INTRODUCTION

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver and is the second leading cause of cancer-related deaths worldwide.^1,2 Among various staging systems for HCC, the Barcelona Clinic Liver Cancer (BCLC) system is the most widely recognized. The BCLC guidelines recommend several initial treatments, such as ablation, hepatic resection, liver transplantation (LT), trans-arterial chemoembolization (TACE), trans-arterial radioembolization (TARE), and systemic therapy, tailored to each stage of the disease. In 2022, the updated BCLC guidelines further subdivided BCLC-B (intermediate stage) patients into three groups and recommended subsequent LT after successful downstaging in a selected subgroup (Fig. 1).³ Downstaging of HCC is generally defined as a reduction in the size or number of viable tumors using locoregional therapy (LRT) to meet the established criteria for LT. Recent studies have reported that successful downstaging rates after LRT are nearly 50%, and post-LT recurrence rates are comparable to those of patients within the Milan criteria (MC) in highly selected patients.⁴

Recent developments in systemic treatments for HCC, particularly immuno-oncologic (IO) agents, have been promising,^5,6 offering additional opportunities for downstaging. Furthermore, many clinical trials have focused on a multidisciplinary approach (MDA), combining LRT and systemic therapy. Results from retrospective studies and phase I and II trials on the efficacy and safety of MDA for downstaging have been published. In this review, we will also discuss the future protocols of MDA for downstaging to achieve better clinical outcomes.

DOWNSTAGING - PRESENT

Which stage and subgroup is the best candidate for downstaging?

According to the updated BCLC guidelines, patients classified as BCLC-B (intermediate stage) are subdivided into three groups. The first subgroup includes patients who meet the extended LT criteria (beyond the MC) and for whom LT is recommended as an initial treatment.³ Among the various extended LT criteria, the University of California San Francisco (UCSF) criteria are relatively well-validated. The UCSF criteria define eligibility as either one tumor ≤6.5 cm or ≤3 tumors, with the largest tumor ≤4.5 cm and a total tumor diameter ≤8 cm. A recent multicentric study on the efficacy of living donor LT showed that overall survival (OS) rates were not significantly different between the MC and UCSF groups (1-, 5-, and 10-year survival rates, 90.9%, 78.5%, and 64.1% vs. 88.6%, 73.5%, and 69.4%, respectively; P=0.85).⁷ The second subgroup consists of patients with diffuse, infiltrative, extensive bi-lobar tumors, for whom systemic treatment is recommended. The third subgroup includes patients with well-defined nodules, preserved portal flow, and selective vascular access; for these patients, TACE is recommended. Importantly, LT is advised for third subgroup patients if they can be successfully downstaged. Therefore, according to the updated BCLC guidelines, the third subgroup is considered the best candidate for downstaging.

Which downstaging criteria is the most reliable?

The United Network Organ Sharing downstaging (UNOS-DS) protocol, developed based on the UCSF LT criteria (Table 1),⁸ extends beyond the UCSF criteria in terms of tumor size and number (up to 8 cm in a single tumor, up to 5 cm in 2-3 tumors, and up to 3 cm in 4-5 tumors). Successful downstaging is defined as follows: 1) achievement of tumor control within the MC after treatment, 2) durable tumor control within the MC for more than 6 months, and 3) alpha-fetoprotein (AFP) levels <500 ng/mL if pretreatment AFP >1,000 ng/mL.

Several studies demonstrate the clinical efficacy of LT under the UNOS-DS protocol. Mehta et al.⁹ analyzed 3,698 patients who underwent LT (3,276 within MC, 422 under UNOS-DS) and found no significant difference in 3-year post-LT survival rates between the MC and UNOS-DS groups (83.2% vs. 79.1%; P=0.17). They also noted that post-LT mortality risk was higher in regions with shorter wait times (less than 9 months from successful downstaging to LT) compared to longer wait regions (hazard ratio [HR], 3.1; P=0.005) and in patients with AFP levels ≥100 ng/mL at LT (HR, 2.4; P=0.009). Tabrizian et al.¹⁰ analyzed 2,463 patients who underwent LT (2,122 within MC, 341 under UNOS-DS) and reported that 10-year post-LT OS rates were 61.5% for MC and 52.1% for UNOS-DS, respectively (P<0.001), with 10-year post-LT recurrence rates of 13.1% for MC and 20.6% for UNOS-DS, respectively (P<0.001). Based on these findings, they concluded that the UNOS-DS protocol could aid in LT prioritization decisions as the 10-year post-LT outcomes were relatively favorable. They also identified factors associated with poor recurrence-free survival (RFS) in the downstaged group, such as a neutrophil-to-lymphocyte ratio (NLR) >5 at LT (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.34-3.09; P<0.001) and largest viable tumor on explant pathologic findings >5 cm (OR, 2.18; 95% CI, 1.34-3.56; P=0.002), regardless of pretreatment tumor size, number, or tumor marker. Clinical factors associated with downstaging failure included more than three tumors at diagnosis (OR, 2.34; 95% CI, 1.22-4.50; P=0.01), tumor size >7 cm at diagnosis (OR, 2.62; 95% CI, 1.20-5.75; P=0.02), and an AFP response of at least 20 ng/mL with less than 50% improvement (OR, 1.99; 95% CI, 1.14-3.46; P=0.02). Mehta et al.¹¹ further supported the importance of tumor markers in predicting downstaging failure, noting that a pretreatment AFP level >1,000 ng/mL was a better predictor of downstaging failure (HR, 3.3; P<0.001) compared to poor liver function (HR, 1.6; P<0.001). Therefore, more powerful treatment modalities are needed for this high-risk group to achieve successful downstaging, as the improvement in tumor biology, such as NLR and real pathologic viable tumor size at LT, are crucial for predicting RFS. Mazzaferro et al.¹² conducted a randomized, controlled phase 2b/3 trial analyzing 45 patients (23 who underwent LT, 22 who continued follow-up until progression after successful downstaging) with similar conditions under UNOS-DS. They reported that the 5-year OS rate was 77.5% in the LT group versus 31.2% in the control group (HR, 0.32; 95% CI, 0.11-0.92; P=0.035) and concluded that subsequent LT should definitely be considered if HCC patients beyond MC are successfully down-staged. Tan et al.¹³ conducted a meta-analysis of 25 studies (3,997 patients) on downstaging and reported that the success rate of downstaging and post-LT recurrence rate between two groups (UNOS-DS vs. beyond UNOS-DS) were 83.21% vs. 28.60% (P<0.001) and 9.06% vs. 20.42% (P<0.001), concluding that UNOS-DS criteria are the most reliable, showing the best downstaging success and postLT outcomes.

According to the updated BCLC guideline, TACE and TARE are recommended as treatment modalities for downstaging. Mehta et al.¹⁴ analyzed 194 HCC patients who met UNOS-DS criteria and received trans-arterial treatment (TACE, 132 patients; TARE, 62 patients). They reported that 174 patients (83%) were successfully down-staged, with no significant difference in time to or probability of successful downstaging between the TACE and TARE groups.

DOWNSTAGING - FUTURE

Expansion of downstaging criteria: BLCL-B (beyond UNOS-DS)

All comers (AC) are patients whose tumor burden initially exceeds UNOS-DS criteria. Therefore, the inclusion criteria of the AC-DS protocol are defined as patients with HCC beyond UNOS-DS criteria but still classified within BCLC-B. The definition of successful downstaging in the AC-DS protocol is nearly identical to that of the UNOS-DS protocol. However, studies on the clinical outcomes of the AC-DS protocol are less common than those on the UNOS-DS protocol.

In the study conducted by Metha et al.⁹ the 3-year post-LT OS rate was significantly different between the MC and ACDS (83.2% vs. 71.4%; P=0.04). Natarajan et al.¹⁵ analyzed 311 patients who underwent LT (229 in UNOS-DS, 82 in ACDS) and reported a 3-year OS rate from LRT of 69% in the UNOS-DS group and 58% in the AC-DS group (P=0.05). The 3-year post-LT OS rate was also not significantly different between the two groups (91% vs. 81%; P=0.67). They noted that the 3-year OS rate from LRT in AC-DS patients without high-risk factors (AFP >500 ng/mL or Child-Pugh class B/C cirrhosis) was 67.7% compared to 29.9% in AC-DS patients with one or two high-risk factors (P=0.003). They suggested that LT could be considered for highly selected AC-DS patients with favorable tumor biology if successful downstaging is achieved.

Expansion of downstaging criteria: BLCL-C (portal vein tumor thrombus)

Portal vein tumor thrombus (PVTT) has traditionally been considered a contraindication for LT. However, recent studies have reported that both deceased donor LT (DDLT) and living donor LT (LDLT) showed acceptable clinical benefits. Yu et al.¹⁶ analyzed 961 patients who underwent LT (489 within MC, 296 beyond MC but without PVTT, 83 with type 1 PVTT, and 93 with type 2 PVTT) and reported that the 5-year OS rate for patients with type 1 PVTT was not significantly different compared to those within MC (78.3% vs. 79.1%; P=0.062) and was superior compared to patients beyond MC but without PVTT (78.3% vs. 50.0%; P=0.012). They mentioned that OS and RFS rates for PVTT patients with AFP ≤100 ng/mL were significantly superior compared to those of patients beyond MC or PVTT patients with AFP >100 ng/mL (P<0.01). Notably, OS rates were not significantly different between PVTT patients with AFP ≤100 ng/mL and those within MC (P=0.065). Soin et al.¹⁷ analyzed 405 patients who underwent LT (382 without PVTT, 23 with down-staged PVTT) based on prospectively collected data. They reported that 5-year OS and RFS rates for patients with down-staged PVTT were not significantly different compared to patients without PVTT (57% vs. 65%, P=0.06; 66% vs. 51%, P=0.33). They also noted that the 1-year OS rate for patients with down-staged PVTT was better than in PVTT patients receiving sorafenib monotherapy (82% vs. 0%; P<0.001). Serenari et al.¹⁸ conducted a pilot prospective study analyzing the clinical outcomes of five HCC patients with PVTT who underwent DDLT after successful downstaging by TARE. They reported that the 5-year OS rate of the DDLT group was significantly better compared to the observation group (60% vs. 0%; P=0.03). Based on these results, we can propose that LT should be carefully considered for highly selected patients with PVTT after successful downstaging.

Expansion of downstaging criteria: the role of a multidisciplinary approach in the era of IO therapy

It is well established that MDA enhances survival in patients with HCC. El Dahan et al.¹⁹ conducted a meta-analysis of 12 studies encompassing 15,365 HCC patients and found that MDA was associated with improved overall survival (HR, 0.63; 95% CI, 0.45-0.88). Sinn et al.²⁰ analyzed 6,619 HCC patients (738 receiving MDA care, 5,881 not) and reported significantly higher 5-year survival rates for patients under MDA care compared to those without (71.2% vs. 49.4%; P<0.001). They noted that MDA care was particularly beneficial for patients with BCLC-B or BCLC-C and AFP levels over 200 ng/mL, who could be candidates for downstaging.

As previously mentioned, successful downstaging, including the durable stabilization of tumor biology, can lead to favorable survival and prognosis after LT, even if the initial tumor burden exceeds extended LT criteria (such as UNOS-DS, AC-DS, PVTT). Thus, more robust treatment modalities, such as combination therapies based on MDA, increase the chances of successful downstaging followed by subsequent LT.

Recent advancements in the systemic treatment of HCC, particularly trials on immune checkpoint inhibitor (ICI)-based treatments, have shown promising results. The IMbrave150 trial reported that patients treated with a combination of atezolizumab and bevacizumab had better overall survival (19.2 vs. 13.4 months; HR, 0.66) compared to those treated with sorafenib.⁵ Similarly, the HIMALAYA trial demonstrated improved overall survival with durvalumab-tremelimumab combination therapy (16.4 vs. 13.8 months; HR, 0.78) compared to sorafenib.⁶

Combining IO therapy with LRT such as TACE, TARE, and radiation therapy (RT) could be a potent strategy for enhancing the success rate of downstaging. This approach is promising because LRT may induce the release of tumor-associated antigens and activate antigen-presenting cells, potentially converting the tumor microenvironment to become more immunesensitive.²¹

Kudo et al.²² analyzed 110 patients with unresectable or TACE-unsuitable BCLC-B HCC who were treated with atezolizumab plus bevacizumab, finding that 28 patients (25%) achieved a complete response (CR) and became candidates for curative-intent treatments post-therapy. Ding et al.²³ performed a meta-analysis (1,174 patients from three databases and 19 studies) and found that the group treated with a combination of cellular immunotherapy and LRT (predominantly TACE) had significantly improved 1-year OS (OR, 3.52; P<0.0001) compared to those treated with LRT alone.

Yeo et al.²⁴ reported on the clinical outcomes of 1,664 advanced HCC patients, comparing 142 treated with immunotherapy plus TARE and 1,522 treated with immunotherapy alone. They found that the OS of the combination group was significantly higher than that of the immunotherapy-alone group (19.8 vs. 9.5 months; P<0.001). Tai et al.²⁵ conducted a phase 2 trial on TARE followed by nivolumab in 36 advanced HCC patients and reported an objective response rate (ORR) of 41.7%. Lee et al.²⁶ carried out a phase 1/2a trial on TARE followed by durvalumab in 24 BCLC-B and BCLC-C patients and found an ORR of 83.3% (CR, 29.2%; partial response, 54.2%) and an 18-month OS rate of 58.3%.

Hwang et al.²⁷ analyzed 98 advanced HCC patients with high-risk factors (bile duct invasion, main portal vein invasion, large tumor) treated with atezolizumab plus bevacizumab, with or without RT. They reported that the OS of the RT combination group was significantly higher than that of the non-combination group (12.00 vs. 5.75 months; P<0.001). Chiang et al.²⁸ conducted a phase 2 trial evaluating the clinical outcomes of sequential TACE and stereotactic body RT followed by avelumab in locally advanced HCC with 64% macrovascular invasion. They enrolled 33 patients, 18 patients (55%) of whom were converted to curative treatment, 14 patients (42%) achieved a CR and did not require further therapy, and the median OS was 30.3 months.

The use of IO agents is generally considered a contraindication in LT patients due to the potential for graft rejection. However, some reports suggest that pre-LT use of IO agents can be safe if there is an appropriate cessation period before LT, known as a washout strategy. Wang et al.²⁹ analyzed 16 HCC patients treated with ICIs before LT and reported an acute rejection rate of 56.3%, though all cases of acute rejection were resolved with immunosuppressive treatment. They also noted that the interval between the last ICI administration and LT in the rejection group was significantly shorter than in the non-rejection group (21.0 [15.5-27.5] vs. 60 [34.0-167.0] days; P=0.01). RezaeeZavareh et al.³⁰ performed a meta-analysis of 30 studies involving 91 HCC patients treated with ICIs before LT and reported an allograft rejection rate of 26.4%. However, overall survival was not different between patients with and without allograft rejection. They also mentioned that the probability of allograft rejection was ≤20% if the median washout period was 94 days.

CONCLUSION

Currently, LT after successful downstaging in BCLC-B HCC patients using the UNOS-DS protocol is considered a feasible approach with favorable long-term clinical outcomes. Looking ahead, it is crucial to consider expanding the downstaging criteria to include patients beyond UNOS-DS (AC-DS, PVTT). Effective treatment strategies that achieve significant tumor response are essential for broadening these criteria, as the clinical outcomes of subsequent LT depend on successful tumor control and stabilization of tumor biology through treatment. Recently, promising systemic treatments for HCC, such as tyrosine kinase inhibitors and IO agents, have been developed, with many clinical trials focusing on MDA that combine LRT and systemic therapy. Although concrete evidence of MDA’s superiority for HCC downstaging is still lacking, promising results from retrospective studies and phase I/II trials demonstrating the efficacy and safety of MDA for downstaging have been reported. We must, therefore, await the outcomes of ongoing prospective trials that are investigating downstaging based on MDA.

Article information

Conflicts of Interest

The authors have no conflicts to disclose.

Ethics Statement

This review article is fully based on articles which have already been published and did not involve additional patient participants. Therefore, IRB approval is not necessary.

Funding Statement

No specific grant was received from any funding agency in the public, commercial, or not-for-profit sectors.

Data Availability

Not applicable.

Author Contributions

Conception: SYH, HC, WJ, RGK

Manuscript preparation: SYH, HC, WJ, RGK

Critical revision: SYH, HC, WJ, RGK

All authors reviewed the paper and approved the final version.

Figure 1.

Treatment algorithm for patients with intermediate stage of hepatocellular carcinoma. BCLC, Barcelona Clinic Liver Cancer; LT, liver transplantation; AFP, alpha fetoprotein; TACE, trans-arterial chemoemolization.

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Figure & Data

References

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