Patient demographic characteristics
In this study, 53 patients were included from January 2015 to December 2019. Patient selection was executed as described in Figure 1, and Table 1 summarizes the patients’ clinical characteristics. The median follow-up time was 20 months (2–61 months). By the end of follow-up (September 20, 2021), 44 (81.48%) patients had died.
Table 1
Baseline characteristics of patients
Characteristics | Patients with TACE-Apatinib treatment (No, %; Mean±SD) |
Age(years) | 58.6±8.4 |
Gender | |
Male | 40 |
Female | 13 |
ALT (IU/L) | 32.7±26.7 |
AST (IU/L) | 34.7±16.4 |
Neutrophils(109/L) | 4.4±2.6 |
Lymphocytes(109/L) | 1.3±0.4 |
Leukocyte(109/L) | 5.8±2.8 |
CEA (ng/ml) | 185.7±352.7 |
CA724 (ng/ml) | 25.9±71.7 |
CA199 (ng/ml) | 215.3±410.8 |
CA125 (ng/ml) | 33.1±71.5 |
AFP (ng/ml) | 5.8±7.5 |
Primary tumor | |
Gastric cancer | 17 |
Colorectal cancer | 36 |
Tumor numbers in the liver | |
1 | 1 |
≥2 | 48 |
Tumor size in the liver | |
≤5 cm | 35 |
>5 cm | 17 |
Extrahepatic spread | |
Yes | 24 |
No | 29 |
TACE session | |
1 | 7 |
≥2 | 46 |
Child-Pugh | |
A | 44 |
B | 9 |
ECOG scores | |
0 | 27 |
1 | 20 |
2 | 6 |
Tumor Response And Survival Outcomes
The mOS and overall mPFS of patients were 17 months (95% CI: 13.1-20.9 months) and 7 months (95% CI: 5.7-8.3 months), respectively. The mPFS of the liver tumors was 12 months (95% CI: 7.3-16.7 months) (Figure 2). For the liver tumors, 3 patients (5.7%) had CR, 23 patients (43.4%) had PR, 20 patients (37.7%) had SD and 7 patients (13.2%) had PD three months after receiving TACE combined with apatinib. Therefore, the ORR and DCR of patients for the liver tumors were 49.1% (26/53) and 86.8% (46/53), respectively.
Predictors for OS, overall PFS, and PFS of the liver tumors
For OS, univariable regression analysis showed that carbohydrate antigen 125 (CA 125) (HR: 1.006, 95%CI: 1.002-1.010, P=0.004), primary tumor (HR: 0.460, 95%CI: 0.240-0.880, P=0.019), extrahepatic spread (HR: 0.277, 95%CI: .0143-0.538, P<0.001), TACE session (HR: 0.122, 95%CI: 0.047-0.316, P<0.001), Child-Pugh (HR: 6.102, 95%CI: 2.674-13.928, P<0.001) and Eastern Cooperative Oncology Group (ECOG) scores (1 vs 0: HR: 3.876, 95%CI: 1.901-7.901, P<0.001; 2 vs 0: HR: 14.961, 95%CI: 5.049-44.332, P<0.001) were its independent predictors. However, only TACE session (HR: 0.183, 95%CI: 0.051-0.654, P=0.009), Child-Pugh (HR: 4.834, 95%CI: 1.816-12.868, P=0.002) and ECOG scores (1 vs 0: HR: 2.681, 95%CI: 1.111-6.472, P=0.028; 2 vs 0: HR: 6.385: HR: 1.459-27.934, P=0.014) were identified as the independent predictors of OS in the multivariable regression analysis (Table 2).
Table 2
Univariable regression analysis and multivariable regression analysis for overall survival
| Univariable analysis | | Multivariable analysis | |
Characteristics | HR (95%CI) | P value | HR (95%CI) | P value |
Age(years) | 1.107 (0.983,1.052) | 0.324 | | |
Gender | | | | |
Male | Ref | | | |
Female | 0.808 (0.396,1.646) | 0.557 | | |
ALT (IU/L) | 0.997 (0.984,1.09) | 0.611 | | |
AST (IU/L) | 1.009 (0.991,1.027) | 0.321 | | |
Neutrophils(109/L) | 1.027 (0.923,1.143) | 0.624 | | |
Lymphocytes(109/L) | 1.272 (0.626,2.585) | 0.505 | | |
Leukocyte(109/L) | 0.952 (0.845,1.072) | 0.416 | | |
CEA (ng/ml) | 1.001 (1.000,1.001) | 0.180 | | |
CA724 (ng/ml) | 1.004 (1.000,1.007) | 0.051 | | |
CA199 (ng/ml) | 1.001 (1.000,1.001) | 0.073 | | |
CA125 (ng/ml) | 1.006 (1.002,1.010) | 0.004 | 0.998 (0.991,1.005) | 0.568 |
AFP (ng/ml) | 00.981 (0.938,1.025) | 0.385 | | |
Primary tumor | | | | |
Gastric cancer | Ref | | Ref | |
Colorectal cancer | 0.460 (0.240,0.880) | 0.019 | 0.659 (0.305,1.424) | 0.289 |
Tumor numbers in the liver | | | | |
1 | Ref | | | |
≥2 | 1.309 (0.463,3.705) | 0.612 | | |
Tumor size in the liver | | | | |
≤5 cm | Ref | | | |
>5 cm | 1.273 (0.676,2.395) | 0.455 | | |
Extrahepatic spread | | | | |
Yes | Ref | | Ref | |
No | 0.277 (0.143,0.538) | <0.001 | 0.723 (0.282,1.856) | 0.500 |
TACE session | | | | |
1 | Ref | | Ref | |
≥2 | 0.122 (0.047,0.316) | <0.001 | 0.183 (0.051,0.654) | 0.009 |
Child-Pugh | | | | |
A | Ref | | Ref | |
B | 6.102 (2.674,13.928) | <0.001 | 4.834 (0.051,0.654) | 0.009 |
ECOG scores | | | | |
0 | Ref | | Ref | |
1 | 3.876 (1.901,7.901) | <0.001 | 2.681 (1.111,6.472) | 0.028 |
2 | 14.961 (5.049,44.332) | <0.001 | 6.385 (1.459,27.934) | 0.014 |
For overall PFS, univariable regression analysis showed that CA 724 (HR: 1.006, 95%CI: 1.002-1.010, P=0.050), CA 199 (HR: 1.001, 95%CI: 1.000-1.001, P=0.031), CA 125 (HR: 1.005, 95%CI: 1.001-1.009, P=0.009), TACE session (HR: 0.192, 95%CI: 0.081-0.563, P<0.001), Child-Pugh (HR: 4.568, 95%CI: 2.000-10.434, P<0.001) and ECOG scores (2 vs 0: HR: 9.106, 95%CI: 3.040-21.612, P<0.001) were its independent predictors. On the other hand, CA 724 (HR: 1.005, 95%CI: 1.001-1.010, P=0.017), CA 199 (HR: 1.000-1.002, P=0.007), TACE session (HR: 0.271, 95%CI: 0.089-0.825, P=0.021), Child-Pugh (HR: 4.137, 95%CI: 1.664-10.288, P=0.002) and ECOG scores (2 vs 0: HR: 4.405, 95%CI: 1.368-14.184, P=0.013) were identified as the independent predictors of overall PFS in the multivariable regression analysis (Table 3).
Table 3
Univariable regression analysis and multivariable regression analysis for progression-free survival
| Univariable analysis | | Multivariable analysis | |
Characteristics | HR (95%CI) | P value | HR (95%CI) | P value |
Age(years) | 1.107 (0.985,1.050) | 0.304 | | |
Gender | | | | |
Male | Ref | | | |
Female | 0.949 (0.493,1.826) | 0.875 | | |
ALT (IU/L) | 0.994 (0.982,1.006) | 0.294 | | |
AST (IU/L) | 1.001 (0.984,1.019) | 0.869 | | |
Neutrophils(109/L) | 0.998 (0.895,1.112) | 0.965 | | |
Lymphocytes(109/L) | 1.351 (0.704,2.593) | 0.366 | | |
Leukocyte(109/L) | 0.952 (0.860,1.054) | 0.344 | | |
CEA (ng/ml) | 1.000 (1.000,1.001) | 0.370 | | |
CA724 (ng/ml) | 1.006 (1.002,1.010) | 0.005 | 1.005 (1.001,1.010) | 0.017 |
CA199 (ng/ml) | 1.001 (1.000,1.001) | 0.031 | 1.001 (1.000,1.002) | 0.007 |
CA125 (ng/ml) | 1.005 (1.001,1.009) | 0.009 | 1.002 (0.997,1.007) | 0.547 |
AFP (ng/ml) | 0.993 (0.955,1.032) | 0.720 | | |
Primary tumor | | | | |
Gastric cancer | Ref | | | |
Colorectal cancer | 0.552 (0.299,1.021) | 0.058 | | |
Tumor numbers in the liver | | | | |
1 | Ref | | | |
≥2 | 1.174 (0.464,2.972) | 0.735 | | |
Tumor size in the liver | | | | |
≤5 cm | Ref | | | |
>5 cm | | | | |
Extrahepatic spread | | | | |
Yes | Ref | | | |
No | 1.204 (0.655,2.212) | 0.550 | | |
TACE session | | | | |
1 | Ref | | Ref | |
≥2 | 0.192 (0.081,0.453) | <0.001 | 0.271 (0.089,0.825) | 0.021 |
Child-Pugh | | | | |
A | Ref | | Ref | |
B | 4.568 (2.000,10.434) | <0.001 | 4.137 (1.664,10.288) | 0.002 |
ECOG scores | | | | |
0 | Ref | | Ref | |
1 | 1.876 (0.998,3.524) | 0.051 | 1.303 (0.644,2.637) | 0.462 |
2 | 8.106 (3.040,21.612) | <0.001 | 4.405 (1.368,14.184) | 0.013 |
For PFS of liver tumors, univariable regression analysis showed CA 125 (HR: 1.007, 95%CI: 1.003-1.011, P=0.001), primary tumor (HR: 0.525, 95%CI: 0.279-0.985, P=0.045), extrahepatic spread (HR: 0.354, 95%CI: 0.190-0.659, P=0.001), TACE session (HR: 0.129, 95%CI: 0.051-0.325, P<0.001), Child-Pugh (HR: 3.474, 95%CI: 3.474, 95%CI: 1.056-8.011, P=0.003) and ECOG scores (1 vs 0: 2.518, 95%CI: 1.296-4.890, P=0.006; 2 vs 0: HR: 14.407, 95%CI: 5.157-46.033, P<0.001) were its independent predictors. On the other hand, TACE session (HR: 0.197, 95%CI: 0.059-0.661, P=0.009) and ECOG scores (2 vs 0: HR: 6.608, 1.639-26.633, P=0.008) were identified as the independent predictors of PFS of liver tumors in the multivariable regression analysis (Table 4).
Table 4
Univariable regression analysis and multivariable regression analysis for progression-free survival of tumors in liver
| Univariable analysis | | Multivariable analysis | |
Characteristics | HR (95%CI) | P value | HR (95%CI) | P value |
Age(years) | 1.106 (0.984,1.049) | 0.326 | | |
Gender | | | | |
Male | Ref | | | |
Female | 0.845 (0.436,1.635) | 0.616 | | |
ALT (IU/L) | 0.995 (0.984,1.007) | 0.458 | | |
AST (IU/L) | 1.004 (0.987,1.022) | 0.625 | | |
Neutrophils(109/L) | 1.011 (0.902,1.133) | 0.854 | | |
Lymphocytes(109/L) | 1.271 (0.648,2.490) | 0.485 | | |
Leukocyte(109/L) | 0.985 (0.885,1.096) | 0.775 | | |
CEA (ng/ml) | 1.000 (0.999,1.001) | 0.722 | | |
CA724 (ng/ml) | 1.004 (1.000,1.007) | 0.053 | | |
CA199 (ng/ml) | 1.001 (1.000,1.001) | 0.058 | | |
CA125 (ng/ml) | 1.007 (1.003,1.011) | 0.001 | 0.999 (0.993,1.006) | 0.794 |
AFP (ng/ml) | 0.990 (0.951,1.031) | 0.640 | | |
Primary tumor | | | | |
Gastric cancer | Ref | | Ref | |
Colorectal cancer | 0.525 (0.279,0.985) | 0.045 | 0.795 (0.374,1.692) | 0.552 |
Tumor numbers in the liver | | | | |
1 | Ref | | | |
≥2 | 1.041 (0.410,2.646) | 0.932 | | |
Tumor size in the liver | | | | |
≤5 cm | Ref | | | |
>5 cm | 1.137 (0.620,1.084) | 0.678 | | |
Extrahepatic spread | | | | |
Yes | Ref | | Ref | |
No | 0.354 (0.190,0.659) | 0.001 | 0.668 (0.269,1.656) | 0.384 |
TACE session | | | | |
1 | Ref | | Ref | |
≥2 | 0.129 (0.051,0.325) | <0.001 | 0.197 (0.059,0.661) | 0.009 |
Child-Pugh | | | | |
A | Ref | | Ref | |
B | 3.474 (1.506,8.011) | 0.003 | 1.911 (0.744,4.910) | 0.179 |
ECOG scores | | | | |
0 | Ref | | Ref | |
1 | 2.518 (1.296,4.890) | 0.006 | 1.605 (0.689,3.737) | 0.273 |
2 | 14.407 (5.157,46.033) | <0.001 | 6.608 (1.639,26.633) | 0.008 |
The Changes Of Blood Examinations And Tumor Markers
The leukocyte, lymphocyte, neutrophils, CEA, CA 724, CA 199, CA 125 of patients before receiving the treatment and after receiving the treatment were reported. There was no significant statistically difference of the factors in patients before the treatment and after the treatment (all P>0.05) (Figure 3).
Complications
Adverse event evaluations for patients after receiving the combination treatment are shown in Table 5, in which no treatment-related deaths were observed. There were 23 patients (43.4%) with any grades of fever, 25 patients (47.2%) with abdominal pain, 14 patients (26.4%) with nausea, 22 patients (41.5%) with vomiting, 34 patients (64.2%) with poor appetite, 20 patients (37.7%) with diarrhoea, 19 patients (35.8%) with headache, 14 patients (26.4%) with fatigue, 30 patients (56.6%) with hypertension, 27 patients (50.9%) with hand-foot syndrome and 13 patients (24.5%) with proteinuria. For severe adverse events (grade III and IV), there were 4 patients (7.5%) with fever, 8 patients (15.1) with abdominal pain, poor appetite, and hand-foot syndrome, 3 patients (5.7%) with nausea and diarrhea, 5 patients (9.4%) with vomiting and proteinuria, 2 patients (3.8%) with headache, 1 patient (1.9%) with fatigue and 11 patients (20.8%) with hypertension. All adverse events were relieved or eliminated after symptomatic treatments, dose reduction, or temporary dose interruption.
Table 5
Adverse events evaluation of patients after they receiving the treatment
Adverse events | TACE-A |
Hand-foot skin reactions | 34(64.2%) |
Hypertension | 22(41,5%) |
Diarrhea | 10(18.9%) |
Headache | 8(15.1%) |
Gastrointestinal hemorrhage | 2(3.8%) |
scanty ascites | 2(3.8%) |
liver abscess | 1(1.9%) |