.7)	2 (20.0)	-	1 (10.0)	-	-	-	1 (10.0)
HCP usually diagnosing
GP/PCP	1 (1.4)	-	-	-	-	-	-	1 (10.0)
Medical oncologist	3 (4.3)	-	-	-	-	1 (10.0)	-	2 (20.0)
Gastroenterologist/hepatologist	54 (77.1)	10 (100.0)	6 (60.0)	8 (80.0)	10 (100.0)	9 (90.0)	8 (80.0)	3 (30.0)
Radiologist	8 (11.4)	-	2 (20.0)	2 (20.0)	-	-	2 (20.0)	2 (20.0)
Surgeon	3 (4.3)	-	2 (20.0)	-	-	-	-	1 (10.0)
Other	1 (1.4)	-	-	-	-	-	-	1 (10.0)
Mean estimated proportion of patients diagnosed by stage, %
Early stage (BCLC-0 or -A)	19.8	32.9	10.7	11.8	27.5	28.0	11.5	16.5
Intermediate stage (BCLC-B)	31.7	33.5	28.3	25.2	33.5	27.2	34.7	39.5
Advanced stage (BCLC-C)	32.8	26.6	36.0	39.0	26.0	32.3	40.3	29.5
End stage (BCLC-D)	15.6	7.0	25.0	24.0	13.0	12.5	13.5	14.5

¹Not applicable as data relate to availability of national screening programmes and are therefore country specific.

N/A: Not applicable; HCC: Hepatocellular carcinoma; HCP: Healthcare professional; GP: General practitioner; PCP: Primary care physician; BCLC: Barcelona Clinic Liver Cancer.

Despite the high availability of screening programmes, respondents estimated that almost half of HCC cases were diagnosed at end or advanced stage (mean estimated proportions diagnosed at end and advanced stage: 15.6% and 32.8%, respectively), with a further 31.7% on average estimated to be diagnosed at intermediate stage. Early diagnosis was more common in some countries than others, with Korea and Taiwan estimating the highest proportions of patients being diagnosed with early- or intermediate-stage HCC combined (mean estimated proportions diagnosed at early and intermediate stage: 66.4% and 55.2%, respectively). Conversely, the Philippines and Malaysia estimated the highest proportion of patients being diagnosed with advanced- or end-stage HCC (mean estimated proportions diagnosed at advanced and end stage: 63.0% and 61.0%, respectively).

Improvements in national screening programmes were seen as key to improving diagnosis rates, with 72.9% (51/70) of respondents noting this as one of the most important factors for increasing the rate of early diagnosis (Table 4). Other important factors included improved education/awareness of patients (82.9%; 58/70) and of general practitioners/primary care physicians (PCPs; 52.9%; 37/70).

Table 4 Most important factors for improving the rate of early diagnosis of hepatocellular carcinoma among survey responders (n = 70), n (%).

Factors for improving the rate of early diagnosis	Responders (n = 70)
Patient education/awareness	58 (82.9)
Availability of a national screening programme	51 (72.9)
GP/PCP education	37 (52.9)
Reimbursement of diagnostic methods	31 (44.3)
Availability of specific imaging technologies	16 (22.9)
Specialist training	12 (17.1)
Improvement in turnaround time of laboratory or imaging results	4 (5.7)

GP: General practitioner; PCP: Primary care physician.

Treatment decision making

When asked to consider the treatment decision makers for patients with iHCC, 44.3% (31/70) of respondents identified gastroenterologists/hepatologists as the primary decision maker (Table 5). Interviewees reported that gastroenterologists/hepatologists are often the first point of contact for investigations and therefore act as gatekeepers to other professionals, making relevant referrals based on patient need. While gastroenterologists/hepatologists were the most common primary treatment decision maker overall, there were some variations between countries, with surgeons being the most common primary treatment decision maker in Malaysia and Singapore and interventional radiologists in Thailand and Vietnam. These differences likely reflect the diverse approaches in iHCC management among countries and may also be a consequence of the sample of doctors taking part in the survey. Interviewees also reported that the exact stage of diagnosis, proposed treatment modality, and availability (or lack) of systemic therapies could affect the primary treatment decision maker in iHCC.

Table 5 Primary treatment decision makers in intermediate-stage hepatocellular carcinoma as identified by survey respondents and respondent guideline usage (n = 70), n (%).

	Responders (n = 70)
Primary treatment decision makers in iHCC
Surgeon	15 (21.4)
Gastroenterologist/hepatologist	31 (44.3)
Interventional radiologist	17 (24.3)
Medical oncologist	7 (10.0)
Guidelines used
EASL	45 (64.3)
AASLD	38 (54.3)
ESMO	36 (51.4)
NCCN	33 (47.1)
APPLE	22 (31.4)
ASCO	21 (30.0)
Local guidelines	31 (44.3)
Other	11 (15.7)

iHCC: Intermediate-stage hepatocellular carcinoma; EASL: European Association for the Study of the Liver; AASLD: American Association for the Study of Liver Disease; ESMO: European Society for Medical Oncology; NCCN: National Comprehensive Cancer Network; APPLE: Asia Pacific Primary Liver Cancer Expert; ASCO: American Society of Clinical Oncology.

Overall, the most commonly followed guidelines were the European Association for the Study of the Liver (EASL) clinical practice guidelines [followed by 64.3% (45/70) of participants; Table 5]; however, as this question allowed multiple answers, it was found that high proportions of respondents followed multiple guidelines. As above, guideline use varied slightly by country. Local guidelines played an important role in treatment decision making and were followed by 44.3% (31/70) of participants. Interviewees reported that treatment recommendations within local guidelines generally followed internationally recognized guidelines and clarified that the main role of local guidelines was to provide additional details that may be useful to treatment decision makers, such as administration or aftercare instructions and reimbursement information.

Access to MDTs

MDT access across the region was thought to be high, with 94.3% (66/70) of respondents overall reporting access to an MDT for the management of iHCC within their institution; however, it should be noted that respondents were mostly from national or regional cancer centres or large or mid-sized regional hospitals, potentially influencing the results. Interviewees reported that access to MDTs for the management of iHCC may not be as common in lower-tier or rural hospitals. Professionals commonly represented in the MDT included medical oncologists, interventional radiologists, gastroenterologists/hepatologists, and surgeons, all of whose presence was reported by approximately 90% of respondents. Conversely, less than 30% of respondents reported that nurses, project coordinators, or patient liaisons/educators were represented in their MDT, and no respondents reported pharmacists as being part of their MDT (Table 6). The majority of MDTs met weekly (39.7%; 27/68); however, significant proportions reported meeting monthly (22.1%; 15/68) or every other week (20.6%; 14/68).

Table 6 Multidisciplinary team availability and composition among survey responders (n = 70).

	Responders
Access, n (%)
Within hospital	66 (94.3)
Within country (e.g., in collaboration with another institution)	43 (61.4)
MDTs incorporating given specialty, n/N (%)
Medical oncologist	59/68 (86.8)
Interventional radiologist	65/68 (95.6)
Gastroenterologist/hepatologist	64/68 (94.1)
Surgeon	66/68 (97.1)
Nurse	19/68 (27.9)
Project coordinator/administrator	19/68 (27.9)
Patient liaison/educator	9/68 (13.2)
Other	12/68 (17.6)

MDT: Multidisciplinary team.

Most survey respondents reported being very satisfied (25.0%; 17/68) or satisfied (44.1%; 30/68) with the MDT arrangements at their institution; however, barriers to MDT implementation persist, including lack of time (72.9%; 51/70) and budget (42.9%; 30/70; Figure 1). Overall, despite high levels of access to MDTs in the region, results point to uneven capacity for MDT planning across the region.

Figure 1 Barriers to multidisciplinary team access in Asia Pacific, as identified by survey responders (n = 70). Values are shown as % (n) of respondents selecting each barrier. Percentages were calculated using all survey respondents as the denominator (n = 70). Respondents could select more than one barrier. MDT: Multidisciplinary team.

Treatment landscape

As treatment strategies in iHCC differ by the exact stage of diagnosis and the availability and reimbursement status of locoregional and systemic therapies, we asked respondents to identify the preferred first- and second-line treatments in patients with different BCLC-B substages of iHCC, as defined by Bolondi et al[16], as well as BCLC-C HCC (Table 7). Considering BCLC-B1 iHCC, 38.6% (27/70) of respondents reported that C-TACE was the preferred first-line treatment, with a further 28.6% (20/70) identifying resection. Interviewees cited the possibility of cure as the primary motivating factor in treatment choice for this substage. For BCLC-B2 iHCC, C-TACE (38.6%; 27/70) and the combination of systemic therapy with LRT (22.9%; 16/70) were the preferred first-line treatments. The proportion of respondents choosing resection at this substage was much lower, with only 4.3% (3/70) considering it as a preferred first-line therapy. In BCLC-B3 iHCC, systemic therapy alone or in combination with LRT was the most common first-line treatment choice, preferred by 55.7% (39/70) and 24.3% (17/70), respectively. This was also the case in BCLC-C HCC, with 72.9% (51/70) preferring systemic therapy alone and 18.6% (13/70) preferring systemic therapy in combination with LRT. Considering the transition from use of LRT to systemic therapy over the course of BCLC-B and BCLC-C HCC progression, respondents were asked to define ‘TACE unsuitability’. Most respondents identified previous TACE refractoriness/failure (71.4%; 50/70), presence of massive tumours (67.1%; 47/70), and presence of ‘up-to-seven’ criteria out nodules (57.1%; 40/70) as the most important defining factors. Country-level preferred treatment choices by BCLC stage are presented descriptively in Supplementary Table 1. These data suggest variation in reported treatment preferences across countries; however, because there were only 10 respondents per country, country-level findings were not formally compared and should be interpreted with caution.

Table 7 Preferred first-line treatment choices by Barcelona Clinic Liver Cancer substage among survey responders (n = 70), n (%).

Preferred first-line treatment choice	BCLC-B1	BCLC-B2	BCLC-B3	BCLC-C
C-TACE	27 (38.6)	27 (38.6)	4 (5.7)	1 (1.4)
DEB-TACE	5 (7.1)	9 (12.9)	5 (7.1)	-
TARE	9 (12.9)	10 (14.3)	4 (5.7)	3 (4.3)
Ablation	2 (2.9)	-	-	-
Resection	20 (28.6)	3 (4.3)	-	-
Systemic therapy alone	1 (1.4)	4 (5.7)	39 (55.7)	51 (72.9)
Systemic therapy in combination/sequence with LRT	5 (7.1)	16 (22.9)	17 (24.3)	13 (18.6)

BCLC: Barcelona Clinic Liver Cancer; C-TACE: Conventional transarterial chemoembolization; DEB-TACE: Drug-eluting beads transarterial chemoembolization; TARE: Transarterial radioembolization; LRT: Locoregional therapy.

When asked about factors influencing treatment choice across BCLC-B and BCLC-C HCC, interviewees reported that, besides physical considerations such as the size, location, and number of target lesions, the choice of therapy was also highly dependent on both availability and reimbursement status, which vary by country. For example, the reported use of transarterial radioembolization was most common in Korea compared with other countries, reflecting the availability and reimbursement status of the treatment (50% reimbursed for all liver malignancies) in Korea[17].

Systemic therapy integration

Most prescribers in Asia Pacific (98.1%; 53/54) had experience of using a systemic therapy in combination or sequence with LRT. Systemic therapies were most commonly combined or sequenced with C-TACE (Table 8), with the timing of C-TACE in relation to systemic therapy reported by interviewees as being dependent on the prescriber’s own preference, as well as on clinical evidence. Lenvatinib and sorafenib were most commonly given peri-TACE, with interviewees reporting that this sequence is often used with a view to inducing tumour shrinkage before LRT to lower the risk of relapse and/or reduce the number of TACE cycles needed. On the other hand, atezolizumab + bevacizumab and durvalumab + bevacizumab were primarily given post-TACE, in accordance with the TALENTACE and EMERALD-1 protocols.

Table 8 Experience of using systemic therapies in combination/sequence with locoregional therapy for the treatment of intermediate-stage hepatocellular carcinoma among all Asia Pacific prescribers (n = 54).

	Lenvatinib	Sorafenib	Pembrolizumab + lenvatinib	Atezolizumab + bevacizumab	Durvalumab + bevacizumab	Durvalumab + tremelimumab	Other	None of the above
Respondents with experience of using systemic therapy in combination/sequence with LRT, n (%)	51 (94.4)	24 (44.4)	14 (25.9)	37 (68.5)	11 (20.4)	19 (35.2)	3 (5.6)	1 (1.9)
LRTs used in combination with systemic therapy, n/N (%)
C-TACE	43/47 (91.5)	17/18 (94.4)	11/12 (91.7)	28/32 (87.5)	9/10 (90.0)	14/18 (77.8)	-	-
DEB-TACE	20/47 (42.6)	6/18 (33.3)	6/12 (50.0)	15/32 (46.9)	2/10 (20.0)	10/18 (55.6)	-	-
TARE	7/47 (14.9)	3/18 (16.7)	1/12 (8.3)	11/32 (34.4)	-	1/18 (5.6)	-	-
Other radiotherapy	8/47 (17.0)	2/18 (11.1)	1/12 (8.3)	6/32 (18.8)	-	1/18 (5.6)	-	-
Ablation	10/47 (21.3)	2/18 (11.1)	1/12 (8.3)	11/32 (34.4)	1/10 (10.0)	2/18 (11.1)	-	-
Timing of systemic therapy use in relation to TACE, n/N (%)
Pre-TACE	14/44 (31.8)	3/17 (17.6)	4/12 (33.3)	7/31 (22.6)	-	4/16 (25.0)	-	-
Peri-TACE	16/44 (36.4)	7/17 (41.2)	3/12 (25.0)	5/31 (16.1)	4/10 (40.0)	5/16 (31.3)	-	-
Post-TACE	12/44 (27.3)	6/17 (35.3)	4/12 (33.3)	18/31 (58.1)	6/10 (60.0)	6/16 (37.5)	-	-
Other	2/44 (4.5)	1/17 (5.9)	1/12 (8.3)	1/31 (3.2)	-	1/16 (6.3)	-	-

LRT: Locoregional therapy; C-TACE: Conventional transarterial chemoembolization; DEB-TACE: Drug-eluting beads transarterial chemoembolization; TARE: Transarterial radioembolization; TACE: Transarterial chemoembolization.

When asked to consider the most suitable candidates for first-line systemic therapy + LRT combinations, 83.3% (45/54) and 77.8% (42/54) of prescribers identified patients with BCLC-B2 and BCLC-B3 iHCC as the most suitable candidates, respectively. According to interviewees, these patients would most benefit from tumour reduction before LRT begins. Conversely, patients with BCLC-B1 iHCC or advanced HCC (BCLC-C) were identified by only 22.2% (12/54) and 50.0% (27/54) of respondents as good candidates for combination therapy, respectively. Patients with BCLC-B1 iHCC were not seen as good candidates for systemic therapy and LRT combinations as they should receive treatment with curative intent, while patients with BCLC-C HCC were unlikely to benefit from LRT because of the invasive nature of the disease.

When asked to identify a preferred systemic therapy for combination with LRT in patients with BCLC-B2 or BCLC-B3 iHCC, respondents noted a considerable variety of treatments (Figure 2). Lenvatinib with/without pembrolizumab and atezolizumab + bevacizumab were the most common choices. In the first-line treatment of BCLC-B2 iHCC, the most favoured systemic therapy to combine with TACE was lenvatinib alone (33.3%; 15/45), with 20.0% (9/45) each preferring lenvatinib + pembrolizumab and atezolizumab + bevacizumab. In the first-line treatment of BCLC-B3 iHCC, atezolizumab + bevacizumab was the most favoured systemic therapy to combine with TACE (35.7%; 15/42). Lenvatinib alone (28.6%; 12/42) and lenvatinib + pembrolizumab (14.3%; 6/42) were the next most preferred treatments.

Figure 2 Preferred choice of systemic therapy for combination with locoregional therapy for the treatment of intermediate-stage hepatocellular carcinoma according to Barcelona Clinic Liver Cancer stage, as identified by Asia Pacific prescribers. Values within pie charts are shown as % (n). Denominators for each pie chart are shown beside each panel: Barcelona Clinic Liver Cancer (BCLC)-B2 first line, n = 45; BCLC-B3 first line, n = 42; BCLC-B2 second line, n = 36; and BCLC-B3 second line, n = 36. BCLC: Barcelona Clinic Liver Cancer; Pem: Pembrolizumab; Atezo: Atezolizumab; bev: Bevacizumab; Durval: Durvalumab; treme: Tremelimumab.

Efficacy data was consistently the most important factor in determining which systemic therapy to combine with LRT, noted by 75.6% (34/45) and 81.0% (34/42) of respondents, respectively, when queried about patients with BCLC-B2 and BCLC-B3 iHCC. Despite this, interviewees did not generally perceive one systemic therapy as having stronger evidence than another in combination with TACE, citing lack of head-to-head evidence and the ongoing nature of clinical studies as key evidence gaps. Cost and the reimbursement status of the approved treatments were also seen by 90.7% (49/54) and 74.1% (40/54) of prescribers, respectively, as the main barriers to the adoption of TACE + systemic therapy combinations in the region.

DISCUSSION

Our study is the first to investigate current practices surrounding the integration of locoregional and systemic therapies in the treatment of iHCC in Asia. With recent updates to the ESMO guidelines and upcoming updates to the ESMO pan-Asian guidelines recommending the integration of locoregional and systemic therapies in the treatment of iHCC[12,13], this study provides important insights into practices in the region.

Despite limited regulatory approval for the use of tyrosine kinase inhibitors or immuno-oncology-based therapies in combination with LRT, we found that physicians in Asia were relatively well acquainted with the use of such treatments for iHCC, with 98.1% (53/54) of physicians in Asia having experience of combination strategies. While 94.4% (51/54) of respondents had used lenvatinib in combination/sequence with LRT, reflecting its long-standing application in patients with HCC, experience with immuno-oncology was lower in this setting: 68.5% (37/54) had used atezolizumab + bevacizumab, around one-quarter pembrolizumab + lenvatinib, and one in five durvalumab + bevacizumab. High levels of familiarity with newer combinations indicate that the use of systemic therapy in combination with LRT is an area of interest for practitioners in Asia, and such treatment approaches are gaining well-deserved traction.

While our survey revealed that awareness and initial experience of integrating locoregional and systemic therapies in iHCC was high, it also found that most physicians in Asia still preferred to use LRT or systemic therapy alone in the treatment of iHCC, with C-TACE being the most preferred treatment in BCLC-B1 and BCLC-B2 iHCC and systemic therapy alone in BCLC-B3 iHCC; however, further real-world evidence on this topic is lacking. These results suggest that BCLC-B substage plays an important role in determining eligibility for systemic therapy and LRT combinations, as does TACE unsuitability, defined by respondents to our survey as TACE refractoriness, presence of massive tumours, and presence of ‘up-to-seven’ criteria out disease. While guidelines provide valuable recommendations on the treatment of BCLC-B and BCLC-C HCC, treatment recommendations for BCLC-B substages are usually not well defined and lack detail regarding the identification of optimal candidates for locoregional and systemic therapy combinations, as well as the preferred sequence and duration of such combination therapies. Although treatment recommendations fall beyond the scope of this survey, there is an evident need for regional expert consensus to address these clinical questions.

A secondary barrier to the integration of locoregional and systemic therapies in the treatment of iHCC exists in the form of system-level readiness, which we found varied widely in the countries surveyed. Late diagnosis remains a key challenge, with our survey determining that one in two patients is estimated to be diagnosed with advanced or end-stage HCC. Shifting diagnosis from advanced to intermediate stage is generally associated with improved patient outcomes and would increase eligibility rates for innovative systemic therapy and LRT combinations. In particular, our survey respondents identified patients with BCLC-B2 and BCLC-B3 iHCC as the most likely candidates for systemic therapy and LRT combinations. As one in two patients with HCC is estimated to be diagnosed at a more advanced stage (BCLC-C), this highlights the importance of earlier diagnosis for improving patient outcomes and increasing opportunities for the use of systemic therapy and LRT combinations in the region.

In our survey, education/awareness of patients and of PCPs were identified by 82.9% (58/70) and 52.9% (37/70) of respondents, respectively, as key factors for improving the rate of early diagnosis with education, thereby representing a key area for improvement. These results are supported by a similar survey in Asia Pacific that found gaps in PCP and patient awareness[14]. In addition, 72.9% (51/70) highlighted the availability of a national screening programme as an important factor. Taken together, these results may suggest a need for stronger referral networks, as also pointed out in one-to-one interviews.

While our survey found that 94.3% (66/70) of respondents reported having access to an MDT within their institution, interviewees doubted that this was the case in lower-tier or rural hospitals, highlighting an unmet need in the region. Among those who reported using an MDT, further barriers to their implementation existed: MDTs typically comprised medical oncologists, interventional radiologists, gastroenterologists/hepatologists, and surgeons, but they lacked nurses, project coordinators/administrators, and patient liaisons/educators. These essential support functions provide vital assistance to patients with HCC; indeed, their presence in MDTs has been associated with improved quality of life post-surgery for patients with HCC[18]. While many studies suggest that MDTs in other regions meet weekly[19,20], our survey found that only 39.7% (27/68) of MDTs in the region met weekly. Significant proportions met with less frequency (monthly or every other week), which may not be adequate to ensure agile treatment decision making or enable efficient patient management. In summary, while patients with HCC derive significant benefit from MDT care, our survey found equitable access to MDT care in Asia to be lacking, especially in certain contexts.

The integration of systemic therapies with LRT requires a high degree of MDT coordination owing to the multiple treatment modalities employed (Figure 3). Both the management of systemic therapies in HCC and the administration of LRTs require specialist knowledge, and their combination necessitates interdisciplinary discussion to tailor targeted therapy choice and timing in relation to TACE on a case-by-case basis. International guidelines strongly recommend the use of MDTs for all patients with HCC[12,21-23], and the use of MDTs in the management of HCC has been associated with better patient outcomes in multiple studies[24,25]. As such, heterogeneous access to MDTs in the Asia Pacific region could represent a key barrier to uptake of systemic and LRT combinations, thus impacting patient outcomes. We recommend that regional education initiatives highlighting the benefits of MDT care in HCC are warranted. The development of clearer guidance on MDT meeting frequency and make-up and patient prioritization in resource-constrained settings may also facilitate more standardized care delivery.

Figure 3 Increasing role of multidisciplinary team management in the intermediate-stage hepatocellular carcinoma patient journey. BCLC: Barcelona Clinic Liver Cancer; MDT: Multidisciplinary team; TACE: Transarterial chemoembolization; LRT: Locoregional therapy; TARE: Transarterial radioembolization.

Despite varying guideline recommendations, results from our survey suggest that physicians in Asia are well acquainted with the use of systemic therapy + LRT combinations for the treatment of iHCC, with 98.1% (53/54) of prescribers reporting experience of using such combinations. However, we found a high degree of heterogeneity in the systemic therapies used and the timing of systemic therapy in relation to LRT. While the ESMO guidelines were recently updated to include recommendations for the adoption of systemic therapy in combination with LRT[11], other guidelines are awaiting changes. The most commonly followed guidelines in our survey, those of the EASL, state that further evidence is needed to support the integration of systemic therapies with intra-arterial therapies[21]. Similarly, the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) state that systemic therapies can be used after arterially directed therapies in patients with adequate liver function and evidence of residual tumours, but they lack details on treatment pathways and systemic therapy choices[22], leading to ambiguity. The 2024 clinical practice guidelines by the Asian Pacific Association for the Study of the Liver on systemic therapy for HCC recommend that embolization-eligible patients with unresectable HCC should be considered for treatment with DEB-TACE or C-TACE + durvalumab, followed by durvalumab + bevacizumab; recommendations on other systemic therapy and LRT combinations are not addressed in these guidelines[26]. Overall, it should be considered that clear and concise guideline recommendations on these topics would be beneficial to ensure the optimal use of systemic therapy + LRT combinations.

When asked to identify barriers to adopting systemic therapy with LRT in iHCC, respondents to our survey primarily noted the cost and reimbursement status of the therapies used, which are known to vary significantly across the countries surveyed. International guideline recommendations are important in unlocking access to locoregional and systemic therapy combinations with iHCC, as they play a key role in influencing decision-making processes for payers[27]. Overall, greater evidence generation on the topic of systemic therapy and LRT integration in HCC is needed to aid guideline development and reimbursement decision making.

Further to this, up-to-date regional guidelines are needed to support the reimbursement and uptake of locoregional and systemic therapy combinations in patients with iHCC. Understandably, local guidelines, while playing an important practical role in treatment decision making, often lag behind international guideline updates. Recently, during the ESMO Asia 2025 congress, forthcoming updates to the ESMO pan-Asian guidelines were discussed. These include a recommendation for systemic therapies, including lenvatinib and atezolizumab + bevacizumab in combination with LRT for the treatment of iHCC. The recommendation of lenvatinib + LRT, rather than pembrolizumab + lenvatinib + LRT, as cited in the core ESMO guidelines, reflects the unique situation in the region, where the high costs of immuno-oncology agents are unaffordable for many[13].

This study has several limitations, including the self-reported and descriptive nature of the data. The sample size was relatively small and was not designed to generate nationally representative data, and the survey was not powered for cross-country or multivariate analysis. While efforts were made to ensure the wide geographical and specialty distribution of respondents, high proportions of respondents came from national or regional cancer centres (48.6%) or large to mid-sized hospitals (28.6%), meaning that results may not be generalizable nationwide, particularly in lower-tier or rural hospitals. In addition, the survey was not validated externally before use and a convenience sampling approach was adopted, which further reduces the generalizability of our findings. In summary, further robust research in larger, more diverse populations are warranted to confirm our findings, assess their geographical generalizability, and identify predictors for combination therapy use. Targeted surveys of PCPs (regarding diagnosis) and rural hospitals may be of particular interest, given the high proportion of respondents from tertiary institutes in our survey.

Finally, as with any industry-sponsored study, the findings should be interpreted in the light of potential sponsorship bias. The sponsor reviewed the survey instrument before administration, although recruitment, survey administration, data analysis, interpretation, and reporting were handled by an independent third-party research organization. Sponsor involvement may have influenced the framing or emphasis of some questions. Therefore, findings on preferred systemic therapies and readiness to adopt systemic therapy and LRT combinations should be interpreted with appropriate caution.

CONCLUSION

This multinational survey presents a comprehensive snapshot of real-world iHCC management across Asia and provides evidence of a growing role for locoregional and systemic therapy combinations in the management of iHCC in the region. Despite increasing awareness of combination strategies, structural and economic barriers indicate that improvements are needed across the region to fully implement the evolving treatment paradigm. Shifting diagnosis from advanced to intermediate stage, improved MDT care, and the development of relevant regional guidelines would support access to locoregional and systemic therapy combinations, thereby improving outcomes for patients with iHCC.