Yttrium-90 radioembolization of unresectable hepatocellular carcinoma – a single center experience

Figures & data

Table 1 Patient baseline characteristics and procedural data

	Overall	BCLC-A	BCLC-B	BCLC-C
Patients	115	7	39	69
Gender (%)
Female	29 (25.2)	1 (14.3)	11 (28.2)	17 (24.6)
Male	86 (74.8)	6 (85.7)	28 (71.8)	52 (75.4)
Mean age, (years; range)	69.3±10.6 (34.8–90.0)	72.7±12.1 (54.2–86.4)	69.4±10.7 (40.5–82.3)	68.8±10.6 (34.8–90.0)
Time between first diagnosis of	14.9±26.0	26.4±34.2	17.3±35.4	12.0±16.3
HCC and RE (months) (n=99)	(0.3–198.4)	(1.9–101.5)	(0.8–198.4)	(0.3–84.1)
ECOG status (n=84) (%)
0	38 (45.2)	4 (80)	19 (61.3)	15 (31.3)
1	30 (35.7)	0 (0)	7 (22.6)	23 (47.9)
2	16 (19.1)	1 (20)	5 (16.1)	10 (20.8)
Estimated relative liver tumor burden (n=113)
<25%	53 (46.9)	6 (100)	23 (59.0)	24 (35.3)
25%–50%	50 (44.2)	0 (0)	14 (35.9)	36 (52.9)
>50%	10 (8.9)	0 (0)	2 (5.1)	8 (11.8)
Pattern of tumor manifestation (%)
Solitary	18 (15.7)	4 (57.1)	6 (15.4)	8 (11.6)
Oligofocal	19 (16.5)	3 (42.9)	7 (17.9)	9 (13.0)
Multifocal	72 (62.6)	0 (0)	26 (66.7)	46 (66.7)
Diffuse	6 (5.2)	0 (0)	0 (0)	6 (8.7)
Distribution of metastases (%)
Unilobar right	28 (24.4)	5 (71.4)	7 (18.0)	14 (20.3)
Unilobar left	9 (7.8)	0 (0)	5 (12.8)	4 (5.8)
Bilobar	78 (67.8)	2 (28.6)	27 (69.2)	51 (73.9)
Liver cirrhosis (%)
Yes	86 (74.8)	6 (85.7)	31 (79.5)	49 (71.0)
No	29 (25.2)	1 (14.3)	8 (20.5)	20 (29.0)
Cause of cirrhosis (n=86) (%)
Hepatitis	37 (43.0)	2 (40)	10 (32.3)	25 (50)
Alcohol	49 (57.0)	3 (60)	21 (67.7)	25 (50)
Child–Pugh-status (%)
A	104 (90.4)	7 (100)	39 (100)	58 (84.1)
B	11 (9.6)	0 (0)	0 (0)	11 (15.9)
BCLC (%)
A	7 (6.1)
B	39 (33.9)
C	69 (60.0)
Mean MELD score	8.4±2.4 (5–20)	6.9±2.0 (5–10)	7.9±2.1 (5–13)	9.1±2.5 (6–20)
Ascites prior to RE (n=112) (%)
No	86 (76.8)	6 (100)	34 (89.5)	46 (67.7)
Minimal	23 (20.5)	0 (0)	4 (10.5)	19 (27.9)
Extensive	3 (2.7)	0 (0)	0 (0)	3 (4.4)
Extrahepatic disease (%)
Overall	43 (37.4)	0 (0)	0 (0)	43 (62.3)
Nodal	28 (24.3)	0 (0)	0 (0)	28 (40.6)
Pulmonary	13 (11.3)	0 (0)	0 (0)	13 (18.8)
Osseous	7 (6.1)	0 (0)	0 (0)	7 (10.1)
Brain	0 (0)	0 (0)	0 (0)	0 (0)
Others	8 (2 cutaneous, 2 peritoneal, 2 adrenal, 1 pancreatic, 1 diaphragm infiltration)	0 (0)	0 (0)	8 (11.6)
Vascular invasion (%)
Overall	29 (25.2)	0 (0)	0 (0)	29 (42.0)
Portal vein	26 (22.6)	0 (0)	0 (0)	26 (37.7)
Hepatic vein	2 (1.7)	0 (0)	0 (0)	2 (2.9)
Both	1 (0.9)	0 (0)	0 (0)	1 (1.4)
Previous liver resection (%)
Overall	21 (18.3)	3 (42.9)	8 (20.5)	10 (14.5)
Atypical	7 (6.1)	1 (14.3)	2 (5.1)	4 (5.8)
Segmental	8 (7.0)	0 (0)	4 (10.3)	4 (5.8)
Left hemihepatectomy	2 (1.7)	0 (0)	1 (5.1)	1 (1.4)
Right hemihepatectomy	4 (3.5)	2 (28.6)	1 (5.1)	1 (1.4)
Previous application of sorafenib (n=113) (%)
Yes	24 (21.2)	1 (14.3)	7 (17.9)	16 (23.9)
No	89 (78.8)	6 (85.7)	32 (82.1)	51 (76.1)
Previous TACE (%)
Overall	31 (27.0)	2 (28.6)	15 (38.5)	14 (20.3)
1×	14 (12.2)	1 (14.3)	8 (20.5)	5 (7.3)
2×	3 (2.6)	0 (0)	2 (5.1)	1 (1.4)
>2×	14 (12.2)	1 (14.3)	5 (12.8)	8 (11.6)
No	84 (73.0)	5 (71.4)	24 (61.5)	55 (79.7)
Mean baseline bilirubin (mg/dL) (n=111)	1.0±0.6 (0.10–3.6)	0.8±0.5 (0.3–1.6)	0.8±0.4 (0.1–1.4)	1.1±0.7 (0.3–3.6)
Mean baseline ALT (U/L) (n=112)	57.4±47.2 (12–325)	58.3±42.4 (20–140)	42.1±26.7 (13–126)	65.3±54.1 (12–325)
Mean baseline AST (U/L) (n=111)	88.6±79.5 (15–440)	112.4±150.0 (23–440)	57.9±41.8 (15–257)	102.5±81.7 (18–372)
Mean baseline GGT (U/L) (n=111)	349.0±608.7 (35–6,188)	132.7±87.5 (46–274)	301.4±276.6 (37–1,189)	396.4±747.9 (35–6,188)
Mean baseline albumin (mg/dL) (n=90)	34.81±5.41 (20.70–47.00)	37.6±6.0 (31.1–47.1)	37.5±4.9 (20.7–44.5)	33.3±5.1 (21.9–45.2)
Mean intended Y90 activity (resin [n=117]/glass [n=39]) (GBq)	1.69±0.74/2.03±0.95	1.43±0.78/2.00±0.0	1.57±0.80/2.22±1.29	1.80±0.67/1.95±0.83
Mean administered Y90 activity (resin [n=117]/glass [n=38]) (GBq)	1.64±0.76/2.03±0.95	1.43±0.48/2.00±0.0	1.52±0.81/2.22±1.29	1.75±0.72/1.95±0.83
Single session whole liver (resin [n=117]/glass [n=38]) (GBq)	1.2±0.55/3.00±0.99
Unilobar (resin [n=117]/glass [n=38]) (GBq)	1.81±0.69/1.95±0.72
Sequential bilobar (per lobe) (resin [n=117]/glass [n=38]) (GBq)	1.62±0.89/2.13±1.35
Repeated RE (resin [n=117]/glass [n=38]) (GBq)	1.42±0.77/1.84±0.89
Device of primary RE (%)
Resin	87 (75.7)	6 (85.7)	32 (82.1)	49 (71.0)
Glass	28 (24.3)	1 (14.3)	7 (17.9)	20 (29.0)
Early stasis in resin-based RE	13 (14.9)	0 (0)	6 (18.8)	7 (14.3)
Vessel embolization (%)
No	49 (42.6)	4 (57.1)	16 (41.0)	29 (42.0)
GDA	37 (32.2)	3 (42.9)	12 (30.8)	22 (31.9)
GDX	4 (3.5)	0 (0)	2 (5.1)	2 (2.9)
GDA + GDX	25 (21.7)	0 (0)	9 (23.1)	16 (23.2)
TIPS (%)
Yes	4 (3.5)	0 (0)	2 (5.1)	2 (2.9)
No	111 (96.5)	0 (0)	37 (94.9)	67 (97.1)
Mean pulmonary shunt fraction (range) (n=75)	5.7±5.6 (0.1–35.0)	3.7±4.7 (0.8–13.0)	6.5±7.2 (1.0–35.0)	5.5±4.6 (0.1–21.3)
Extrahepatic progression after RE (%)
Yes	11 (9.6)	1 (14.3)	2 (5.1)	8 (11.6)
No	104 (90.4)	6 (85.7)	37 (94.9)	61 (88.4)

Abbreviations: ALT, alanine-aminotransferase; AST, aspartate-aminotransferase; BCLC, Barcelona Clinic Liver Cancer; ECOG, Eastern Co-operative Oncology Group; GDA, gastroduodenal artery; GDX, right gastric artery; GGT, gamma glutamyl transferase; HCC, hepatocellular carcinoma; MELD, model for end-stage liver disease; RE, radioembolization; TACE, transarterial chemoembolization; TIPS, transjugular intrahepatic portosystemic shunt.

Table 2 Laboratory and clinical toxicities according to CTCAE v. 4.0

Parameter	Whole liver RE						Sequential lobar RE*						Unilobar RE
	Toxicity grade						Toxicity grade						Toxicity grade
	N	0	1	2	3	4	N	0	1	2	3	4	N	0	1	2	3	4
Bilirubin
Baseline	18	13	3	2	0	0	18	8	6	4	0	0	72	41	17	11	3	0
1 week	14	9	1	4	0	0	15	9	4	0	2	0	66	39	14	11	2	0
1 month	8	5	1	1	1	0	11	5	0	3	3	0	41	30	4	3	4	0
3 months	10	6	2	0	2	0	11	3	2	3	2	1	36	17	8	9	1	1
ALT
Baseline	18	6	9	1	2	0	19	2	13	3	0	0	73	30	35	7	1	0
1 week	14	4	7	2	1	0	15	0	11	4	0	0	68	20	38	4	6	0
1 month	8	5	2	1	0	0	13	2	9	1	1	0	42	19	19	2	2	0
3 months	10	7	2	1	0	0	11	1	8	2	0	0	37	15	15	3	4	0
AST
Baseline	18	4	8	4	2	0	19	1	11	4	3	0	72	14	40	12	6	0
1 week	14	3	7	2	2	0	15	1	8	5	1	0	67	10	32	11	13	1
1 month	6	3	3	0	0	0	10	0	9	1	0	0	39	9	24	3	3	0
3 months	8	2	4	1	0	1	9	1	3	3	2	0	31	4	18	3	6	0
GGT
Baseline	18	0	3	4	10	1	19	0	1	15	3	0	72	2	12	20	34	4
1 week	14	0	2	5	7	0	15	0	1	11	3	0	68	0	12	20	34	2
1 month	9	0	2	3	4	0	11	0	2	8	1	0	42	0	9	12	20	1
3 months	9	0	2	3	4	0	10	0	1	8	1	0	36	0	5	6	23	2
Ascites
Baseline	18	14	3	1	0	0	19	14	5	0	0	0	73	54	17	2	0	0
After RE	17	6	8	3	0	0	17	2	12	3	0	0	66	36	23	7	0	0

Note:

* After completed whole liver treatment.

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTCAE, common terminology criteria for adverse events; GGT, gamma glutamyl transferase; RE, radioembolization.

Table 3 Increase in laboratory toxicity levels after radioembolization (according to CTCAE v. 4.0)

	Whole liver RE			Sequential lobar RE*			Unilobar RE
	No increase	Temporary increase	Permanent increase	No increase	Temporary increase	Permanent increase	No increase	Temporary increase	Permanent increase
Bilirubin (%)	10 (58.8)	2 (11.8)	5 (29.4)	6 (33.3)	1 (5.6)	11 (61.1)	49 (68.0)	2 (2.8)	21 (29.2)
ALT (%)	13 (76.5)	0	4 (23.5)	15 (83.3)	2 (11.1)	1 (5.6)	49 (67.1)	4 (5.5)	20 (27.4)
AST (%)	12 (70.6)	2 (11.8)	3 (17.6)	12 (66.7)	2 (11.1)	4 (22.2)	44 (61.1)	6 (8.3)	22 (30.6)
GGT (%)	14 (82.3)	1 (5.9)	2 (11.8)	16 (88.9)	0	2 (11.1)	54 (74.0)	1 (1.4)	18 (24.61)

Note:

* Increasing values are categorized as “permanent” if persisting at the last available follow-up.

Abbreviations: ALT, alanine aminotransferase; AST, aspartate-aminotransferase; CTCAE, common terminology criteria for adverse events; GGT, gamma glutamyl transferase; RE, radioembolization.

Table 4 Best imaging response to radioembolization in patients with available imaging follow-up according to mRECIST-criteria on a per-patient basis after completion of a RE-cycle

	Treated liver area	Liver overall
Overall (%)
Number of patients	90	90
CR	8 (8.9)	6 (6.7)
PR	31 (34.4)	26 (28.9)
SD	36 (40.0)	37 (41.1)
PD	15 (16.7)	21 (23.3)
Unilobar (%)
Number of patients	60	60
CR	6 (10.0)	4 (6.7)
PR	18 (30.0)	13 (21.7)
SD	28 (46.7)	29 (48.3)
PD	8 (13.3)	14 (23.3)
Whole liver single session (%)
Number of patients	14
CR	7 (50)
PR	3 (21.4)
SD	4 (28.6)
PD	0 (0)
Whole liver sequential (%)
Number of patients	16
CR	2 (12.5)
PR	6 (37.5)
SD	5 (31.3)
PD	3 (18.7)
Repeated RE (%)
Number of patients	16	16
CR	0 (0)	0 (0)
PR	5 (31.3)	2 (12.5)
SD	6 (37.5)	9 (56.3)
PD	5 (31.3)	5 (31.3)

Abbreviations: CR, complete response; mRECIST, modified response evaluation criteria in solid tumors; PD, progressive disease; PR, partial response; RE, radioembolization; SD, stable disease.

Figure 1 Kaplan–Meier curves.

Notes: (A) OS by ECOG status (broken line: ECOG >0, continuous line: ECOG 0); (B) OS by estimated relative liver tumor burden (broken line: ≥25% of liver volume, continuous line: <25%); (C) OS by previous surgical liver tumor resection (broken line: no resection, continuous line: previous resection); (D) OS by presence of ascites prior to RE (dark gray dashed line: extensive ascites, light gray broken line: minimal ascites continuous line: no ascites).
Abbreviations: ECOG, Eastern Co-operative Oncology Group; OS, overall survival; RE, radioembolization.

Table 5 Results of univariate analysis of overall survival after first radioembolization

Parameter	Overall		BCLC-B		BCLC-C
	Median survival (months) (95% CI)	Univariate p-value	Median survival (months) (95% CI)	Univariate p-value	Median survival (months) (95% CI)	Univariate p-value
Gender
Female	7.7 (5.8; 9.7)	0.710	9.2 (1.2; 172)	0.508	4.3 (2.8; 5.8)	0.828
Male	8.4 (6.5; 10.3)		13.4 (7.2; 19.7)		6.5 (3.6; 9.3)
Mean age (range) (at time of RE)		0.325		0.944		0.022
Time between first diagnosis of HCC and RE (n=99)		0.210		0.643		0.748
ECOG status (n=84)
0	13.6 (7.5; 19.7)	0.004	9.0 (0; 19.8)	0.935	12.3 (3.0; 21.5)	0.103
≥1	6.5 (4.2; 8.7)		9.8 (5.8; 13.8)		6.0 (3.9; 8.1)
Estimated relative liver tumour burden
≤25%	13.1 (8.0; 18.2)	0.0002	14.2 (8.2; 20.3)	0.532	10.3 (1.5; 13.2)	0.014
>25%	6.5 (4.6; 8.3)		8.2 (6.8; 11.2)		4.9 (3.1; 6.6)
Pattern of tumour manifestation
Solitary	9.0 (0; 25.5)	0.187	13.6 (4.9; 22.4)	0.643	3.9 (2.2; 5.6)	0.790
Oligofocal	13.1 (7.4; 15.5)		11.5 (1.9; 21.0)		13.1 (5.9; 20.3)
Multifocal	8.0 (6.7; 9.4)		9.8 (0.7; 18.9)		6.1 (2.6; 9.6)
Diffuse	4.2 (0; 14.1)				4.2 (0; 14.1)
Distribution of metastases
Unilobar right	13.1 (7.5; 18.7)	0.127	16.2 (13.2; 19.3)	0.928	4.9 (0; 14.6)	0.704
Unilobar left	5.7 (2.0; 9.4)		57 (4.8; 6.6)		8.0 (0; 16.5)
Bilobar	8.1 (6.5; 9.6)		9.2 (3.2; 15.2)		6.0 (3.1; 8.8)
Liver cirrhosis
Yes	8.1 (6.1; 10.1)	0.357	36.3 (0; 59.8)	0.085	8.0 (2.8; 13.2)	0.991
No	9.0 (7.4; 10.5)		9.8 (3.3; 16.3)		6.0 (3.9; 8.1)
Cause of cirrhosis
Hepatitis	8.4 (6.9; 9.8)	0.682	13.6 (0.7; 26.6)	0.816	8.0 (6.5; 9.4)	0.258
Alcohol	6.2 (4.6; 7.7)		9.8 (0; 19.6)		3.1 (1.2; 5.0)
Child–Pugh status
A	8.4 (7.2; 9.6)	0.110			7.1 (4.5; 9.6)	0.003
B	1.7 (1.3; 2.1)				1.5 (1.1; 1.9)
BCLC
A	52.8 (0; 109.7)	0.0005
B	12.4 (4.9; 18.0)
C	6.1 (3.2; 9.0)
Mean MELD score		<0.0001		0.498		0.005
Ascites prior to RE
No	9.2 (7.2; 11.2)	<0.0001	11.5 (6.2; 16.7)	0.876	8.4 (6.7; 10.1)	0.004
Minimal	6.0 (4.2; 7.8)		16.2		4.5 (2.3; 6.7)
Extensive	2.1 (1.4; 2.7)				2.1 (1.4; 2.7)
Extrahepatic disease
Yes	9.0 (6.6; 11.4)	0.772			7.1 (4.2; 10.0)	0.111
No	7.7 (5.4; 10.0)				3.6 (0; 7.4)
Vascular invasion
Yes	6.0 (1.6; 10.4)	0.058			6 (1.6; 10.4)	0.659
No	8.4 (7.1; 9.6)				4.3 (0.8; 7.7)
Previous liver resection
Yes	13.6 (7.3; 20.0)	0.012	13.6 (3.8; 23.5)	0.606	8.4 (3.9; 8.0)	0.033
No	7.7 (6.1; 6.9)		11.5 (3.6; 19.3)		6.0 (3.9; 8.0)
Previous application of sorafenib
Yes	12.3 (7.4; 17.1)	0.122	13.4 (7.2; 19.7)	0.929	8.4 (2.7; 14.1)	0.040
No	8.1 (6.2; 10.0)		9.8 (2.7; 16.9)		5.2 (2.9; 7.5)
Previous TACE
Yes	8.4 (6.1; 10.7)	0.939	9.8 (5.7; 13.9)	0.435	6.0 (3.7; 8.3)	0.930
No	8.2 (7.4; 9.1)		15.5 (5.8; 25.2)		6.5 (2.8; 9.8)
Baseline bilirubin toxicity grade
0	10.6 (7.2; 14.0)	0.001	13.6 (9.1; 18.1)	0.502	8.4 (6.9; 9.9)	0.022
≥1	4.5 (2.6; 6.4)		5.7 (4.6; 6.8)		3.6 (1.5; 5.7)
Baseline ALT toxicity grade
0	9.3 (4,5; 14.0)	0.201	15.5 (8.4; 22.6)	0.071	8.0 (5.0; 10.9)	0.942
≥1	4.5 (4.9; 10.0)		9.0 (6.6; 11.3)		4.9 (1.9; 7.9)
Baseline AST toxicity grade
0	18.9 (13.8; 24.0)	0.002	21.2 (8.2; 34.2)	0.124	12.3 (9.2; 15.4)	0.129
≥1	7.5 (5.5; 9.4)		9.2 (6.8; 1.6)		5.2 (3.4; 7.0)
Baseline GGT toxicity grade
≤1	18.9 (6.9; 30.9)	0.001	15.5 (10.7; 20.3)	0.451	18.9 (0.2; 37.6)	0.033
>1	7.7 (6.0; 9.5)		9.2 (5.4; 13.0)		6.0 (3.9; 8.0)
Mean radioembolization activity (n =156)
Administered		0.111		0.290		0.264
Device of primary RE
Resin	8.3 (6.9; 9.6)	0.303	9.8 (2.7; 16.9)	0.348	6.0 (3.7; 8.3)	0.580
Glass	9.9 (5.6; 14.2)		11.5 (2.7; 20.3)		8.0 (0.4; 15.5)
TIPS
Yes	5.7 (0; 16.9)	0.710	11.5 (5.1; 17.8)	0.724	6.1 (3.3; 8.9)	0.985
No	8.4 (7.0; 9.7)		5.7		2.7
Extrahepatic progression after RE
Yes	8.4 (7.1; 9.7)	0.140	4.6	0.699	4.3 (1.7; 6.9)	0.234
No	6.1 (1.8; 10.4)		11.5 (5.1; 17.8)		6.5 (3.5; 9.4)
Best overall hepatic response
CR	18.9 (0; 61.7)	0.002		0.188	18.9 (18.4; 19.4)	0.131
PR	14.2 (8.8; 19.6)		16.2 (8.0; 24.4)		8.4 (0; 17.1)
SD	7.7 (6.3; 9.1)		7.7 (5.8; 9.7)		7.1 (3.7; 10.5)
PD	8.3 (4.9; 11.7)		15.5 (0; 34.8)		6.1 (0.1; 12.1)
Time to progression, treated area		0.005		0.628		0.104
Time to progression, non-treated area		0.096				0.243
Repeated RE
Yes	16.2 (3.8; 28.7)	0.033	11.5 (0; 23.6)	0.697	17.1 (2.5; 31.8)	0.002
No	7.4 (5.5; 9.4)		9.8 (4.0; 15.6)		5.2 (3.4; 7.0)

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BCLC, Barcelona Clinic Liver Cancer; CR, complete response; ECOG, Eastern Cooperative Oncology Group; GGT, gamma glutamyl transferase; HCC, hepatocellular carcinoma; MELD, model for end-stage liver disease; PD, progressive disease; PR, partial response; RE, radioembolization; SD, stable disease; TACE, transarterial chemoembolization; TIPS, transjugular intrahepatic portosystemic shunt.