Pretreatment Levels of Soluble Tumor Necrosis Factor Receptor 1 and Hepatocyte Growth Factor Predict Toxicity and Overall Survival After 90Y Radioembolization: Potential Novel Application of Biomarkers for Personalized Management of Hepatotoxicity

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FIGURE 1.
Example baseline MRI (A) and ⁹⁰Y PET/CT (B) after treatment (3.2 GBq) are shown. Lesion contours (green) were defined on MRI and applied to coregistered PET/CT. Nontumoral liver (red) accounts for 1-cm expansion around lesions to address PET resolution. Dose map (C) and DVH (D) are provided for treatment with MLD 24 Gy and DC90 48 Gy.
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FIGURE 2.
Scatterplots of log-transformed sTNFR1 (A) and HGF (B) vs. ΔALBI. Solid red line represents simple linear fit.
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FIGURE 3.
Kaplan–Meier curves for overall survival stratified by median value of sTNFR1 (A) and HGF (B) with log-rank P value.

TABLE 1.

Summary of Patient Characteristics, Radiation Dose, and Outcomes

Variable	Summary
n	43
Age at ⁹⁰Y (y)	65.0 (37.0–82.0)
Female sex	17 (39.5)
White race	38 (88.4)
Baseline cirrhosis	16 (37.2)
Cancer details	—
Primary	21 (48.8)
HCC	16 (37.2)
Metastatic	22 (51.2)
Treatment history	—
Prior liver-directed therapy	15 (34.9)
Prior systemic therapy	26 (60.0)
Two ⁹⁰Y treatments	14 (32.6)
Baseline liver scores	—
Child–Pugh	—
5	27 (62.8)
6	11 (25.6)
7	1 (2.3)
8	Not applicable
9	1 (2.3)
Unavailable	3 (7.0)
MELD-NA	9.0 (6.4–18.7)
Baseline ALBI	−2.70 (−3.38 to −1.28)
Dose metrics (Gy)	—
Mean dose	50.2 (1.2–132.1)
Mean BED	145.1 (1.3–770.5)
DC10	0.9 (0.0–40.0)
DC90	128.7 (1.7–345.1)
DC700cc	15.7 (0.2–203.1)
Baseline cytokines (pg/mL)	—
sTNFR1	1,736.5 (924.4–5,518.0)
HGF	2,557.7 (1,328.1–6,876.2)
Outcomes	—
Toxicity follow-up (mo)	6.0 (3.0–6.0)
ΔALBI (n = 34)	0.3 (−0.3 to 1.9)
Positive ΔALBI (n = 34)	28 (82.4)
Overall survival follow-up (mo)	10.9 (1.2–41.8)
Number of deaths	25 (58.1)

Continuous factors are summarized as median and range; and categoric factors are summarized as number and percentage.

TABLE 2.

Univariate Linear Models for ΔALBI

Model	Covariate	Coefficient	R²	95% CI LB	95% CI UB	P
1	MLD	0.001	0.004	−0.004	0.006	0.737
2	BED	0.000	0.0001	−0.001	0.001	0.951
3	DC10	0.001	0.0002	−0.017	0.018	0.940
4	DC30	−0.001	0.001	−0.009	0.007	0.866
5	DC90	0.001	0.028	−0.001	0.003	0.348
6	DC700cc	0.001	0.004	−0.002	0.003	0.734
7	DC10 − DC90	−0.001	0.029	−0.003	0.001	0.333
8	(DC10 − DC90)/DC50	0.001	0.013	−0.002	0.005	0.524
9	Log(sTNFR1)	0.477	0.119	0.029	0.925	0.045
10	Log(HGF)	0.572	0.222	0.201	0.944	0.005
11	Pre-⁹⁰Y liver therapies (n)	−0.020	0.002	−0.171	0.130	0.792
12	Cirrhosis	0.195	0.044	−0.122	0.513	0.236
13	Metastatic	−0.082	0.008	−0.400	0.236	0.615
14	Baseline ALBI score	0.014	0.0001	−0.385	0.413	0.947
15	Baseline Child–Pugh = 6	0.077	0.005	−0.307	0.462	0.696
	Baseline Child–Pugh = 7	−0.006		−0.968	0.956	0.990
16	Pre-⁹⁰Y systemic therapies (n)	−0.087	0.042	−0.232	0.058	0.247

TABLE 3.

Multivariable Linear Models for ΔALBI

Model	Covariate	Coefficient	95% CI LB	95% CI UB	P
1	MLD	0.003	−0.002	0.008	0.319
	Log(sTNFR1)	0.622	0.099	1.145	0.027
	Baseline ALBI score	−0.166	−0.583	0.251	0.442
	Prior liver-directed therapy	−0.026	−0.362	0.311	0.883
2	MLD	0.003	−0.001	0.008	0.181
	Log(HGF)	0.709	0.285	1.133	0.003
	Baseline ALBI score	−0.143	−0.514	0.229	0.458
	Prior liver-directed therapy	0.079	−0.246	0.405	0.636
3	DC90	0.002	−0.0004	0.004	0.124
	Log(sTNFR1)	0.628	0.132	1.125	0.019
	Baseline ALBI score	−0.081	−0.493	0.331	0.702
	Prior liver-directed therapy	−0.034	−0.359	0.290	0.837
4	DC90	0.002	−0.00003	0.004	0.064
	Log(HGF)	0.706	0.306	1.106	0.002
	Baseline ALBI score	−0.045	−0.414	0.324	0.813
	Prior liver-directed therapy	0.065	−0.245	0.375	0.686

TABLE 5.

Univariate and Multivariable Cox Proportional Hazards Model Results for Overall Survival

Model	Covariate	HR	95% CI LB	95% CI UB	P	c-index
1	Log(sTNFR1)	12.27	3.54	42.53	<0.001	0.71
2	Log(HGF)	7.48	2.42	23.08	<0.001	0.69
3	MLD (Gy)	0.99	0.98	1.01	0.403	0.58
4	DC90 (Gy)	0.99	0.99	1.00	0.383	0.55
5	Log(sTNFR)	18.76	4.95	71.14	<0.001	0.71
	Metastatic	2.27	0.87	5.93	0.093
	DC90 (Gy)	0.99	0.99	1.00	0.521
6	Log(HGF)	15.32	3.93	59.74	<0.001	0.72
	Metastatic	2.98	1.01	8.81	0.049
	DC90 (Gy)	0.99	0.99	1.00	0.516
7	Log(sTNFR)	19.32	5.12	72.86	<0.001	0.70
	Metastatic	2.36	0.92	6.05	0.075
	MLD (Gy)	0.99	0.98	1.01	0.348
8	Log(HGF)	15.60	4.05	60.14	<0.001	0.72
	Metastatic	3.22	1.05	9.90	0.042
	MLD (Gy)	0.99	0.98	1.01	0.426