Factors associated with increased incidence of severe toxicities following yttrium-90 resin microspheres in the treatment of hepatic malignancies

Table 1 Baseline characteristics

Characteristics	Values1
Patient characteristics (n = 58)
Sex
Female	28 (48.3)
Male	30 (51.7)
Race
White	44 (75.9)
Black	14 (24.1)
Age at primary diagnosis	57.64 ± 10.18 (32-84)
< 65	47 (81.0)
≥ 65	11 (19.0)
Primary diagnosis
Colorectal adenocarcinoma	30 (51.7)
Neuroendocrine	12 (20.7)
Cholangiocarcinoma	5 (8.6)
Other primaries	11 (19.0)
Age at liver diagnosis	58.45 ± 10.43 (32-86)
< 65	44 (75.9)
≥ 65	14 (24.1)
Liver steatosis	7 (12.1)
Number hepatic lesions
< 10	11 (19.0)
≥ 10	47 (81.0)
Prior treatment
None	6 (10.3)
Radiofrequency ablation	6 (10.3)
Surgery	11 (19.0)
TACE	3 (5.2)
EBRT	2 (3.4)
Chemotherapy	52 (89.7)
Number chemo regimens	1.78 ± 1.38 (0-7)
Treatment characteristics (n = 79)
Age at treatment	59.54 ± 10.99 (32-86)
Years from primary diagnosis	2.68 ± 2.79 (0.14-12.88)
Years from liver diagnosis	1.85 ± 1.80 (0.12-8.49)
< 65	53 (67.1)
≥ 65	26 (32.9)
KPS
< 80%	11 (13.9)
≥ 80%	68 (86.1)
Child-Pugh
A	74 (93.7)
B	5 (6.3)
MELD score	7.61 ± 1.49 (6-13)
Max primary index tumor size (mm)	61.03 ± 41.65 (9-223)
Sum primary index tumors (mm)	82.18 ± 49.08 (9-223)
Lobe treated
Right	55 (69.6)
Left	24 (30.4)
BMI (kg/m2)	26.5 ± 4.46 (18.40-36.65)
BSA (m2)	1.89 ± 0.24 (1.46-2.65)
Total liver
Volume (mL)	1927.67 ± 779.16 (1002-6243)
Tumor volume (mL)	336.56 ± 460.83 (5.1-3096)
% Tumor	14.35 ± 11.90 (0.27-49.59)
< 25%	62 (78.5)
≥ 25%	17 (21.5)
Treated liver
Volume (mL)	1124.06 ± 585.45 (346-3946)
Tumor volume (mL)	253.73 ± 435.82 (3-3096)
% Tumor	17.26 ± 16.97 (0.29-78.46)
< 25%	58 (73.4)
≥ 25%	21 (26.6)
Lung shunt (%)	7.11 ± 3.62 (1.3-17.4)
Calculated dose (mCi)	27.5 ± 9.68 (8.2-56.8)
Unadjusted2	47.61 ± 9.51 (22.9-77.7)
Administered dose (mCi)	27.48 ± 9.91 (8.2-56.9)
Unadjusted	47.76 ± 10.64 (10.6-77.8)
Difference in dose (mCi)	-0.02 ± 1.71 (-9.53-3.2)
% Difference	-0.25 ± 8.31 (-53.84-10.46)
Dose to lung (Gy)	3.4 ± 1.77 (0.55-8.41)
Intra-procedural complications
Stasis	10 (12.7)
Reflux

¹Values presented as numbers (percentage) or mean ± SD (range);

²Unadjusted indicates dose prior to being adjusted for lobar treatment. TACE: Transcatheter arterial chemoembolization; EBRT: External beam radiation therapy; KPS: Karnofsky Performance Status; MELD: Model for End-Stage Liver Disease; BMI: Body mass index; BSA: Body Surface Area; mCi: Millicurie; Gy: Gray.

Table 2 Toxicity incidence

Toxicity	n1(%)
Post-embolization syndrome2	11 (12.79)
Constitutional toxicities2	48 (55.81)
Fatigue	41 (47.67)
Loss of appetite	15 (17.44)
Weakness	11 (12.79)
Fever	6 (6.98)
Weight loss	5 (5.81)
Flu-like symptoms	5 (5.81)
Malaise	4 (4.65)
Chills	2 (2.33)
Gastrointestinal toxicities2	47 (55.29)
Abdominal pain	34 (40.00)
Nausea	23 (27.06)
Emesis	10 (11.76)
Constipation	6 (7.06)
Diarrhea	3 (3.53)
Abdominal Cramps	1 (1.18)
Hepatic toxicities2	38 (44.19)
Alkaline phosphatase	27 (34.18)
Albumin	21 (26.58)
Total bilirubin	18 (22.78)
Aspartate aminotransferase	9 (11.39)
INR	3 (4.29)
Encephalopathy	2 (2.33)
Jaundice	2 (2.33)
Ascites	1 (1.16)

¹n for this Table was determined based on the number of the original 104 patients included in our study with clinical or laboratory follow-up. There were 86 patients with clinical follow-up but only 79 patients with laboratory follow-up, 9 of whom did not have post-treatment INR values obtained;

²High incidence of toxicity. INR: International normalized ratio.

Table 3 Severe toxicity incidence

Severe toxicities	Our patients		Time to toxicity development			Literature
	n	%	mean ± SD	range	Number of resolved1
Any	17	21.5				7%-38%[7,9,39]
INR	1	1.4	25.00 ± 0.00		0	1.3%-1.8%[20,27]
Albumin	10	12.7	97.80 ± 40.59	(35-174)		0%-2%[9,27,40]
AST	2	2.5	98.00 ± 19.80	(84-112)	0	0%-8%[7,9,20,22,23,27,40]
ALT	0	0.0
ALP	14	17.7	86.46 ± 58.37	(3-182)	5	0.5%-20%[7,9,20,23,40]
Total bilirubin	8	10.1	80.75 ± 51.63	(14-182)	1	0%-27%[7,9,20,22,23,27,40]

¹Toxicities were considered irreversible if values remained grade ≥ 3 until last recorded measurement. INR: International normalized ratio; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase.

Table 4 Multivariate analyses of severe toxicities

Toxicity	Factor	Univariate		Multivariate
		P value	OR	P value	OR	95%CI
Any
	Pre-treatment albumin	0.001	33.600	0.010	26.166	2.194-312.072
	Pre-treatment INR	0.016	9.231	0.048	17.743	1.027-306.461
	Colorectal adenocarcinoma	0.022	4.213	0.070	4.527	0.885-23.155
	Pre-treatment ALP	0.018	12.343	0.187	4.770	0.468-48.651
	Pre-treatment total bilirubin	0.031	13.071	0.327	33.100	0.030-36243.627
	Pre-treatment hemoglobin	0.047	3.467	0.449	1.881	0.366-9.674
	MELD score	0.068	1.364	Excluded1
	Pre-treatment AST	0.032	3.552	Excluded1
Albumin
	Pre-treatment hemoglobin	0.040	9.265	0.025	12.492	1.349-114.011
	Pre-treatment AST	0.039	5.517	0.025	7.404	1.283-42.714
	Pre-treatment total bilirubin	0.047	8.375	0.355	3.349	0.259-43.374
Total bilirubin
	MELD score	0.020	1.625	0.033	1.830	1.050-3.187
	Pre-treatment albumin	0.035	10.138	0.056	9.042	0.941-86.840
	Administered dose	0.099	0.933	0.117	0.922	0.833-1.020
	Pre-treatment INR	0.075	5.583	0.658	1.694	0.165-17.429
	Pre-treatment total bilirubin	0.025	11.500	Excluded1
ALP
	Colorectal adenocarcinoma	0.030	4.552	0.043	5.362	1.058-27.185
	Pre-treatment ALP	0.037	9.237	0.070	15.615	0.803-303.636
	Pre-treatment hemoglobin	0.019	6.581	0.084	4.886	0.809-29.519
	KPS	0.067	0.953	0.150	0.947	0.879-1.020
	Pre-treatment INR	0.049	5.636	0.189	4.903	0.456-52.716
	KPS < 80 vs KPS ≥ 80	0.093	3.314	Excluded1
	Pre-treatment AST	0.050	3.519	Excluded1

¹Variables marked as Excluded were excluded from multivariate analysis due to interdependence. INR: International normalized ratio; ALP: Alkaline phosphatase; MELD: Model for end-stage liver disease; AST: Aspartate aminotransferase; KPS: Karnofsky performance score.