Clinical practice guidelines and real-life practice in hepatocellular carcinoma: A Taiwan perspective

Clinical guidelines

TLCA guidelines specify that patients with chronic hepatitis B or C and cirrhosis are at high risk of HCC and should enroll in a surveillance program for HCC that provides opportunities for curative treatment and improves overall survival [12]. Surveillance should be performed using abdominal ultrasonography and alpha-fetoprotein tests (both are covered by the NHI program) at 6-month intervals (with a range of 3–12 months) [2]. Dynamic computed tomography (CT), magnetic resonance imaging (MRI), or gadolinium ethoxybenzyl-diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)-enhanced MRI (EOB-MRI) may be recommended every 6 to 12 months for extremely high-risk patients and for patients with difficulty in ultrasound imaging of the liver because of liver atrophy, severe obesity, or postoperative deformity [11]. Kupffer-phase contrast-enhanced ultrasound (CEUS) may also be recommended as a first-line screening tool for HCC in patients with renal dysfunction and liver cirrhosis (Table 1) [11,13,14].

Table 1.

Comparison of HCC surveillance programs between international and Taiwan guidelines and real-world practice

Real-world practice

A major discrepancy exists between the execution of the guidelines and real-world practice due to poor patient adherence to surveillance recommendations. According to the NHI claim database, among 685,000 patients with a primary diagnosis of hepatitis or cirrhosis in 2008, only 13% received ultrasound and alanine aminotransferase examinations every 6months. To facilitate regular surveillance of HCC, the National Health Insurance Administration of Taiwan introduced a medical care improvement plan in 2000 for patients with chronic hepatitis B or C. This patient-centered program is intended to motivate physicians to perform regular ultrasonography for HCC surveillance every 6 months as recommended by the current guidelines and to encourage HCC identification in the early stage through additional reimbursement to institutions. Examination of protein induced by vitamin K absence or antagonist-II (PIVKA-II) every 6 months has been reimbursed by NHI since 2020 for patients with cirrhosis and those receiving curative therapy for HCC. However, EOB-MRI and CEUS are not reimbursed by NHI.

Radiological diagnosis

In Taiwan, HCC can be diagnosed noninvasively through dynamic contrast-enhanced CT or MRI if a ≥1.0 cm lesion is identified through ultrasound during surveillance [11]. Furthermore, guidelines in Asian countries, including those of the Japan Society of Hepatology and the Asian Pacific Association for the Study of the Liver (APASL), recommend EOB-MRI as the first-line diagnostic tool because it is more sensitive than dynamic CT for diagnosing HCC [15,16]. Additionally, EOBMRI performed after dynamic CT in patients with early-stage HCC can detect additional small nodules, increase the accuracy of cancer staging, and improve outcomes after curative treatment [17,18]. However, the cost of EOB-MRI is not covered by the NHI program in Taiwan even though it is categorized as both a first- and second-line imaging diagnostic tool [10].

The guidelines of the American Association for the Study of Liver Disease (AASLD) standardize the terminology for interpreting imaging features indicating the presence of HCC; the American College of Radiology released the Liver Imaging Reporting and Data System (LI-RADS) in 2011 [19]. LI-RADS describes the following categorization: LI-RADS 1 (LR-1, definitely benign), LI-RADS 2 (LR-2, probably benign), LI-RADS 3 (LR-3, intermediate probability), LI-RADS 4 (LR-4, probably HCC), LI-RADS 5 (LR-5, definitely HCC), LI-RADS M (LR-M, malignant but not HCC specific), and LI-RADS TIV (LR-TIV, tumor in vein) based on the likelihood of HCC, non-HCC malignancy, and venous tumors. The Taiwan Society of Interventional Radiology has introduced the use of the LI-RADS in clinical practice for liver tumor diagnosis. However, no study has compared the diagnostic performance and clinical value of LI-RADS v2018.

Pathology diagnosis

Clinical practice guidelines

The Barcelona Clinic Liver Cancer (BCLC) staging system stratifies patients with HCC into very early, early, intermediate, and advanced stages, with 5-year survival rates of 40–70%, 14–45%, 6–14%, and 10%, respectively, and the terminal stage, for patients with tumors beyond the transplantation threshold [25]. Because of improvements in the HCC surveillance program, the proportion of patients with HCC diagnosed in the early stage has increased from 5–10% to 40–60%, leading to more patients eligible for curative treatments [26].

Accurate identification of the tumor (T) stage is crucial for extending disease-free survival after curative treatment because tumor size, tumor number, and microvascular invasion are significant predictors of survival [27,28]. These tumor characteristics can be examined through preoperative imaging such as liver dynamic CT and MRI [29]. The strengths of MRI include low operator dependence, no radiation exposure, and ability to analyze the whole liver parenchyma. Furthermore, EOB-MRI has detected more HCCs than dynamic CT in 16.4% of patients receiving concurrent EOB-MRI [17]. Studies have suggested that higher numbers of HCCs necessitate a change in BCLC staging system, TNM staging, and treatment strategy [18,30]. However, liver MRI usually do not visualize lung clearly, which may be the most common area of metastasis in HCC. Therefore, additional liver MRI is suggested in patients with very-early to early-stage HCC, and whole-body CT is recommended for patients with intermediate to advanced HCC.

Real-world practice

TLCA guidelines recognize the BCLC staging system as the most common in Taiwan in terms of prognostic prediction [2]. The BCLC staging system used in Taiwan has two modifications from the original system. One is that, since 2002, a single tumor of size >5 cm has been classified as BCLC stage B [31]; the other is that a patient with Eastern Cooperative Oncology Group (ECOG) performance status 1 can still be classified as stage 0, stage A, or stage B according to the tumor burden (Table 2). These differences must be noted when comparing the prognosis of patients with HCC of various BCLC stages in Taiwan and with those in other countries. Other staging systems, including the HKLC staging system [32], CLIP score [33], Tokyo score [34], Japan Integrated Staging score [35], and TNM system, also provide meaningful prognosis predictions. Another key goal of staging systems is to inform treatment selection. Although the BCLC staging system is the most used in Taiwan, the treatment guidance recommended by the BCLC staging system does not reflect true daily practice in Taiwan and other Asian countries. Such practice is characterized by availability of diverse locoregional therapy and endorsement of chemotherapy (systemic and hepatic arterial infusion chemotherapy [HAIC]).

Table 2.

Comparison between the current BCLC staging and the modified BCLC staging used in Taiwan

Surgery and liver transplantation

Surgical intervention plays a major role in HCC management. Taiwan’s 2019 cancer statistics indicate that, among 8,521 patients newly diagnosed with HCC, 2,289 (26.9%) underwent resection and 44 (0.5%) underwent liver transplantation [36]. Safe liver resection for HCC is performed in accordance with Makuuchi’s criteria including ascites, serum total bilirubin, and indocyanine green clearance tests; these tests are commonly employed to determine the limit of the liver to be resected [37]. Additionally, in patients without liver cirrhosis, no limitations (e.g., tumor size or number and involvement of portal vein invasion) preclude resection [2].

Liver reserve is a relative term denoting the interplay between underlying liver disease (cirrhosis, fatty liver, and hepatitis/fibrosis) and the resected functional parenchyma excluding the tumor mass. If the remnant liver reserve is sufficient, the surgical method for HCC resection should be selected based on surgeon capability and experience. Resection can be performed through an open approach or a minimally invasive approach (laparoscopic or robotic assistance); robotic assistance is gaining popularity, with comparable survival duration [38]. Surgeons can conduct anatomical or parenchymal-sparing (non-anatomical) liver resection. TLCA guidelines recommend a surgical strategy of adequate surgical margin (>1 cm) when possible [2]. However, a narrow surgical margin, even a null-margin, may achieve cure after resection [2].

Repeated resection or resection after other local or systemic therapy for HCC recurrence is common in Taiwan. Long-term survival can also be achieved [39]. Rapid progress of HCC therapeutics (systemic therapy and local treatments) and surgical innovation (Associating Liver Partition and Portal vein Ligation for Staged hepatectomy [ALPPLS]) may further contribute to the trend of treatment migration [40].

A shortage of transplantable organs from deceased individuals in Taiwan necessitates the development of living-donor liver transplantation. The Milan criteria and UCSF criteria for liver transplantation for eligible patients with HCC are practiced [2]. Salvage transplantation using liver resection as the primary treatment for patients, followed by transplantation in the event of HCC recurrence or liver failure does not increase the risk of recurrence or similar long-term outcomes compared with primary liver transplantation [2]. The overall transplantable pool of patients after resection has not decreased [41]. Downstaging and bridging treatment should be offered to all patients to avoid waitlist dropout. The estimated wait time for transplantation is more than 6 months [2]. Less strict criteria and incorporation of biological markers are being used in patient selection worldwide, and their long-term effects in Taiwan require investigation [42].

Radiofrequency ablation, transarterial chemoembolization, and radioembolization

Radiofrequency ablation (RFA) is a safe and effective curative therapy for patients with very early or early stage HCC who are unsuitable for surgery [2,25,43]. Furthermore, the percutaneous approach for RFA has the advantages of lower morbidity and a shorter length of hospital stay because of its minimal invasiveness [44]. Because of its safety, simplicity, and low cost, ultrasound is vital in guiding needle insertion and monitoring the ablation effect during RFA [45,46]. Moreover, in ultrasound-guided RFA, many strategies (e.g., artificial ascites or pleural effusion creation, real-time ultrasound-CT/MRI fusion imaging, and CEUS) can be used to decrease the incidence of complications and increase the rate of complete ablation [47,48]. However, because of the limitations in the ultrasound window and resolution, ultrasound-guided RFA in tumors with difficult locations and poor visibility is associated with a higher local recurrence rate [49].

In contrast, CT-guided RFA presents no limitation to the depth and field of view. However, one study have reported comparable efficacy and complications between ultrasound- and CT-guided RFA for HCC [50]. Additionally, the combination of transarterial chemoembolization (TACE) and RFA may lead to longer hospital stays and increased patient discomfort [51]. Wu et al. [52] reported that CT-guided RFA after intra-arterial iodized oil injection may achieve more prolonged recurrence-free survival than ultrasound guidance, and that CT-guided RFA is more suitable in this clinical context.

TACE has served as a first-line treatment for intermediate to advanced HCC for over a decade [43]. Other intra-arterial therapies, such as drug-eluting beads (DEBs), transarterial radioembolization, and HAIC, are available in Taiwan. These techniques provide interventional radiologists in Taiwan with more options for unresectable HCC treatment [53]. Although the NHI program does not reimburse DEB-TACE or transarterial radioembolization, a consensus exists in Taiwan on the DEB-TACE recommendation, and physicians have experience attending randomized controlled trials of transarterial radioembolization [54,55]. HAIC is also recommended for patients with portal vein thrombosis, but no consensus or large-scale randomized controlled trial exists. Practice guidelines recommend DEB-TACE, transarterial radioembolization, and HAIC for patients with multiple tumors or vascular invasion [11].

Clinical guidelines

TLCA guidelines recommends sorafenib and lenvatinib therapy for treatment-naive patients with Child–Pugh A liver function, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and HCC that is unresectable and not amenable to locoregional therapy [1] or is refractory to TACE [11]. Atezolizumab and bevacizumab combination therapy can be used for treating patients with unresectable HCC who have not received prior systemic therapy and do not have a high risk of upper gastrointestinal bleeding [11]. Sorafenib or nivolumab immunotherapy may be considered for selected patients with Child Pugh class B liver function whose tumors are unresectable and not amenable to locoregional therapy, but the evidence remains insufficient [11].

In cases of disease progression after sorafenib, additional treatment with regorafenib, cabozantinib, and ramucirumab (when Alpha-fetoprotein ≥400 ng/mL) extend the survival of patients with HCC and Child Pugh class A liver function, whose tumors are unresectable and not amenable to locoregional therapy [11]. Nivolumab with or without ipilimumab or pembrolizumab can be considered for patients who are intolerant to or have progressed when treated with approved tyrosine kinase inhibitors (Table 3) [11,14,56-58].

Table 3.

Comparison between international and Taiwan guidelines and real-world practice for systemic therapy

A paradigm shift in adopting systemic therapy in BCLC stage B HCC has occurred [59]. TLCA guidelines and clinical studies suggest that targeted therapy combined with TACE can be considered in highly selected patients with unresectable BCLC stage B HCC with Child Pugh class A and ECOG performance status 0-1 [11].

Real-world practice

Because of economic factors, real-world practice mainly depends on the reimbursement criteria of the NHI program. The NHI program has reimbursed sorafenib and lenvatinib as first-line therapy since 2012 and 2020, respectively. To receive sorafenib and lenvatinib treatment, HCC must exhibit extrahepatic spread, major vascular invasion (Vp 2-4), or be refractory to TACE, which is defined as failure to respond to more than 3 TACE sessions within 12 months. Lee et al. [60] investigated 22 and 44 BCLC stage C patients who received first-line lenvatinib and sorafenib, respectively. The objective response rate (ORR; 36.4% vs. 11.4%, P=0.023) and disease control rate (DCR) (81.9% vs. 56.9%, P=0.039) were higher in the lenvatinib group than in the sorafenib group, but patients had a similar overall survival of approximately 9 months [60].

No first-line immunotherapy is currently reimbursed by the NHI program in Taiwan. In clinical practice, patients receive treatment regimens such as atezolizumab with bevacizumab or lenvatinib with pembrolizumab based on shared decision-making between physician and patient. Shao et al. evaluated 40 participants from Taiwan in the IMbrave 150 and the GO30140 trials. The ORR was 37.5%, including 3 (7.5%) complete responses, and the median duration of response was 21.4 months (95% confidence interval, 16.6-not reached) [61], which was consistent with the findings for the global intentto-treat populations. Wu et al. [62] evaluated 71 patients who received lenvatinib plus pembrolizumab for unresectable HCC and reported an ORR of 34.1% in the first-line setting and of 18.5% for systemic therapy-experienced cases. Regorafenib and ramucirumab are reimbursed by the NHI program as second-line therapy in cases of failed first-line sorafenib administration. Nivolumab monotherapy had previously been reimbursed after failure of sorafenib; however, since April 2020, it is no longer reimbursed for new cases.