Bridging and downstaging with TACE in early and intermediate stage hepatocellular carcinoma: Predictors of receiving a liver transplant

Abstract

Background and Aims

In patients with surgically unresectable early and intermediate stage hepatocellular carcinoma (HCC), only liver transplant (LT) offers a cure. Locoregional therapies, such as transarterial chemoembolization (TACE), are widely used to bridge patients waiting for an LT or downstage tumors beyond Milan Criteria (MC). However, there are no formal guidelines on the number of TACE procedures patients should receive. Our study explores the extent to which repeated TACE might offer diminishing gains toward LT.

Approach

We retrospectively analyzed 324 patients with BCLC stage A and B HCC who had received TACE with the intention of disease downstaging or bridging to LT. In addition to baseline demographics, we collected data on LT status, survival, and the number of TACE procedures. Overall survival (OS) rates were estimated using the Kaplan‐Meier method, and correlative studies were calculated using chi‐square or Fisher's exact test.

Results

Out of 324 patients, 126 (39%) received an LT, 32 (25%) of whom had responded favorably to TACE. LT significantly improved OS: HR 0.174 (0.094‐0.322, P < .001). However, the LT rate significantly decreased if patients received ≥3 vs < 3 TACE procedures (21.6% vs 48.6%, P < .001). If their cancer was beyond MC after the third TACE, the LT rate was 3.7%.

Conclusions

An increased number of TACE procedures may have diminishing returns in preparing patients for LT. Our study suggests that alternatives to LT, such as novel systemic therapies, should be considered for patients whose cancers are beyond MC after three TACE procedures.

The ultimate goal in treating patients with early and intermediate stage HCC is liver transplantation; surgery is the only means of a cure in HCC. Locoregional therapies such as transarterial chemoembolization (TACE) has historically played a crucial role in optimizing patients for liver transplantation. However, we call into question whether these patients still derive the greatest benefit from repeated TACE procedures, particularly in the current landscape of new and effective systemic therapy options.

1. INTRODUCTION

Primary liver cancer, 75%‐85% of which is hepatocellular carcinoma (HCC), is the seventh leading cancer and the second leading cause of cancer‐related death globally. ¹ Gaining an understanding of the risk factors and pathophysiology of HCC and improving screening practices for at‐risk patients have led us to diagnose more patients at an earlier disease stage. Diagnosis at an earlier stage offers the best prognosis and overall survival through curative surgery, including liver transplantation (LT). ² , ³ However, this early‐stage subset still represents only around 30% of HCC cases in Western countries. ² , ⁴ The current standard criteria listed for LT eligibility are the Milan Criteria (MC; a single lesion of ≤5 cm or a maximum of three lesions of ≤3 cm without gross vascular invasion), which were established in 1996. ⁵ After adopting the MC for transplant eligibility, liver transplant outcomes of patients with HCC improved; thereafter, 5‐year survival ranged from 71%‐75%. ⁶ , ⁷ Additional data from high‐volume centers revealed 5‐year survival rates of 60%‐70%. ⁸ However, there is still far more demand for transplantable livers from eligible HCC patients than there is supply. ⁹ The LT registration for patients with HCC significantly increased between 2002 to 2015 across all liver disease etiologies (i.e., NASH, HCV, other). ⁹

The MC have been widely adopted in the assessment of LT eligibility, and many patients diagnosed beyond MC have been disqualified from LT consideration. Hence, over the past two decades, there have been attempts to broaden transplant eligibility. For example, in 2001, Yao et al came up with the UCSF criteria when they demonstrated that patients with HCC who received an LT based on an expanded set of selection criteria (a single lesion ≤6.5 cm or a maximum of 3 lesions ≤4.5 cm without gross vascular invasion) had comparable outcomes to patients who were selected based on MC. This finding was later confirmed in a systematic review and meta‐analysis. ¹⁰ Nonetheless, MC remains the gold standard for LT recipient selection in the United States and most parts of the world. ⁵

There has also been growing interest in various systemic therapeutic and locoregional methods to downstage tumors to improve LT eligibility. ¹¹ Several prospective trials were designed to evaluate outcomes of HCC downstaging (generally in patients between MC and UCSF criteria). They reported a downstaging success rate of >65% and a transplant rate of >54% overall. ¹² , ¹³ The 2020 phase 2b/3 trial by Mazzaferro et al showed a significant survival advantage for patients undergoing HCC downstaging followed by LT (5‐year OS rate, 77.5%) compared to no LT but locoregional and systemic treatment (5‐year OS rate, 31.2%) (P = .04). This LT‐related OS rate is in the range of that reported by high‐volume centers for LT recipients. ¹¹

Similar therapeutic strategies used in HCC downstaging are employed as bridging therapies to LT among patients already within MC and on the LT waiting list. It was estimated that, without bridging therapies, 20%‐30% of patients diagnosed with HCC within the MC would suffer disease progression while waiting for a liver to be available to them, no longer be within MC, and be removed from the waiting list. Therefore, most patients are recommended for bridging therapies when their wait time is more than 6 months. ⁸ , ¹⁴ Strategies employed for downstaging and bridging purposes usually involve locoregional therapy. Although there is no standard locoregional treatment guide, transarterial chemoembolization (TACE) is the most commonly used downstaging and bridging strategy in North America and Europe. The American Association for the Study of Liver Diseases (AASLD) recommends TACE as the first‐line therapy (level 1 evidence) for Barcelona stage B (multinodular, ECOG PS 0‐1) HCC, the goal of which is to downstage the disease in preparation for LT. ¹⁵ In a prospective study of patients with unresectable HCC, a mean of 2.8 TACE procedures was associated with an OS of around 29 months (without liver transplant). ¹⁶

In 2016, the Organ Procurement and Transplant Network (OPTN) adopted a downstaging protocol for patients with HCC beyond MC, which helped make HCC downstaging a standard therapeutic approach. ¹⁷ In a systematic review and pooled analysis, successful downstaging was achieved in approximately 48% of patients, ¹⁸ providing a 5‐year post‐transplant survival rate of 78%. ¹³

Our study comes at a time when there is a booming number of new systemic therapies available for HCC. It has historically been common practice to use a “TACE on‐demand” approach to downstage or bridge patients to LT, where the need for retreatment with TACE is guided by the radiographical response, and often exceeds two treatments. Nonetheless, more than half of the patients beyond MC cannot be successfully downstaged and do not ultimately receive LT. Despite advances made in locoregional therapy, the outcome and overall survival of patients treated with TACE but ultimately no LT (~29 months) is far shorter than those receiving LT (5‐year OS >70%). In this retrospective study, we will use our institutional experience with early and intermediate stage (BCLC stage A and B) HCC to analyze real‐world data on the success rate of HCC downstaging with TACE and the rate of LT among patients who are bridged or undergoing downstaging. The novel goal of our study is to suggest a time point where further TACE treatment may not be beneficial to patients, particularly in terms of their odds of eventually receiving LT, which is an important marker of prognosis. In the cases where TACE is not immediately beneficial, we will discuss the potential benefit for early initiation of alternative treatments such as systemic therapy, where even patients with more locally advanced or metastatic HCC can achieve a mOS as high as 26 months and ORR upwards of 40% with various immunotherapy and anti‐VEGF therapies. ¹⁹ , ²⁰

2. EXPERIMENTAL PROCEDURES

2.1. Patient selection

We carried out a single‐institutional retrospective analysis of patients with early and intermediate stage HCC (BCLC stage A and B). Patients were treated and followed by transplant hepatology and interventional radiology with the aim of downstaging or bridging to LT between January 1, 2004, to December 31, 2018.

2.2. Data collection

This study was carried out under an IRB‐approved protocol. Retrospective chart review and data mining were carried out for eligible study subjects, which proceeded through October 2020. Baseline characteristics and information on relevant clinical factors were collected for further analysis. These included but were not limited to sex, race, date of HCC diagnosis, LT evaluation (within MC, beyond MC but within UCSF criteria, or beyond both criteria), viral etiology and status of corresponding viral treatment, serum alpha‐fetoprotein (AFP) level, number of TACE procedures, LT status, overall survival, and additional therapies.

We recorded the total number of TACE procedures each subject received and the procedure dates. Tumor responses were assessed using contrast‐enhanced MRI or multiphasic abdominal CT, generally 30‐45 days after each procedure. We evaluated each scan and categorized the responses as either within or beyond MC.

2.3. Treatment of viral hepatitis

Hepatitis B virus (HBV) and hepatitis C virus (HCV) were treated according to institutional practice and AASLD guideline.

2.4. TACE procedures

In our study, there were two indications for TACE procedures: for bridging or downstaging the patients' HCC. For patients who are already eligible for LT (i.e., within MC and meeting standard UNOS criteria) and are on the waitlist for LT, bridging therapy was used to prevent progression of disease while waiting for organ donors. On the other hand, TACE, for the purpose of downstaging, was performed on patients who were not readily LT candidates (i.e., beyond MC) in attempt to shrink the tumor(s) to fit within MC and improve LT candidacy.

TACE was performed using “conventional” methodology encompassing selective infusion of a mixture of ethiodized oil contrast medium (Lipiodol; Guerbet, Aulnay‐sous‐Bois, France) and doxorubicin (Adriamycin; Ildong Pharmaceutical, Seoul, Korea) followed by embolization of feeding arteries using varying embolic material (gelfoam, tris‐acryl polymer, etc.) or “drug‐eluting beads” TACE (DEB‐TACE), where doxorubicin was bound to embolic beads, which were infused concurrently, based on operating physician's preference. Embolization was performed until stasis was achieved in the second‐ or third‐order branches of the right or left hepatic arteries. TACE was repeated on an “as needed” basis at 8‐ to 12‐week intervals when, on follow‐up assessment, viable residual tumor or new intrahepatic lesions were detected based on AASLD criteria using arterial phase enhancement on CT or MRI in the absence of extrahepatic metastases, major portal vein invasion, or deterioration in clinical status or laboratory values. This also allows for the evaluation of the tumor(s) based on MC.

HCC staging and response evaluation was carried out by experienced radiologists at our institution and the study team. Treatment responses were assessed after the initial TACE using a modified Response Evaluation Criteria in Solid Tumors (mRECIST) guideline.

2.5. Liver transplantation

All potential liver transplant candidates underwent multidisciplinary evaluation according to institutional protocols. Candidacy for liver transplantation was determined by the liver transplant selection committee. Patients approved for liver transplant listing were placed on the waitlist using standard UNOS criteria and MELD exception if appropriate. Only patients within MC remained on the transplant list. Patients who were beyond MC but within UCSF criteria without contraindication to LT were attempted for downstaging.

2.6. Statistical analysis

Baseline characteristics and relevant clinical factors were summarized using counts and percentages. When appropriate, associations between clinical factors and patient outcomes were checked using the chi‐square test or Fisher's Exact test. Overall survival (OS) was estimated using the Kaplan‐Meier method. The log‐rank test was used to compare survival time between different groups. Cox proportional hazard models were fitted to estimate the Hazard Ratio (HR) between different groups. A P‐value of <.05 was considered statistically significant. SAS version 9.4 (SAS Ins.) was used for statistical analysis.

3. RESULTS

3.1. Baseline characteristics

Our patient cohort consisted of 324 HCC patients. Demographics and clinical characteristics are detailed in Table 1. The majority of patients were male (74.4%, N = 241). Fifty‐six percent were Caucasian, 12% African American, 15% Asian, and the remainder were identified as “other” or “ethnicity unknown.” Viral hepatitis infection was evident in 222 patients (69% of total): 39 had hepatitis B virus (HBV), 178 had hepatitis C virus (HCV), and five had both HBV and HCV. Baseline AFP levels were available in 192 patients: 163 had levels ≤400 ng/mL, 11 had levels between 400 ng/mL and 1000 ng/mL, and 18 had levels ≥1000 ng/mL. With respect to LT eligibility criteria, 216 patients (66.7%) were diagnosed within MC versus 108 (33.4%) diagnosed beyond MC. Among those beyond MC, 46 were still within UCSF criteria.

TABLE 1.

Demographics and clinical characteristics

	N	Patient/clinical characteristics	Number of subjects (%)
Gender	324	Female	83 (25.6)
		Male	241 (74.4)
Race	324	African American	40 (12.3)
		Asian	48 (14.8)
		Caucasian	182 (56.2)
		Unknown	54 (16.7)
Staging at diagnosis	324	Within MC	216 (66.7)
		Beyond MC; within UCSF	46 (14.1)
		Beyond MC and UCSF	62 (19.1)
Received liver transplant (LT)	324	No	198 (61.1)
		Yes	126 (38.9)
Viral etiologies	222	HBV	39 (17.6)
		HBV + HCV	5 (2.3)
		HCV	178 (80.2)
Viral hepatitis treatment	222	HBV treatment	33 (14.9)
		HCV treatment	103 (46.4)
		Untreated	86 (38.7)
Viral treatment response	230	SVR achieved (HCV only)	69 (31.1)
		No SVR (HCV) and treated HBV	67 (30.2)
		Untreated	86 (38.7)
AFP	324	≤ 400 ng/mL	163 (50.3)
		400‐1000 ng/mL	11 (3.4)
		≥1000 ng/mL	18 (5.6)
		Unknown	132 (40.7)
Downstaging attempt a	155	Not downstaged	70 (45.2)
		Downstaged	85 (54.8)
Total number of TACE	324	0	8 (2.5)
		1	95 (29.3)
		2	105 (32.4)
		3	52 (16.0)
		4	31 (9.6)
		≥5	33 (10.1)
Timing of viral treatment in LT recipients	60	Ongoing during LT	3 (5.0)
		After LT	20 (33.3)
		Before LT	30 (50.0)
		Unknown	7 (11.7)
Viral treated patients and LT	136	Did not receive LT	71 (52.2)
		Received LT	65 (47.8)

^a Downstaging was attempted in a total of 155 patients who were beyond MC either at the time of HCC diagnosis (N = 108) or progressed beyond MC after diagnosis (N = 45).

3.2. Clinical factors impacting liver transplantation

During our study time frame, 126 patients (39% of total) received an LT. Patients diagnosed within MC received LT at a significantly higher rate than those diagnosed beyond MC (48% vs 21%, P < .001). Of those diagnosed beyond MC but within UCSF criteria, 31% ultimately received LT.

The majority of patients receiving LT were male (N = 97) and Caucasian (N = 70), but race and gender did not reveal any differences concerning the rate of LT (P = .59 and P = .39, respectively). The incidence of LT was not affected by AFP levels (P = .47). We found that 92 of 126 (73%) LT recipients were infected with HBV and/or HCV; the type of viral infection did not impact the rate of LT. The majority of LT recipients received treatment for their viral hepatitis (79%), and the presence of viral hepatitis did not impede the rate of LT. However, treatment of viral hepatitis with antiviral therapy was positively associated with an increased rate of LT compared to no treatment (54% vs 22%, P < .001). These clinical variables are outlined in Table 2.

TABLE 2.

Clinical variables and chances of LT

	Received Liver Transplant (LT)		P‐value
	No (N = 198) # of subjects (%)	Yes (N = 126) # of subjects (%)
Gender
Female	54 (27.3)	29 (23.0)	.39
Male	144 (72.7)	97 (77.0)
Race
African American	25 (12.6)	15 (11.9)	.59
Asian	32 (16.2)	16 (12.7)
Caucasian	112 (56.6)	70 (55.6)
Unknown	29 (14.6)	25 (19.8)
Staging at diagnosis
Within MC	113 (57.1)	103 (81.7)	<.001
Beyond MC; within UCSF	32 (16.2)	14 (11.1)
Beyond UCSF	53 (26.7)	9 (7.1)
Viral hepatitis
HBV	23 (17.7)	16 (17.4)
HCV	103 (79.2)	75 (81.5)
HBV + HCV	4 (3.1)	1 (1.1)
Hepatitis treatment
HBV treated	18 (13.8)	15 (16.3)	<.001
HCV treated	45 (34.6)	58 (63.0)
Untreated	67 (51.5)	19 (20.7)
Viral treatment
Untreated	67 (51.5)	19 (20.7)	<.001
Treated	63 (48.5)	73 (79.3)
AFP, ng/mL
≤400	103 (83.1)	60 (88.2)	.47
400‐1000	7 (5.6)	4 (5.9)
≥1000	14 (11.3)	4 (5.9)
Downstaging attempt
Not downstaged	70 (57)	0 (0)	<.001
Downstaged	52 (42.6)	33 (100)

3.3. Downstaging from beyond MC

To improve their transplant eligibility, 155 patients who were beyond MC anytime during their disease course received TACE to attempt downstaging, while the remaining patients within MC received LT for the purpose of bridging to LT. Of these 155 patients for whom downstaging was attempted, 85 (54.8%) were successfully downstaged to within MC. Thirty‐three of 85 downstaged patients (38.8%) received LT, while 52 did not. The ability to be downstaged significantly improved a patient's chances of receiving LT (P < .001).

There were 49 patients who were initially diagnosed within MC but progressed to beyond MC while on the transplant waitlist. In this group, the median time to progression beyond MC was 10.5 months. Twenty‐two of these 49 patients (44.9%) were later downstaged to within MC through TACE, and 10 of these 22 downstaged patients received LT (45.4%).

3.4. Number of TACE procedures vs LT

In our 324‐patient cohort, a median of two TACE procedures were received, ranging from zero to nine. The majority of our patient cohort received between one and four procedures (N = 283). Following HCC diagnosis within MC, 97% (209 of 216 patients) received at least one TACE while waiting for LT (seven patients did not make it to TACE; of these, four still received LT). Following HCC diagnosis beyond MC, 99% (107 of 108 patients) received at least one TACE. As outlined in Table 3, among all subjects, the rate of receiving LT decreased significantly with three or more TACE procedures compared to fewer than three procedures (21.5% vs 48.6%, P < .001); this trend was similar for patients diagnosed within MC (26.5% vs 57.4%, P < .001), and outside MC (14.6 vs 26.7%, P = .16). It was also noted that a greater proportion of patients diagnosed beyond MC had three or more TACE procedures compared to those within MC (44.4% vs 31.5%, P = .02).

TABLE 3.

Number of TACE procedures vs LT rate

	LT	Total # of TACE		P‐value (Fisher's exact test)
		≤2 (N = 208)	≥3 (N = 116)
All patients	No	107 (51.4)	91 (78.4)	<.001
	Yes	101 (48.6)	25 (21.6)

We evaluated the radiographic response after each TACE procedure as an independent predictor of LT, summarized in Table 4. Radiographic response data were available for 282 of 316 patients receiving TACE; it should be noted that 27 patients did not undergo imaging after the first TACE due to a planned sequential TACE. The rates of eventually receiving LT are significantly better if the patient's tumor evaluation after the first, second, or third TACE procedure is within MC: 52%, 53%, and 44%, respectively, compared to 22%, 11%, and 3.7%, respectively, for those beyond MC (but subsequently downstaged with further TACE(s), P = .001) (Figure 2).

TABLE 4.

Response after each TACE and LT rate

	LT	Staging		P‐value (chi‐square test/Fisher's exact test)
		Beyond MC # of subject (%)	Within MC # of subject (%)
After 1st TACE	No	75 (78.12)	77 (48.43)	<.001
	Yes	21 (21.88)	82 (51.57)
After 2nd TACE	No	88 (88.89)	45 (46.88)	<.001
	Yes	11 (11.11)	51 (53.12)
After 3rd TACE	No	52 (96.3)	28 (56)	<.001
	Yes	2 (3.7)	22 (44)

FIGURE 2.

Rate of eventually receiving LT according to post‐TACE staging after the first three TACE procedures. Tumors were evaluated after each TACE procedure. After the first TACE, 52% of patients who were within MC would eventually receive LT (although some may continue to receive more TACE as bridging therapy), while 22% of patients who were beyond MC would eventually receive LT (after successful downstaging on subsequent TACE(s)). Similarly, after the second TACE, 52% of patients who were within MC would eventually receive LT, while 11% of patients who were beyond MC would eventually receive LT (after successful downstaging to within MC on subsequent TACE(s)). After the third TACE, 44% of patients who were within MC would eventually receive LT, while only 3.7% of patients who were beyond MC eventually received LT (after successful downstaging to within MC on subsequent TACE(s)).

3.5. Overall survival

Patient survival data is outlined in Table 5. Receipt of LT significantly improved patient median OS (mOS); mOS was not reached for LT recipients vs 55 months for non‐recipients (HR = 0.174; 95% CI, 0.094‐0.322; P < .001). In the downstaged patient subset, receipt of LT trended toward increased OS (HR = 0.231; 95% CI. 0.051‐1.061; P = .06). Patients diagnosed within MC had similar OS to those diagnosed beyond MC; however, those initially within UCSF (also within MC) trended toward better OS than those who were beyond UCSF criteria (HR = 0.601; 95% CI, 0.339‐1.063; P = .08). AFP levels at the time of diagnosis did not affect OS. Kaplan‐Meier curves for OS is presented in Figure 1. Among 126 patients who received LT, 15 patients were deceased at the cutoff of the study period. Three out of these 15 patients had recurrent and/or metastatic HCC which led to their deaths. Other causes included sepsis (three patients), HCV cirrhosis (three patients), transplant rejection (one patient).

TABLE 5.

Clinical variables and OS

		OS Hazard Ratio (95% CI)	chi‐square P‐value
LT status	LT vs no LT	0.174 (0.094–0.322)	<.001
Staging at diagnosis	Within MC vs Beyond MC	0.871 (0.523–1.45)	.60
	Within MC vs Beyond UCSF	0.631 (0.354–1.12)	.12
Downstaged patients	LT vs no LT	0.231 (0.051–1.061)	.06
Viral etiology	Viral vs non‐viral etiology	0.75 (0.46–1.222)	.25
	HBV vs HCV	0.52 (0.206–1.311)	.17
Viral treatment	Treated vs not treated	0.45 (0.258–0.784)	.005
Viral treated patients	SVR vs non‐SVR	0.468 (0.2–1.093)	.08
	SVR: LT vs no LT	0.137 (0.027–0.698)	.02
	Non‐SVR: LT vs no LT	0.321 (0.114–0.903)	.03
AFP	≤400 ng/mL vs ≥1000 ng/mL	1.29 (0.174–2.64)	.80

FIGURE 1.

Overall survival according to staging and treatment. (A) OS for subjects receiving an LT (mOS not reached; > 80% were alive after 5 years) vs no LT (mOS = 55 months); (B) OS of all subjects by initial staging. 1 = within MC, 2 = beyond MC but within UCSF, 3 = beyond MC and UCSF. mOS not reached for all. (C) OS for all downstaged patients who had LT vs no LT. mOS not reached for all.

For patients with viral hepatitis (HBV and HCV), there were no differences in OS between viral and non‐viral etiologies (HR = 0.75; 95% CI, 0.46‐1.222; P = .25) or HBV and HCV (HR = 0.52; 95% CI, 0.206‐1.311; P = .17). For patients with HBV or HCV, receiving antiviral treatment was associated with improved OS compared to no antiviral treatment (HR = 0.45; 95% CI, 0.256‐0.784; P = .005). In addition, OS of patients with HCV who achieved sustained virologic response (SVR) trended toward being longer than those not achieving SVR (HR = 0.468; 95% CI, 0.2‐1.093; P = .08). OS was further improved in patients with SVR who received LT (HR = 0.137; 95% CI, 0.026‐0.698; P = .02). The timing of LT with respect to viral treatment (before, during, or after) did not impact OS.

4. DISCUSSION

In this retrospective study, we present our institutional experience in using TACE to bridge and/or downstage early and intermediate stage HCC (BCLC stage A and B) patients with the goal of LT. Collected data revealed several key trends, which are discussed below.

Consistent with published data, we found that LT prolongs the survival of patients with HCC. In almost every subgroup analysis performed, receiving LT improved OS compared to no LT. In addition, our data showed that while patients diagnosed within MC and patients between MC and UCSF criteria had similar OS, they trended toward improved survival compared to patients diagnosed beyond UCSF criteria. These findings are consistent with other accounts in the literature. ²¹

4.1. Viral hepatitis and LT

It is well‐recognized that viral hepatitis plays a significant role in the development of HCC. We confirmed that treatment of viral hepatitis—HBV, HCV, or both—improves OS. In addition, the presence of viral hepatitis did not hinder the rate of LT. As expected, LT improved OS in patients with HBV, HCV, or both, and this benefit was possibly enhanced in patients with HCV who achieved SVR compared to those who did not. Furthermore, the timing of LT regarding viral treatment (before, during, or after) did not impact survival. We also noted that LT recipients with viral hepatitis were more likely to have received antiviral therapy than non‐transplanted patients. It is unclear from our data whether receiving antiviral treatment could impact a patient's chances of receiving an LT. However, 62% of patients with a known temporal relationship between LT and antiviral therapy received their donor graft during or after antiviral treatment, and 38% received LT before antiviral treatment.

4.2. Downstaging from beyond MC

In this population of early and intermediate stage HCC, 54.8% of patients were downstaged using TACE if their disease was beyond MC at any point during the disease course. These findings are consistent with those from several pooled analyses, which report a downstaging success of approximately 48%. ¹⁸ However, in studies carried out according to prospectively designed protocols for downstaging, investigators report significantly higher success rates (68%) than those found in retrospective studies (48%). ¹⁸ , ²² In a more recent prospective study, four of nine patients (44%) were successfully downstaged with locoregional therapies, including TACE, and underwent LT. In prior studies, LT outcomes of downstaged patients were comparable to those of patients within MC at diagnosis. ²³

The MC are used to determine eligibility for transplant. The risk for recurrence is low if the patient received a liver transplant while within MC. Being within MC is the most reliable clinical surrogate marker for tumor biology. The most important morphological feature of HCC indicating tumor viability is arterial enhancement and venous washout in triple phase CT scan or MRI, as defined at LR‐5 lesion by AASLD. After a patient has received TACE treatment, only viable tumor on imaging is factored in determining whether he/she is within MC.

Of the patients downstaged to MC in our study, 38.8% (33 of 85) received an LT. The ability to downstage and receive LT supports the notion that local therapies such as TACE offer an important and meaningful opportunity for patients who would otherwise not be candidates for LT. Furthermore, it was notable that patients who were initially within MC but who progressed to beyond MC while on waitlist still had a good chance of receiving LT if they were downstaged (10 of 22 patients). Nonetheless, while sequential TACE remains a widely used means of bridging and downstaging for LT, its efficacy diminishes with each subsequent TACE procedure.

4.3. TACE limitations

We carried out this study with the initial aim of defining a point at which repeated TACE no longer benefits patients and transitioning them to systemic treatment might provide better outcomes. There are irrefutable data to show that LT maximizes survival in early‐ and intermediate‐stage HCC patients. Consequently, the ultimate objective for most patients with intermediate‐stage HCC is to receive an LT, and TACE often facilitates this.

When we looked at the total number of TACE procedures for each patient, we found that patients were significantly less likely to receive LT if they had three or more TACE procedures (48.6% vs 21.6%, P < .001). For patients initially diagnosed within MC, this observation held true. For those diagnosed beyond MC, there was a trend toward greater likelihood of LT with fewer TACE procedures (statistically nonsignificant, likely due to the low sample size in this subgroup receiving LT). This conclusion suggests that more TACE procedures, particularly three or more, may have diminishing returns when LT is the goal.

We further calculated the odds of LT as a function of response (i.e., beyond MC vs within MC) after each TACE. Our first observation was that being within MC after each of the first three TACE procedures was independently associated with good odds of ultimately receiving LT. For example, a patient whose tumor was either downstaged to or remained within MC on imaging after the first, second, or third TACE had odds of eventually receiving an LT of 52%, 53%, and 44%, respectively (Figure 2). On the other hand, if a patient's tumor was beyond MC on a post‐TACE scan, the odds of that patient receiving an LT were significantly decreased relative to those still within MC after the corresponding TACE and relative to those who had received fewer TACE procedures. For example, we saw that 22% of patients with tumors beyond MC vs 52% within MC after their first TACE procedure eventually received an LT. However, for patients beyond MC after the second TACE, the odds of LT decreased substantially to 11% (after these patients were successfully downstaged on subsequent TACE(s)). For those beyond MC after the third TACE, the odds of eventual LT declined to just 3.7% (these patients were downstaged after 3+ TACE). These rates are illustrated in Figure 2. The mechanisms behind these observations may be attributable to tumor characteristics (i.e., more aggressive cancers are resistant to TACE) and the reduced likelihood of further downstaging. For example, tumor cells that survive TACE are described as being more aggressive and TACE‐resistant. ²⁴ It is postulated that tissue hypoxia resulting from TACE induces vascular endothelial growth factor (VEGF) production and promotes this aggressiveness. ²⁴ To our knowledge, tumor response to each TACE procedure has not yet been evaluated as an independent factor for LT, even though it may be essential to the treatment plan and lives of patients with HCC.

Our findings prompt us to argue that if patients with early and intermediate stage HCC are beyond MC after their third TACE, there is little benefit to pursuing repeated local therapy. At this point, there is little chance of disease downstaging or bridging for eventual LT. Moreover, if LT is no longer a feasible goal, then it is possible that alternative ways to control disease, using systemic therapy, for example, should be considered. To give context to this statement, the rapidly expanding choice of systemic therapy options, including tyrosine kinase inhibitors (TKI) and immunotherapies, now offer meaningful survival benefits. Before 2007, there were no FDA‐approved systemic therapies for HCC, but there are now eight approved drugs for advanced HCC. Four are TKIs that inhibit angiogenesis, and three are checkpoint inhibitor immunotherapies. Recent treatment highlights include sequential use of sorafenib and regorafenib (RESOURCE), combined bevacizumab with atezolizumab (IMBrave150), and combined lenvatinib plus pembrolizumab (under investigation). ¹⁹ , ²⁰ , ²⁵ , ²⁶ In patients with advanced (mostly BCLC stage C) and metastatic HCC, an mOS as high as 26 months and ORR upwards of 40% have been achieved with these therapies. ¹⁹ , ²⁰

Systemic therapy could have untapped potential to downstage HCC. Comprehensive prospective studies of downstaging via systemic therapies are lacking. Sorafenib is commonly used in clinical practice as a preoperative bridging therapy to LT, ²⁷ although, admittedly, a small number of studies (mostly retrospective) of sorafenib compared to TACE in HCC downstaging have shown mixed responses to sorafenib. However, systemic therapies have not been studied in the setting of TACE resistance. Furthermore, while sorafenib is the oldest approved TKI for HCC, newer drugs may have greater potential in this arena, as suggested by a case series of successfully downstaged early‐stage HCC using lenvatinib. ²⁸ Even immunotherapies, which have been largely avoided in peri‐transplant settings due to concern for graft rejection, are being considered both for use in HCC downstaging and to prevent disease recurrence after LT with some promising results. ²⁹

A leading TACE‐treatment concern is the risk of exacerbated hepatic decompensation. ³⁰ TACE can cause acute hypoxia in the surrounding liver, which induces HIF‐1α and VEGF expression. ³¹ Upregulation of these proteins can lead to angiogenesis, tumor revascularization, and proliferation. ³¹ Several studies have demonstrated that repeated TACE for HCC is associated with worsening liver function. Early disease progression on TACE suggests refractoriness that is difficult to overcome by repeated TACE. ³² , ³³ In fact, a recent Asia‐Pacific Primary Liver Cancer Expert (APPLE) consensus statement in 2020 recommended that TACE should not be continued if patients demonstrate refractoriness, hence conserving liver function. Earlier systemic therapy initiation is recommended, and liver dysfunction often precludes patients from optimal systemic treatment. ³⁴ , ³⁵

In summary, the novelty of our study is to suggest a time point where further TACE treatment may not be beneficial to patients with HCC who are being considered for LT. We hope that by defining this time point, treating physicians may consider taking a more proactive approach in initiating systemic therapy. We also hope that the mechanisms by which HCC becomes refractory to TACE can be better studied and characterized. Ultimately, further prospective studies should define which patients will respond to TACE vs which patients will benefit from earlier systemic therapy initiation. Potential benefits of earlier initiation of systemic therapy and its use to downstage patients for LT should also be evaluated.

5. LIMITATIONS AND FUTURE DIRECTIONS

A major limitation of our study is its retrospective nature. We did not have comprehensive clinical data on all subjects; missing elements included AFP levels, post‐TACE imaging (34 patients), and viral hepatitis status. A carefully designed prospective trial that specifically randomizes patients beyond MC after three TACE procedures to additional procedures vs systemic therapy could help confirm our conclusions.

Another limitation is that the only locoregional therapy studied was TACE, our institution's preferred intervention. However, in practice, techniques such as Y90 radioembolization and ablative methods are also commonly used. Admittedly, even though some patients in our study received Y90 or ablation in conjunction with TACE, our study does not delineate how the use of different locoregional approaches may impact LT candidacy and overall survival, particularly with regards to the potential incorporation of systemic therapies.

Lastly, one might argue that even with our assertion of a 3.7% chance of receiving LT for patients beyond MC after three TACE procedures, it would be difficult for physicians to forgo locoregional attempts to downstage patients to obtain curative treatment via LT. However, we believe that the evolution of systemic therapy for HCC, which historically has been reserved for advanced disease, has reached a point where it can be considered for select individuals with early and intermediate stage disease. The scope of our argument is to spark discussion and consideration of further studies that would better characterize and define this patient population.

DISCLOSURE

Author Contributions: Chao Yin and Samantha Armstrong were involved in data collection/interpretation, drafting, and critical reviews. Richard Shin was involved in data collection. Xue Geng and Hongkun Wang provided statistical analyses. Rohit Satoskar, Coleman Smith, Filip Banovac, and Alexander Kim provided critical reviews. Aiwu Ruth He provided study concept, data interpretation, drafting, and critical reviews.

Funding: The study was supported by the Ruesch Center for the Cure of Gastrointestinal Cancers.

Conflict of Interest: Authors have no conflict of interest for this article.

Ethical Approval: The protocol for this research project has been approved by a suitably constituted Ethics Committee of the institution and it conforms to the provisions of the Declaration of Helsinki. The study was approved by the Georgetown University IRB number 2016–0419. Written informed consent from human subjects were not required, as approved by the Georgetown University IRB. The study was granted an exemption from signed informed consent as it was conducted retrospectively, and all patient data were deidentified. No animal studies were performed. The authors have no conflicts of interest.

Yin C, Armstrong S, Shin R, Geng X, Wang H, Satoskar RS, et al. Bridging and downstaging with TACE in early and intermediate stage hepatocellular carcinoma: Predictors of receiving a liver transplant. Ann Gastroenterol Surg. 2023;7:295–305. 10.1002/ags3.12622