Background
Methods
Patients
Regular Group | Split-dose Group | Untreated Group | P (Regular vs. Untreated) | P (Split-dose vs. Untreated) | P (Regular vs. Split-dose) | |
---|---|---|---|---|---|---|
Number of patients | 27 | 38 | 19 | |||
Age in years, average ± SD | 61.0 ± 10.1 | 54.8 ± 14.9 | 62.8 ± 12.5 | NS | 0.049 | NS |
Gender (Male/Female) | 21/6 | 31/7 | 16/3 | NS | NS | NS |
Etiology | ||||||
HBsAg (+) | 19 (70.4%) | 27 (71.1%) | 10 (52.6%) | NS | NS | NS |
Anti-HCV (+) | 9 (33.3%) | 11 (28.9%) | 5 (26.3%) | NS | NS | NS |
HBsAg (+)/anti-HCV (+) | 1 | 1 | 0 | - | - | |
HBsAg (-)/anti-HCV (-) | 0 | 1 | 4 | - | - | |
Alcoholism | 11 (40.7%) | 21 (55.3%) | 7 (36.8%) | NS | NS | NS |
ECOG performance status | NSa
| NSa
| NSa
| |||
0 | 9 | 19 | 7 | |||
1 | 12 | 10 | 6 | |||
2 | 6 | 9 | 6 | |||
Diagnosis | - | - | - | |||
Biopsy | 5 | 10 | 4 | |||
Cytology | 9 | 9 | 0 | |||
Imaging + alpha-fetoprotein | 13 | 19 | 15 | |||
Liver cirrhosis | 27 (100%) | 36 (94.7%) | 17 (89.5%) | NS | NS | NS |
Tumor size in cm, average ± SD | 6.62 ± 3.81 | 7.99 ± 4.55 | 8.71 ± 3.42 | NS | NS | NS |
Alpha-fetoprotein in ng/mL, median (range) | 448 (3-62208) | 2338 (3-248421) | 1491 (3 - 377218) | NS | NS | NS |
Portal vein thrombosis | 15 (55.6%) | 22 (59.5%) | 13 (68.4%) | NS | NS | NS |
Metastasis | 19 (70.4%) | 19 (50%) | 10 (52.6%) | NS | NS | NS |
Lymph node | 10 | 10 | 4 | |||
Lung | 8 | 10 | 7 | |||
Bone | 1 | 2 | 1 | |||
Duodenum | 1 | 0 | 0 | |||
Adrenal gland | 1 | 0 | 0 | |||
Kidney | 0 | 1 | 0 | |||
Heart | 0 | 1 | 0 | |||
Inferior vena cava | 0 | 1 | 0 | |||
Child-Pugh stage | ||||||
A | 16 (59.3%) | 22 (57.9%) | 10 (52.6%) | NS | NS | NS |
B | 11 | 16 | 9 | |||
Bilirubin in mg/dL, average ± SD | 1.44 ± 0.88 | 2.66 ± 5.20b
| 2.86 ± 2.36c
| 0.006 | NS | NS |
Previous therapy | 18 (66.7%) | 18 (47.4%) | No | - | - | NS |
Percutaneous local ablation | 3 | 2 | ||||
TACE | 15 | 13 | ||||
Partial hepatectomy | 3 | 3 | ||||
Radiotherapy | 1 | 3 | ||||
Course of FMP chemotherapy received | ||||||
1 | 9 (33.3%) | 25 (65.8%) | 0 | - | - | 0.018 |
2 | 11 | 9 | 0 | |||
3 | 2 | 2 | 0 | |||
>3 | 3 | 1 | 0 |
Treatment protocols
Regular protocol
Split-dose protocol
Response and toxicity evaluation
Statistical analysis
Results
Basic clinical data in far advanced HCC patients included in this study
Clinical responses and associated factors
Patients achieving disease control | ||||||
---|---|---|---|---|---|---|
Responders | Patients with progressive disease | |||||
Group | Total | CR | PR | MR | SD | |
Regular | 27 | 2 | 4 | 3 | 5 | 13 (48.1%) |
Split-dose | 38 | 0 | 4 | 5 | 3 | 26 (68.4%) |
Factors | No. of patients | Responder | P | Disease control | P | Median survival (months) | P | |
---|---|---|---|---|---|---|---|---|
Sex | Male | 52 | 13 (25.0%) | 0.489 | 18 (34.6%) | 0.114 | 5.6 | 0.374 |
Female | 13 | 5 (38.5%) | 8 (61.5%) | 7.4 | ||||
Age | ≦ 60 years | 37 | 9 (24.3%) | 0.580 | 10 (27.0%) | 0.021 | 5.1 | 0.050 |
> 60 years | 28 | 9 (32.1%) | 16 (57.1%) | 7.0 | ||||
anti-HCV | (-) | 45 | 10 (22.2%) | 0.229 | 12 (26.7%) | 0.002 | 5.4 | 0.033 |
(+) | 20 | 8 (40.0%) | 14 (70.0%) | 7.6 | ||||
HBsAg | (-) | 19 | 7 (36.8%) | 0.364 | 12 (63.2%) | 0.025 | 7.4 | 0.115 |
(+) | 46 | 11 (23.9%) | 14 (30.4%) | 5.6 | ||||
Alcoholism | (-) | 33 | 11 (33.3%) | 0.407 | 15 (45.5%) | 0.450 | 6.0 | 0.611 |
(+) | 32 | 7 (21.9%) | 11 (34.4%) | 5.8 | ||||
ECOG | 0 | 28 | 10 (35.7%) | 0.267a
| 13 (46.4%) | 0.446 a
| 7.0 | 0.011a
|
1 | 22 | 6 (27.3%) | 11 (50.0%) | 6.1 | ||||
2 | 15 | 2 (13.3%) | 2 (13.3%) | 3.6 | ||||
Cirrhosis | (-) | 2 | 0 (0%) | 0.999 | 0 (0%) | 0.513 | 11.5 | 0.830 |
(+) | 63 | 18 (27.7%) | 26 (40%) | 6.0 | ||||
Portal vein thrombosis | (-) | 28 | 8 (28.6%) | 0.999 | 12 (42.9%) | 0.799 | 6.0 | 0.319 |
(+) | 37 | 10 (27.0%) | 14 (37.8%) | 5.5 | ||||
Tumor size | ≦ 8 cm | 42 | 15 (35.7%) | 0.081 | 23 (54.8%) | 0.001 | 7.1 | 0.001 |
> 8 cm | 23 | 3 (13.0%) | 3 (13.0%) | 4.2 | ||||
Ascites | (-) | 41 | 10 (24.4%) | 0.567 | 16 (39.0%) | 0.999 | 6.0 | 0.014 |
(+) | 24 | 8 (33.3%) | 10 (41.7%) | 3.6 | ||||
Alpha-fetoprotein | ≦ 10000 ng/mL | 50 | 13 (26.0%) | 0.743 | 21 (42.0%) | 0.764 | 7.5 | 0.098 |
> 10000 ng/mL | 15 | 5 (33.3%) | 5 (33.3%) | 4.3 | ||||
Previous treatment | (-) | 29 | 13 (44.8%) | 0.011 | 16 (55.2%) | 0.041 | 6.1 | 0.750 |
(+) | 36 | 5 (13.9%) | 10 (27.8%) | 5.2 | ||||
Extrahepatic metastasis | (-) | 27 | 7 (25.9%) | 0.999 | 8 (29.6%) | 0.201 | 3.7 | 0.014 |
(+) | 38 | 11 (28.9%) | 18 (47.4%) | 7.1 | ||||
Child-Pugh | A | 38 | 9 (23.7%) | 0.414 | 13 (34.2%) | 0.309 | 7.0 | 0.012 |
B | 27 | 9 (33.3%) | 13 (48.1%) | 3.8 | ||||
Okuda stage | I | 27 | 10 (37.0%) | 0.173b
| 14 (51.9%) | 0.127b
| 7.0 | 0.004c
|
II | 28 | 5 (17.9%) | 9 (32.1%) | 5.1 | ||||
III | 10 | 3 (30.0%) | 3 (30.0%) | 3.1 | ||||
CLIP score | 1 or 2 | 27 | 10 (37.0%) | 0.172b
| 15 (55.6%) | 0.041b
| 7.0 | 0.001d
|
3 | 21 | 3 (14.3%) | 5 (23.8%) | 3,8 | ||||
4 or 5 | 17 | 5 (29.4%) | 6 (35.3%) | 3.5 | ||||
Treatment groups | Regular | 27 | 9 (33.3%) | 0.414 | 14 (51.9%) | 0.127 | 6.0 | 0.447 |
Split-dose | 38 | 9 (23.7%) | 12 (31.6%) | 5.2 | ||||
Courses | 1 | 34 | 4 (11.8%) | 0.005 | 6 (17.6%) | < 0.001 | 3.5 | < 0.001 |
> 1 | 31 | 14 (45.2%) | 20 (64.5%) | 7.9 | ||||
Responder | Yes | 18 | 18 (100%) | NC | 18 (100%) | NC | 9.5 | 0.004 |
No | 47 | 0 | 8 (17.0%) | 4.5 | ||||
Disease control | Yes | 26 | 18 (69.2%) | NC | 26 (100%) | NC | 10.6 | < 0.001 |
No | 39 | 0 | 0 | 3.8 |
Adverse effect
NCI Common Toxicity Criteria Grade | ||||||||
---|---|---|---|---|---|---|---|---|
Toxicity | Treatment group | 0 | 1 | 2 | 3 | 4 | Grade 3/4 (%) | P |
Leucopenia | Regular | 2 | 7 | 8 | 8 | 2 | 10 (37.0%) | 0.079 |
Split-dose | 19 | 10 | 3 | 6 | 0 | 6 (15.8%) | ||
Neutropenia | Regular | 8 | 3 | 2 | 7 | 7 | 14 (51.9%) | 0.0005 |
Split-dose | 26 | 3 | 5 | 4 | 0 | 4 (10.5%) | ||
Anemia | Regular | 3 | 15 | 8 | 1 | 0 | 1 (3.7%) | > 0.1 |
Split-dose | 5 | 22 | 9 | 2 | 0 | 2 (5.3%) | ||
Thrombocytopenia | Regular | 6 | 8 | 8 | 3 | 2 | 5 (18.5%) | > 0.1 |
Split-dose | 23 | 8 | 4 | 3 | 0 | 3 (7.9%) | ||
Nausea | Regular | 14 | 11 | 2 | 0 | 0 | 0 | > 0.1 |
Split-dose | 19 | 14 | 5 | 0 | 0 | 0 | ||
Vomiting | Regular | 23 | 2 | 2 | 0 | 0 | 0 | > 0.1 |
Split-dose | 29 | 7 | 2 | 0 | 0 | 0 | ||
Mucositis | Regular | 22 | 0 | 5 | 0 | 0 | 0 | > 0.1 |
Split-dose | 29 | 6 | 1 | 2 | 0 | 2 (5.3%) | ||
Diarrhea | Regular | 18 | 8 | 1 | 0 | 0 | 0 | > 0.1 |
Split-dose | 29 | 6 | 1 | 2 | 0 | 2 (5.3%) | ||
Skin rash | Regular | 27 | 0 | 0 | 0 | 0 | 0 | > 0.1 |
Split-dose | 37 | 1 | 0 | 0 | 0 | 0 | ||
Fatigue | Regular | 13 | 9 | 3 | 2 | 0 | 2 (7.4%) | > 0.1 |
Split-dose | 19 | 11 | 7 | 1 | 0 | 1 (2.6%) | ||
Renal | Regular | 23 | 1 | 0 | 3 | 0 | 3 (11.1%) | 0.067 |
Split-dose | 37 | 1 | 0 | 0 | 0 | 0 | ||
Liver dysfunctiona | Regular | 27 | 0 | 0 | 0 | 0 | 0 | > 0.1 |
Split-dose | 35 | 0 | 3 | 0 | 0 | 0 | ||
Bleeding | Regular | 20 | 3 | 1 | 3 | 0 | 3 (11.1%) | > 0.1 |
Split-dose | 35 | 2 | 0 | 1 | 0 | 1 (2.6%) | ||
Infection | Regular | 23 | 0 | 1 | 0 | 3 | 3 (11.1%) | > 0.1 |
Split-dose | 29 | 2 | 4 | 3 | 0 | 3 (7.9%) |