Hepatotoxicity following external radiotherapy in patients with hepatocellular carcinoma treated with or without prior yttrium-90 radioembolization.
Authors: Niewiara Claire , Feldkamp Sarah , Nelson Bailey , Wang Kyle , Kharofa Jordan 
Published: January 2025

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Background:
A variety of local therapy options exist to treat Hepatocellular Carcinoma (HCC) including external radiotherapy (EBRT). Prior yttrium-90 (Y90) delivered transarterially is often a contraindication to EBRT in clinical trials and guidelines due to concerns of cumulative hepatotoxicity, though clinical data to suggest higher rates of hepatotoxicity is limited. This study examines hepatotoxicity profiles after EBRT with and without prior Y90 treatment using the ALBI grading system.
Methods:
Patients treated for HCC with EBRT from 2016 to 2024 with sufficient laboratory follow-up were retrospectively reviewed. Patients were classified into three ALBI grades based on ALBI scores: 1 (< -2.6), 2 (-2.6 < x < -1.39), and 3 (> -1.39). The total EBRT dose was defined using the EQD2 method (α/β = 10). The ALBI scores at 3- and 6-months post-EBRT were compared to baseline for patients with or without prior Y90 using paired t-tests. The main RT planning goal was ≥700 cc liver- (tumor volume+ Y90 volume) receiving ≤15 Gy.
Results:
62 patients were treated with EBRT with (n=14) or without (n=48) prior Y90. At 6-months post-EBRT, 11 patients with prior Y90 and 39 patients without prior Y90 had appropriate laboratory follow-up. EBRT dose, technique, and baseline liver function are outlined in Table 1. The median time from Y90 to EBRT was 12.3 months (range 4-61 months). In patients with prior Y90, ALBI scores were similar at 3-mo (mean = -2.4 SD = 0.8, vs mean= -2.4 SD = 0.7, p= 0.60) and 6-mo (mean= -2.3 SD= 0.9, vs mean = -2.4 SD = 0.6, p= 0.653) post-EBRT compared to baseline, respectively. In patients without Y90, ALBI scores were clinically similar at 3-mo (mean = -2.2 SD = 0.7, vs mean= -2.3 SD = 0.6, p= 0.15) and 6-mo (mean= -2.1 SD= 0.8, vs mean = -2.3 SD = 0.7, p=0.021) post-EBRT compared to baseline, respectively. The proportion of patients with an increase in ALBI grade at 3- and 6-mo post-EBRT was similar regardless of prior Y90 treatment. In patients treated with Y90, 14.3% and 36.4% had an increase in ALBI grade at 3- and 6-months, respectively. In those treated without prior Y90, 21.3% and 35.9% had an increase in ALBI grade at 3- and 6-months, respectively.
Conclusions:
Patients with HCC treated with EBRT after Y90 appear to have a similar rate of hepatotoxicity defined by the ALBI grading system compared to patients treated without prior Y90. In well-selected patients, prior Y90 should not be an absolute contraindication for EBRT.

Demographics and ALBI changes post-EBRT.

EBRT alone (n = 48)
EBRT after Y90 (n = 14)

Median Age Years (range)
67.6 (17.9-84.3)
65.6 (55.1-85.2)

Proton, IMRT/SBRT
22 (46%), 26 (54%)
9 (64%), 5 (36%)

Baseline Child Pugh Score (A, B, C)
34 (70.8%), 10 (20.8%), 4 (8.4%)
11 (78.6%), 3 (21.4%), 0 (0%)

Median EBRT EQD2 (range)
82 Gy (44-99)
82 Gy (67-86)

Baseline ALBI Grade (1, 2, 3)
23 (47.9%), 20 (41.7%), 5 (10.4%)
6 (42.9%), 7 (50%), 1 (7.1%)