Segmental Yttrium-90 Radioembolization as an Initial Treatment for Solitary Unresectable HCC

Keywords

TARE - hepatocellular carcinoma - segmental - radioembolization

Introduction

Liver cancer is the third leading cause of cancer-related mortality worldwide, with an abysmal 5-year survival rate of 20%, necessitating continued advancement of therapeutic strategies.[1] Over the past decade, primary liver cancer incidence rates have continued to increase globally and in the United States, with hepatocellular carcinoma (HCC) accounting for 75 to 85% of cases.[2] [3] The Barcelona Clinic Liver Cancer (BCLC) classification system incorporates HCC tumor staging, liver function, performance status, and projected prognosis to create treatment guidelines for improved survival outcomes.[4] [5] [6] Surgical resection, transplantation, and thermal ablation serve as curative approaches for patients with early-stage (BCLC-0, BCLC-A) disease. At the same time, liver-directed therapies, including transarterial chemoembolization (TACE) and transarterial radioembolization (TARE), have been traditionally reserved for advanced disease serving as bridges to curative management.

Radiation segmentectomy using yttrium (⁹⁰Y) is an innovative approach to radioembolization, utilizing selective ⁹⁰Y delivery to maximize local administration of cytotoxic radiation and minimize side effects and damage to the surrounding parenchyma.[7] [8] [9] Promising response rates and durable outcomes from the recent LEGACY trial led to the inclusion of segmental radioembolization as a treatment option for patients with BCLC 0 and A HCC in the most recent BCLC guidelines.[9] [10] These data support the continued evaluation of segmental TARE for the treatment of early-stage HCC. Herein, the present study aims to evaluate the objective response rate (ORR), time to progression (TTP), and overall survival (OS) in patients with unresectable solitary HCC less than 5 cm who were treated with segmental delivery of ⁹⁰Y glass microspheres.

Materials and Methods

This study was approved by the Institutional Review Board. Data of patients who underwent ⁹⁰Y radioembolization for the treatment of unresectable HCC at a single institution between November 2012 and April 2020 were retrospectively reviewed. HCC diagnosis was based on contrast imaging following the American Association for the Study of Liver Disease (AASLD) guidelines.[11] The following inclusion criteria were adopted patients who underwent TARE segmentectomy with treatment-naïve, solitary, unilobar, unresectable HCC less than 5 cm in maximal diameter. The decision to perform TARE was based on a multi-disciplinary tumor board discussion comprised hepatobiliary surgery, transplant surgery, hepatology, gastroenterology, oncology, diagnostic radiology, interventional radiology, and radiation oncology. Patients were excluded who had metastatic disease, hepatic encephalopathy, undergone prior orthotopic liver transplant (OLT) or resection or had received prior systemic or regional treatment. Patients with a potential absorbed dose in the lungs >30 Gy (>16.5 mCi of injected ⁹⁰Y) per procedure based on the initial mapping phase were also excluded.

⁹⁰Yttrium (⁹⁰Y) Microspheres Protocol

All patients who received TARE treatment underwent two separate outpatient procedures for mapping and administration. Pre-treatment mapping of eligible patients included a hepatic angiogram and ⁹⁹Tc MAA (⁹⁹technetium macro-aggregated albumin) scan to evaluate hepatic vasculature and pulmonary or gastrointestinal shunting. Dosing of ⁹⁰Y microspheres (TheraSphere; Boston Scientific, Natick MA) was calculated referencing liver mass and volume determined by baseline CT/MR scan or intra-procedural CT using methods previously described in the literature.[12] Dosing range for this study was 21.4 to 131.70 mCi. On the day of administration, TARE microspheres were delivered through a hepatic arterial catheter under fluoroscopic guidance according to the administration procedures outlined in the package.[12] Hepatic arterial catheterization was selective to the segmental level to the maximize tumor dose delivery and minimize collateral liver injury with target dosimetry > 250 Gy.[7] Patient follow-up and survival surveillance were led by the principal oncologist/hepatologist and recorded from electronic medical records for this study.

Data Collection

Patient demographics, comorbidities, laboratory values, MELD and ECOG scores, baseline disease, and tumor characteristics were abstracted from the electronic medical records (EPIC Systems; Verona, WI). Lung shunt fractions, radiation dosimetry, subsequent treatment cycles, and the presence of cirrhotic morphology on imaging (CT or MRI) were also recorded for each patient. Pathological necrosis was documented for patients who received an OLT. Treatment-related adverse events were assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Survival time from first treatment and follow-up treatments, including OLT, TACE, and radiofrequency ablation (RFA), were also documented.

Response Assessment

Follow-up imaging was performed on each patient at 3-, 6-, and 12 months post-treatment. Tumor response was evaluated using the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria and graded as complete (CR), partial (PR), stable disease (SD), or progressive (PD) based on contrast-enhanced imaging.[13] The response/progression within the radioembolization-treated zone was determined by local mRECIST. mRECIST included a combined assessment of treatment response in the targeted region, and a new hepatic lesion development was observed in progressive disease.

Outcomes Assessment

The primary outcomes were objective response rate (ORR), time to progression (TTP), and overall survival (OS). ORR was defined as the combined proportion of patients who exhibited CR and PR following Y90 treatment. Patients were followed until death or the last imaging encounter. TTP was defined as the time from treatment response to local or global progressive disease. The incidence of adverse events and serious adverse events were reported as counts and percentages and coded according to the Medical Dictionary for Regulatory Activities.[14]

Statistical Analysis

Patient demographics, baseline characteristics, and treatment characteristics were analyzed using descriptive statistics, including interquartile ranges (IQR). TTP was summarized as percentages and confidence intervals (CI). Survival was calculated from the time of initial therapy to either the date of death or last known follow-up. Patients were censored at the time of transplantation. Predictors of survival were analyzed with Cox proportional hazards regression. Covariates with a P-value < 0.1 in univariate analysis were subjected to multivariate analysis in a stepwise approach. A P-value < 0.05 was considered statistically significant. Analyses were performed using Stata Version 13 (StataCorp LP, College Station, Texas). Kaplan–Meier analysis was performed using Prism9 (GraphPad Software, San Diego, California). Plots were constructed using a standard statistical software package (R; R Foundation for Statistical Computing, Vienna, Austria).

Results

Patient Demographics and Clinical Characteristics

Among the 35 included patients, the median age was 67 (range: 57–82) years, with 60.6% (21/35) being male. Cirrhosis was present in all patients (35/35, 100%). Predominant HCC etiology was hepatitis C (18/35, 51.4%). The median tumor size was 3 cm (range: 1.0–4.8 cm). A total of 29/35 patients were Child–Pugh class A (82.9%). The median Model for End Stage Liver Disease (MELD) score was 9, with 85.7% (30/35) of patients between 6 and 14. 9/35 patients (25.7%) were Eastern Cooperative Oncology Group (ECOG) 0, and 22/35 were 62.9% ECOG 1; 68.5% (31/35) patients were Barcelona Clinic Liver Cancer (BCLC) stage C. Additional baseline characteristics of included patients are described in [Table 1] and [Fig. 1].

Table 1 Baseline characteristics

		Treated population (N = 35) N (%)
Age (y)
	Younger than 60	2 (6)
	61–70	25 (71)
	71–80	6 (17)
	Older than 80	2 (6)
	Median age	67
Sex
	Female	14 (40)
	Male	21 (60)
Ethnicity and race
	Hispanic or Latino	4 (11.4)
	Native American, Native Alaskan	1 (2.9)
	Black or African American	7 (20)
	Asian or Mideast Indian	2 (5.7)
	White or Caucasian	23 (65.7)
	Not available	2 (5.7)
Etiology
	HCV	12 (34.2)
	HCV/alcohol	5 (14.3)
	HCV/hemochromatosis	1 (2.9)
	Alcohol	4 (11.4)
	HBV	1 (2.9)
	NAFLD	1 (2.9)
	NASH	7 (20)
	Idiopathic/unknown	4 (11.4)
Tumor size
	Median (cm)	3
	Range (cm)	1.4-4.8
Child–Pugh
	A	29 (82.9)
	B	6 (17.1)
BCLC	0	1 (2.9)
	A	1 (2.9)
	C	31 (88.5)
	Not available	2 (5.7)
MELD
	6–14	30 (85.7)
	15–24	5 (14.3)
	Median score	9
ECOG
	0	9 (25.7)
	1	22 (62.9)
	2	2 (5.7)
	Not available	2 (5.7)

Fig. 1 Patient demographics. Baseline patient demographics including age, gender, ethnicity, and HCC etiology were abstracted and compiled from electronic health records and listed above.

Treatment Characteristics

The median segmental infusion administered dose was 49.5 mCi (IQR: 32.1, 80.9). Also, 77.1% (27/35) of patients underwent one TARE treatment. Treatment served as bridging therapy to surgery for 37.1% (13/35) of patients, and 12 out of 13 underwent transplantation (92.5%) at the time of this manuscript preparation. Non-local hepatic tumor recurrence developed in 8/35 (22.9%) of patients by 12 months. Among those with recurrence who did not undergo OLT, three patients received percutaneous microwave ablation (MWA), one patient received TACE, one patient received nivolumab as salvage therapy. One patient received MWA post-TARE and prior to OLT ([Table 2]).

Table 2 Treatment characteristics and course

		Treated Population (N = 35) N (%)
Lung shunt fraction
	Mean (SD)	13.16 (0.6)
	Median (IQR)	2.49 (3.0)
Treatment approach	Segmental	35 (100)
Number of 90Y Treatments
	1	27 (77.1)
	>2	8 (22.9)
Post-procedure treatment
	TACE	1 (2.9)
	MWA	3 (8.6)
	Chemotherapy (nivolumab)	1 (2.9)
	Resection	1 (2.9)
	OLT	12 (34.3)

Treatment Response

Local mRECIST responses at 3 months post-treatment included 88.6% CR, 5.7% PR, 5.7% SD, and 2.9% PD, with a combined ORR of 94.3% ([Fig. 2], [Table 3]). mRECIST ORR at 3 months post-TARE was 85.7%, with patients having 82.9% CR, 2.9% PR, 2.9% SD, and 8.6% PD. Treatment responses evaluated at 3-, 6-, and 12 month intervals are summarized in [Fig. 3]. For the 12 patients who underwent transplantation, the median pathologic necrosis of the targeted region was 98% (IQR: 7.5).

Fig. 2 Waterfall plot of best overall tumor response by localized mRECIST. Response rates were reported as CR, PR, SD, or PD, and the best response rate for each patient is graphically represented as a percent change from baseline.

Table 3 Local mRECIST and mRECIST responses to TARE

	Local mRECIST %	mRECIST %
ORR	94.3	85.7
CR	88.6	82.9
PR	5.7	2.9
SD	5.7	2.9
PD	2.9	8.6

Fig. 3 Local mRECIST and mRECIST responses to TARE. Response rates for all 35 patients at 3-,6-, and 12-months post-TARE treatment.

Time to Progression following ⁹⁰Y Treatment

TTP following ⁹⁰Y treatment is listed in [Table 4]. The mean local TTP among all patients was 11.9 months (CI: 2.7–21.0), and mRECIST TTP was 13.2 months (CI: 6.4–20.0). Among transplant-eligible patients, 1 (7.7%) had local, and 3 (23.1%) had nonlocal hepatic recurrence prior to OLT. Of the transplant-ineligible patients, 3 (13.6%) developed local progression, 1 (4.5%) patient had local and non-local progression, and 8 (36.4%) had non-local progression by 12 months.

Table 4 Time to progression following TARE

	Local mRECIST mean (95% CI)	mRECIST mean (95% CI)
TTP overall in months	11.9 (2.7–21.0)	13.2 (6.4–20.0)
TTP transplant-ineligible patients in months	14.6 (8.7–20.5)	16 (7.4–24.5)
TTP transplant-eligible patients in months	3.7 (0)	5 (−0.8–10.9)

Survival Analysis

In the univariate analysis summarized in [Table 5], none of the following variables are statistically significant predictors of OS: age ≥ 70, Caucasian, ECOG, lesion size, AFP level, MELD score, and Child-Pugh Classification (P > 0.10). The overall survival at 12 months was 97%, while patients who underwent OLT exhibited an OS of 100%. Kaplan–Meier survival curve for both transplant-eligible and transplant-ineligible patients is shown in [Fig. 4].

Table 5 Univariate analysis of predictors of overall survival

Variables	HR	p-Value
Age (≥70 y)	2.12 (0.85–5.29)	0.11
Sex	0.99 (0.41–2.43)	0.99
Caucasian vs. non-Caucasian	1.40 (0.53–3.64)	0.50
ECOG	0.56 (0.23–1.37)	0.21
Lesion size	1.12 (0.80–1.78)	0.39
AFP (normal range vs. elevated)	0.64 (0.23–1.81)	0.40
MELD	1.02 (0.88–1.19)	0.75
Child–Pugh classification	0.88 (0.29–2.69)	0.83

Fig. 4 Kaplan–Meier survival cure for overall survival by transplantation eligibility. X-axis represents days to death or last imaging since ⁹⁰Y treatment. Y-axis represents cumulative surviving proportion or patients. Tick marks represent last imaging since ⁹⁰Y for individual surviving patients.

Adverse Events

Grade 1 adverse events (AE) were present in 4/35 participants, including mild fatigue (N = 1), constipation (N = 2), and mild right upper quadrant pain (N = 1). One patient experienced grade 4 AEs (hypoxia and encephalopathy) after radioembolization. All AEs resolved within 1 month of initial TARE treatment. No deaths occurred secondary to TARE-related complications.

Discussion

The LEGACY study demonstrated that TARE administered with an ablative intent is a promising treatment for solitary, unresectable HCC, and prompted updated BCLC guidelines to include TARE as a treatment for patients with early-stage HCC.[9] Nearly 60% of patients received radiation segmentectomy in the LEGACY study, suggesting the potential therapeutic role of this technique among transplant candidates due to increased localized cytotoxicity and reduced collateral damage. Herein, this single-center study shows that segmental ⁹⁰Y radioembolization is safe and effective in achieving durable radiological response, tumor pathological necrosis, prolonged patient survival, and bridge to transplant for patients with treatment-naïve, unresectable, solitary HCC lesions less than 5 cm.

The ORR for local mRECIST and overall mRECIST at 12 months post-⁹⁰Y radioembolization was 94.3% and 85.7% in the present study, respectively. These results indicate that segmental TARE provided clinically significant local control and were comparable to ORR rates reported in the LEGACY trial and 6-month response rates reported by Lewandowski et al in their evaluation of radiation segmentectomy for early-stage HCC.[9] [15] Long-term responses were observed with a mean local mRECIST TTP of 11.9 months (CI: 2.7–21.0) and non-local mRECIST TTP of 13.2 months (CI: 6.4–20.0). The greatest duration of local control was observed in patients ineligible for transplant who showed a mean TTP of 14.6 months (CI: 8.7–20.5). These results are comparable to the median 13.3 months TTP reported by Salem et al in their posthoc analysis of patients who received radioembolization for HCC.[16] While surmounting evidence for the use of ⁹⁰Y in early-stage (BCLC-0/A) HCC has led to updated BCLC guidelines,[10] similar results observed in this study, in which a majority of patients had a slightly worse performance status indicate clinical utility in more advanced disease as well.

Segmental ⁹⁰Y radioembolization served as a neoadjuvant therapy bridging 37.1% (13/35) patients to surgery, of which 92.5% (12/13) received OLT. With an average transplant wait time of 286 days at the institution in the present study, TARE was useful to ensure eligible patients stayed within Milan transplantation criteria until surgery. Pathologic review of explants exhibited a median necrosis of 98% (IQR 7.5) in regions treated with ⁹⁰Y. Near complete pathologic necrosis noted following treatment indicates the effectiveness of radioembolization on reducing local tumor burden and supports similar explant results reported by Gabr et al and Tohme et al.[17] [18] [19] Survival analysis at 1 year following radioembolization revealed a total OS of 100% for transplant-eligible patients. At 1 year, the remaining 20 patients ineligible for surgery also exhibited a desirable OS of 95% (19/20). Comparable survival outcomes indicate therapeutic benefit of segmental ⁹⁰Y treatment for patients with unresectable, solitary HCC lesions, regardless of eligibility for curative therapy.

The toxicity profile was acceptable in the present study and paralleled previous reports.[9] [16] [17] [19] Among the 14.3% (5/35) patients who experienced an AE following radioembolization, one patient experienced a Grade 4 event involving hypoxia and encephalopathy, while all remaining events classified as Grade 1 included mild fatigue, constipation, and mild right upper quadrant pain. All reported AE resolved within 1 month of the procedure. A well-documented benefit of TARE as a localized therapy for HCC is its improved safety profile compared to chemoembolization, reducing the likelihood of postembolization syndrome and rehospitalization and enabling safe outpatient administration.[20] [21] [22] The limited number of adverse events and the survival benefits observed in this study support existing literature showing selective segmental radioembolization approaches enable higher radiation doses with improved safety profiles.[7]

This study is limited by its single-center retrospective design, lack of randomization, and control arm, and small sample size. Longer follow-up for patients who were treated more recently will be of benefit moving forward to enable more robust survival analysis. Larger, multi-center, prospective studies will enable further identification of clinical correlates predictive of segmental radioembolization response and overall survival to enhance treatment stratification.

In summary, favorable response rates, TTP, OS, and degree of pathologic necrosis observed on the explant indicate that segmental ⁹⁰Y radioembolization effectively treats HCC less than 5 cm and provides durable local tumor control. Segmental TARE is safe and effective as a bridge to curative treatment and a stand-alone therapy for unresectable solitary HCC in patients with ECOG performance status of 0 or 1.

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