Adjuvant heparanase inhibitor PI-88 therapy for hepatocellular carcinoma recurrence

Table 1 Intent-to-treat patient demographics and baseline characteristic in the follow-up study n (%)

	Group A untreated (n = 50)1	Group B 160 mg/d (n = 48)	Group C 250 mg/d (n = 45)	Overall (n = 143)	P-value2
Age (yr)
mean ± SD	55.9 ± 12.2	52.3 ± 12.6	54.3 ± 11.9	54.2 ± 12.2	0.3565
Age group (yr)
Age < 65	36 (72.0)	38 (79.2)	37 (82.2)	111 (77.6)	0.4667
Age ≥ 65	14 (28.0)	10 (20.8)	8 (17.8)	32 (22.4)
Sex
Female	13 (26.0)	10 (20.8)	9 (20.0)	32 (22.4)	0.7445
Male	37 (74.0)	38 (79.2)	36 (80.0)	111 (77.6)
Alcohol use
Never or rarely	43 (86)	35 (72.9)	36 (80.0)	114 (79.7)	0.7547
Monthly	1 (2.0)	1 (2.1)	1 (2.2)	3 (2.1)
Weekly	2 (4.0)	6 (12.5)	3 (6.7)	11 (7.7)
Daily	4 (8.0)	6 (12.5)	5 (11.1)	15 (10.5)
Clip stage
0	30 (60.0)	25 (52.1)	26 (57.8)	81 (56.6)	0.6169
1	13 (26.0)	12 (25.0)	10 (22.2)	35 (24.5)
2	4 (8.0)	6 (12.5)	7 (15.6)	17 (11.9)
3	1 (2.0)	5 (10.4)	2 (4.4)	8 (5.6)
4	2 (4.0)	0	0	2 (1.4)
Ecog performance status score
0	42 (84.0)	40 (83.3)	40 (88.9)	122 (85.3)	0.6496
1	7 (14.0)	8 (16.7)	5 (11.1)	20 (14.0)
2	1 (2.0)	0	0	1 (0.7)
Child-Pugh score
5/6	48 (96.0)	46 (95.8)	43 (95.6)	137 (95.8)	0.6702
7	1 (2.0)	2 (4.2)	2 (4.4)	5 (3.5)
8	1 (2.0)	0	0	1 (0.7)
New York Heart Association classification of functional capacity class activity
Class I	48 (96.0)	47 (97.9)	44 (97.8)	139 (97.2)	0.8144
Class II	2 (4.0)	1 (2.1)	1 (2.2)	4 (2.8)
Differentiation of tumor
Well differentiated	2 (4.0)	7 (14.6)	4 (8.9)	13 (9.1)	0.2487
Moderately differentiated	34 (68.0)	23 (47.9)	26 (57.8)	83 (58.0)
Poorly differentiated or anaplasia	14 (28.0)	18 (37.5)	15 (33.3)	47 (32.9)
Liver cirrhosis
Absence	19 (38.0)	20 (41.7)	12 (26.7)	51 (35.7)	0.6023
Presence	28 (56.0)	24 (50.0)	29 (64.4)	81 (56.6)
Not assessed	3 (6.0)	4 (8.3)	4 (8.9)	11 (7.7)
Hepatitis activity
Absence	7 (14.0)	4 (8.3)	5 (11.1)	16 (11.2)	0.8234
Presence	34 (68.0)	35 (72.9)	29 (64.4)	98 (68.5)
Not assessed	9 (18.0)	9 (18.8)	11 (24.4)	29 (20.3)
Vein invasion (microscopic)
Absence	42 (84.0)	36 (75.0)	36 (80.0)	114 (79.7)	0.7375
Presence	8 (16.0)	11 (22.9)	8 (17.8)	27 (18.9)
Not assessed	0 (0)	1 (2.1)	1 (2.2)	2 (1.4)
Macro vascular invasion
Absence	47 (94.0)	42 (87.5)	42 (93.3)	131 (91.6)	0.4493
Presence	3 (6.0)	6 (12.5)	3 (6.7)	12 (8.4)

¹Includes 1 patient who withdrew consent during follow-up study;

²P-value on Age is by using analyses of variance, on CLIP stage by using Cochran-Mantel-Haenszel modified ridit scores for mean scores difference, on others by using χ² test. Differences in patient demographics and baseline characteristics were not statistically significant.

Table 2 Other treatment or medication for recurrent hepatocellular carcinoma during the 156 wk follow-up period n (%)

Anti-HCC therapy	Group A untreated (n = 58)	Group B 160 mg/d (n = 56)	Group C 250 mg/d (n = 54)	Total (n = 168)
At least one shown below	22 (37.9)	17 (30.4)	22 (40.7)	61 (36.3)
Chemotherapy	3 (5.2)	4 (7.1)	4 (7.4)	11 (6.5)
Percutaneous ethanol injection therapy	2 (3.4)	3 (5.4)	3 (5.6)	8 (4.8)
Radiofrequency ablation	2 (3.4)	3 (5.4)	3 (5.6)	8 (4.8)
Radiotherapy	3 (5.2)	1 (1.8)	1 (1.9)	5 (3.0)
Surgical resection	5 (8.6)	5 (8.9)	7 (13.0)	17 (10.1)
Transcatheter arterial chemoembolization	18 (31.0)	11 (19.6)	15 (27.8)	44 (26.2)
Thalidomide	2 (3.4)	1 (1.8)	1 (1.9)	4 (2.4)
Liver transplantation	0 (0.0)	1 (1.8)	1 (1.9)	2 (1.2)
Sorafenib	1 (1.7)	1 (1.8)	1 (1.9)	3 (1.8)
New clinical trial	3 (5.1)	1 (1.8)	6 (11.3)	10 (6.0)

HCC: Hepatocellular carcinoma.

Table 3 Adverse events (with > 5% incidence) possibly related to treatment observed at the end of the phase II study and in the follow-up study n (%)

Timeline	Week-48	Week-60	Week-102	Week-156
	End of phase II study	3 mo into follow-up study	1 yr into follow-up study	End of follow-up study
MedDRA system
Blood and lymphatic system disorders: Thrombocytopenia
Group B: 160 mg/d	2 (4.2)	2 (4.2)	2 (4.2)	0 (0.0)
Group C: 250 mg/d	3 (6.7)	3 (6.7)	3 (6.7)	3 (6.7)
P-value1	0.671	0.671	0.671	0.109
Investigations; elevated ALT/elevated AST
Group B: 160 mg/d	2 (4.2)/3 (6.3)	2 (4.2)/3 (6.3)	2 (4.2)/1 (2.1)	1 (2.1)/0 (0.0)
Group C: 250 mg/d	7 (15.6)/7 (15.6)	7 (15.6)/7 (15.6)	2 (4.4)/1 (2.2)	1 (2.2)/1 (2.2)
P-value1	0.0843/0.1893	0.0843/0.1893	1.0000/1.0000	1.0000/0.4839

¹Fisher’s exact test. Treatment-related adverse events that were observed only in the phase II study are excluded. All adverse events in the 160 mg/d treatment group reverted to baseline levels by the end of the follow-up study. Adverse events were more frequently observed in the 250 mg/d treatment group. ALT: Alanine aminotransferase; AST: Aspartate aminotransferase.

Table 4 Rate of compliance¹ categoried by drop-out status n (%)

Drop-out status	Group B 160 mg/d (n = 56)	Group C 250 mg/d (n = 54)	P-value2
Drop-outs without recurrence	5	11	0.214
< 80% compliance	3 (60.0)	10 (90.9)
≥ 80% compliance	2 (40.0)	1 (9.1)
Non-withdrawal subjects	51	43	0.171
< 80% compliance	11 (21.6)	15 (34.9)
≥ 80% compliance	40 (78.4)	28 (65.1)

¹≥ 80% compliance denotes received ≥ 80% of required doses (12 doses/cycle × 9 cycles × 80);

²Fisher’s exact test.

Table 5 Summary of time-to-recurrence, disease-free survival probability, and overall survival results from the follow-up study n (%)

Probability	Phase II study		3-yr study
	Week-48		Week-156
	Group A untreated	Group B 160 mg/d	Group A untreated	Group B 160 mg/d
TTR probability1	45.9%	29.8%	61.5%	48.1%
Difference		-16.1%		-13.4%
95%CI		-33.6-1.5		-31.5-4.7
Rate of improvement2		35.1%		21.8%
P value3		0.086		0.187
DFS probability4	54.1%	68.4%	38.5%	49.4%
Difference		14.3%		10.8%
95%CI		-3.4-32.0		-7.3-29.0
Rate of improvement		26.4%		28.1%
P value		0.129		0.257
OS probability	90.9%	88.6%	81.0%	82.8%
Difference		-2.3%		1.7%
95%CI		-13.4-8.8		-12.4-15.9
Rate of improvement		-2.5%		2.2%
P value		0.760		1.000

^1,4Values from Figure 2 respectively;

²Percent change in endpoint probability of treated group from untreated control;

³Fisher’s exact test. Although not statistically significant, time-to-recurrence (TTR) and disease-free survival (DFS) probabilities and rates of improvements in the 160 mg/d group indicate substantial clinical advantages. Similarities in the two rates of DFS improvement indicate that the clinical benefits of 36 wk of treatment with 160 mg/d PI-88 persisted for up to 3 years. Despite the clinical survival benefits indicated by DFS, overall survival (OS) benefits were inconclusive.

Table 6 Subgroup analyses comparing disease-free survival probabilities of the 160 mg/d group to their respective controls in the phase II and follow-up studies

Subgroup analyses	Phase II study		3-yr study
	Week 48		Week 156
	Group A untreated	Group B 160 mg/d	Group A untreated	Group B 160 mg/d
Study cohort
DFS probability	54.1%	68.4%	38.5%	49.4%
Difference		14.3%		10.8%
95%CI		-3.4-32.0		-7.3-29.0
Rate of improvement1		26.4%		28.1%
P value2		0.129		0.257
Intermediate-risk group (multiple or single tumor ≥ 2 cm)
DFS probability	45.1%	63.8%	33.0%	48.4%
Difference		18.7%		15.4%
95%CI		-0.8-38.2		-3.9-34.7
Rate of improvement		41.5%		46.6%
P value		0.104		0.150
High-risk group (multiple or single tumor ≥ 2 cm and positive HBV/HCV infection)3
DFS probability	41.4%	64.9%	29.6%	46.4%
Difference		23.5%		16.8%
95%CI		2.0-45.0		-4.4-38.1
Rate of improvement		56.8%		56.8%
P value		0.045		0.163

^1,2 Table 3 footnote 2 and 3;

³ Values from Figure 3. The clinical benefits of 160 mg/d PI-88 were more pronounced in intermediate and high-risk groups. Statistically significant survival benefits were observed in the high-risk group at the end of the phase II study. TTR: Time-to-recurrence; DFS: Disease-free survival; OS: Overall survival; HBV: Hepatitis B virus; HCV: Hepatitis C virus.