The Characteristics and Mortality of Chinese Herbal Medicine Users among Newly Diagnosed Inoperable Huge Hepatocellular Carcinoma (≥10 cm) Patients: A Retrospective Cohort Study with Exploration of Core Herbs
Abstract
:1. Introduction
2. Material and Methods
2.1. Data Source
2.2. Study Population and Ethical Considerations
2.3. Outcome Assessment
2.4. Study Covariates
2.5. Bias Assessment
2.6. Statistical Analysis
3. Results
3.1. Features of CHM Users
3.2. Overall Survival Analysis
3.3. Prescription Analysis on CHM Used for H-HCC
3.4. Proposed Molecular Pathways of Core CHMs for H-HCC
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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All Subjects (n = 1618) | CHM Users (n = 88) | CHM Nonusers (n = 1530) | p | |
---|---|---|---|---|
Demographics | ||||
Gender | ||||
Female | 252 (15.6%) | 18 (20.5%) | 234 (15.3%) | 0.19 |
Male | 1366 (84.4%) | 70 (79.5%) | 1296 (84.7%) | |
Age (years) | 58.0 (49.0–68.0) | 58.0 (50.5–66.0) | 58.0 (49.0–68.0) | 0.76 |
Age group | ||||
<40 | 167 (10.3%) | 11 (12.5%) | 156 (10.2%) | 0.75 |
41–60 | 747 (46.2%) | 41 (46.6%) | 706 (46.1%) | |
≥61 | 704 (43.5%) | 36 (40.9%) | 668 (43.7%) | |
Comorbidities | ||||
Diabetes | 288 (17.8%) | 11 (12.5%) | 277 (18.1%) | 0.18 |
Hypertension | 434 (26.8%) | 23 (26.1%) | 411 (26.9%) | 0.88 |
Chronic hepatitis | 0.73 | |||
HBV | 787 (48.6%) | 41 (46.6%) | 746 (48.8%) | |
HCV | 186 (11.5%) | 8 (9.1%) | 178 (11.6%) | |
HBV + HCV | 67 (4.1%) | 5 (5.7%) | 62 (4.1%) | |
Fatty liver | 34 (2.1%) | 30 (2.0%) | 4 (4.5%) | 0.10 |
Lifestyle factors | ||||
Cigarette smoking | 312 (19.3%) | 11 (12.5%) | 301 (19.7%) | 0.097 |
Alcohol consumption | 253 (15.6%) | 14 (15.9%) | 239 (15.6%) | 0.94 |
Betel nut chewing | 99 (6.1%) | 2 (2.3%) | 97 (6.3%) | 0.12 |
Disease severity | ||||
Child–Pugh Score classification | ||||
A | 658 (74.8%) | 35 (68.6%) | 623 (75.2%) | 0.51 |
B | 201 (22.8%) | 15 (29.4%) | 186 (22.4%) | |
C | 21 (2.4%) | 1 (2.0%) | 20 (2.4%) | |
Cirrhosis | ||||
No | 967 (59.8%) | 47 (53.4%) | 920 (60.1%) | 0.21 |
Yes | 651 (40.2%) | 41 (46.6%) | 610 (39.9%) | |
Tumor size (cm) | 12.7 (11.0–15.0) | 12.4 (11.0–14.0) | 12.7 (11.0–15.0) | 0.75 |
TNM staging (AJCC 8th version) | ||||
I | 73 (4.5%) | 7 (8.0%) | 66 (4.3%) | 0.43 |
II | 30 (1.9%) | 1 (1.1%) | 29 (1.9%) | |
III | 1057 (65.3%) | 56 (63.6%) | 1001 (65.4%) | |
IV | 458 (28.3%) | 24 (27.3%) | 434 (28.4%) | |
BCLC classification | ||||
B | 194 (17.5%) | 9 (14.8%) | 186 (17.8%) | 0.38 |
C | 834 (75.4%) | 50 (82.0%) | 784 (75.0%) | |
D | 77 (7.0%) | 2 (3.3%) | 75 (7.2%) | |
Initial HCC treatment | ||||
TACE | 437 (27.0%) | 24 (27.3%) | 413 (27.0%) | 0.95 |
RFA/PEI | 20 (1.2%) | 0 (0.0%) | 20 (1.3%) | 0.28 |
Target therapy | 397 (24.5%) | 27 (30.7%) | 370 (24.2%) | 0.17 |
Chemotherapy | 316 (19.5%) | 14 (15.9%) | 302 (19.7%) | 0.38 |
Medications | ||||
Anti-HCV/HBV therapy | 71 (4.4%) | 5 (5.7%) | 66 (4.3%) | 0.54 |
Metformin | 83 (5.1%) | 2 (2.3%) | 81 (5.3%) | 0.21 |
Aspirin | 71 (4.4%) | 4 (4.5%) | 67 (4.4%) | 0.94 |
Diuretics | 129 (8.0%) | 124 (8.1%) | 5 (5.7%) | 0.41 |
Biochemical profiles | ||||
α-Fetoprotein (ng/mL) | 749.7 (26.1–17,359.5) | 179.2 (10.1–7700.1) | 813.7 (27.5–17701.7) | 0.088 |
Albumin (g/dL) | 3.7 (3.3–4.1) | 4.0 (3.5–4.2) | 3.7 (3.2–4.1) | 0.003 |
Hemoglobin (g/dL) | 12.7 (11.1–14.2) | 12.8 (11.2–14.1) | 12.7 (11.1–14.2) | 0.68 |
Platelet (103/μL) | 224.0 (157.0–302.0) | 249.0 (167.5–327.5) | 223.0 (157.0–299.0) | 0.21 |
INR | 1.1 (1.1–1.2) | 1.1 (1.0–1.2) | 1.1 (1.1–1.2) | 0.21 |
AST (U/L) | 85.0 (57.0–135.0) | 80.0 (49.0–149.5) | 86.0 (57.0–134.0) | 0.98 |
ALT (U/L) | 51.0 (32.0–82.0) | 57.5 (35.5–85.0) | 50.0 (32.0–82.0) | 0.31 |
Total bilirubin (mg/dL) | 1.0 (0.7–1.4) | 0.9 (0.7–1.3) | 1.0 (0.7–1.4) | 0.20 |
Crude OR | p | Adjusted OR * | p | |
---|---|---|---|---|
Demographics | ||||
Gender | ||||
Male vs. Female | 0.70 (0.41–1.20) | 0.196 | 0.86 (0.36–2.05) | 0.727 |
Age group | ||||
>60 vs. ≤60 years | 0.89 (0.58–1.38) | 0.613 | 0.76 (0.38–1.51) | 0.433 |
Comorbidities | ||||
Diabetes | 0.65 (0.34–1.23) | 0.185 | 0.96 (0.35–2.64) | 0.937 |
Hypertension | 0.96 (0.59–1.57) | 0.881 | 0.80 (0.35–1.84) | 0.599 |
Viral hepatitis | 0.88 (0.56–1.36) | 0.558 | 0.66 (0.34–1.30) | 0.233 |
Fatty liver | 2.38 (0.82–6.91) | 0.111 | 4.58 (1.09–19.2) | 0.038 |
Lifestyle factors | ||||
Cigarette smoking | 0.58 (0.31–1.11) | 0.101 | 0.36 (0.14–0.90) | 0.029 |
Alcohol consumption | 1.02 (0.57–1.84) | 0.942 | 1.39 (0.60–3.21) | 0.436 |
Betel nut chewing | 0.34 (0.08–1.42) | 0.139 | 0.20 (0.02–1.62) | 0.131 |
Disease severity | ||||
Child–Pugh Score classification | ||||
C vs. A-B | 0.87 (0.12–6.54) | 0.891 | 1.35 (0.11–16.25) | 0.812 |
Cirrhosis | 1.32 (0.85–2.02) | 0.212 | 2.50 (1.14–5.47) | 0.022 |
Tumor size (per 1 cm) | 0.98 (0.92–1.05) | 0.582 | 0.99 (0.89–1.09) | 0.818 |
TNM staging (AJCC 8th version) | ||||
Stage III–IV vs. I–II | 0.66 (0.31–1.41) | 0.285 | 0.83 (0.2–3.41) | 0.799 |
BCLC classification | ||||
C vs. B | 1.32 (0.64–2.73) | 0.457 | 1.38 (0.52–3.67) | 0.521 |
D vs. B | 0.55 (0.12–2.61) | 0.453 | 0.41 (0.03–5.28) | 0.493 |
Initial HCC treatment | ||||
TACE | 1.01 (0.63–1.64) | 0.954 | 0.89 (0.43–1.86) | 0.764 |
Target therapy | 1.39 (0.87–2.22) | 0.170 | 1.76 (0.86–3.62) | 0.125 |
Chemotherapy | 0.77 (0.43–1.38) | 0.379 | 0.59 (0.21–1.61) | 0.301 |
Medications | ||||
Anti-HCV/HBV therapy | 1.34 (0.52–3.41) | 0.544 | 1.94 (0.68–5.52) | 0.212 |
Metformin | 0.42 (0.10–1.72) | 0.226 | 0.61 (0.06–6.01) | 0.675 |
Aspirin | 1.04 (0.37–2.92) | 0.941 | 0.73 (0.08–6.46) | 0.778 |
Diuretics | 0.68 (0.27–1.72) | 0.417 | 0.54 (0.15–1.90) | 0.333 |
Biochemical profiles | ||||
α-Fetoprotein (>400 vs. ≤400 ng/mL) | 0.59 (0.35–0.99) | 0.046 | 0.41 (0.21–0.81) | 0.010 |
Albumin (≤3.5 vs. >3.5 g/dL) | 0.54 (0.32–0.90) | 0.017 | 0.50 (0.23–1.07) | 0.074 |
Hemoglobin (≤10 vs. > 10 g/dL) | 0.71 (0.34–1.51) | 0.374 | 1.29 (0.49–3.37) | 0.610 |
Platelet (≤100 vs. >100 × 103/μL) | 1.18 (0.50–2.78) | 0.709 | 1.75 (0.51–6.00) | 0.372 |
INR (>1.4 vs. ≤1.4) | 0.39 (0.05–2.90) | 0.360 | 1.61 (0.17–14.95) | 0.673 |
AST (>102 vs. ≤102 U/L) | 1.18 (0.75–1.86) | 0.480 | 1.21 (0.58–2.53) | 0.616 |
ALT (>108 vs. ≤108 U/L) | 1.38 (0.80–2.41) | 0.249 | 1.73 (0.75–4.01) | 0.199 |
Total bilirubin (>1.5 vs. ≤1.5 mg/dL) | 0.68 (0.36–1.27) | 0.229 | 0.82 (0.34–2.01) | 0.668 |
All Subjects (n = 1618) | CHM Users (n = 88) | CHM Nonusers (n = 1530) | p | |
---|---|---|---|---|
Overall survival (OS) | ||||
1 year | 30.0% (27.8–32.3) | 46.6% (35.9–56.6) | 29.0% (26.7–31.3) | <0.001 |
2 year | 14.8% (13.1–16.6) | 27.0% (18.2–36.6) | 14.1% (12.3–15.9) | <0.001 |
3 year | 10.0% (8.5–11.5) | 15.0% (8.2–23.7) | 9.7% (8.2–11.3) | 0.002 |
Liver-specific survival (%) * | ||||
1 year | 30.4% (28.0–32.9) | 46.7% (35.1–57.4) | 29.5% (27.0–32.0) | 0.002 |
2 year | 15.2% (13.3–17.2) | 26.4% (17.0–36.8) | 14.5% (12.6–16.6) | 0.002 |
3 year | 10.8% (9.2–12.6) | 13.4% (6.5–22.7) | 10.7% (9.0–12.5) | 0.011 |
HR (95% CI) | p | aHR * (95% CI) | p | |
---|---|---|---|---|
All CHM users (n = 88) | 0.69 (0.56–0.85) | 0.001 | 0.62 (0.44–0.87) | 0.006 |
Use of CHM by accumulative duration (days) | ||||
CHM nonusers (n = 1530) | 1 (reference) | 1 (reference) | ||
≤28 (n = 45) | 0.84 (0.63–1.10) | 0.204 | 0.85 (0.58–1.25) | 0.416 |
>28 (n = 43) | 0.54 (0.40–0.74) | <0.001 | 0.44 (0.26–0.74) | 0.002 |
Unadjusted | Adjusted | |||
---|---|---|---|---|
HR (95% CI) | p | HR * (95% CI) | p | |
Different PS models * | ||||
ATT (n = 1618) | 0.68 (0.54–0.85) | 0.001 | 0.69 (0.54–0.89) | 0.004 |
IPTW (n = 1618) | 0.74 (0.58–0.94) | 0.014 | 0.76 (0.58–0.99) | 0.045 |
Overlap weighting (n = 1618) | 0.68 (0.54–0.86) | 0.001 | 0.69 (0.54–0.89) | 0.004 |
Different populations | ||||
All subjects, without landmark design (n = 2331) | 0.55 (0.44–0.69) | <0.001 | 0.58 (0.44–0.76) | <0.001 |
Model with 120 day landmark analysis (n = 1262) | 0.70 (0.54–0.91) | 0.008 | 0.67 (0.49–0.93) | 0.016 |
Subgroup analysis | ||||
Age, years | ||||
≤60 | 0.75 (0.55–1.01) | 0.059 | 0.64 (0.39–1.04) | 0.069 |
>60 | 0.61 (0.42–0.89) | 0.010 | 0.60 (0.34–1.08) | 0.089 |
Gender | ||||
Female | 0.61 (0.36–1.02) | 0.062 | 0.35 (0.12–1.02) | 0.055 |
Male | 0.71 (0.55–0.93) | 0.011 | 0.72 (0.49–1.07) | 0.102 |
Initial treatment | ||||
No | 0.62 (0.42–0.91) | 0.014 | 0.88 (0.27–2.87) | 0.831 |
Yes | 0.73 (0.54–0.98) | 0.037 | 0.59 (0.40–0.88) | 0.009 |
Albumin | ||||
>3.5 g/dL | 0.84 (0.62–1.13) | 0.245 | 0.72 (0.47–1.11) | 0.135 |
≤3.5 g/dL | 0.49 (0.30–0.81) | 0.005 | 0.44 (0.21–0.93) | 0.032 |
Cirrhosis | ||||
No | 0.63 (0.45–0.87) | 0.005 | 0.44 (0.18–1.09) | 0.076 |
Yes | 0.76 (0.54–1.07) | 0.114 | 0.69 (0.46–1.03) | 0.068 |
α-Fetoprotein | ||||
≤400 ng/mL | 0.85 (0.59–1.23) | 0.396 | 0.81 (0.50–1.33) | 0.411 |
>400 ng/mL | 0.59 (0.39–0.90) | 0.015 | 0.52 (0.29–0.91) | 0.022 |
CHM | Counts | Prevalence (%) |
---|---|---|
Hedyotis diffusa Willd. | 180 | 43.2% |
Salvia miltiorrhiza Bunge | 132 | 31.7% |
Scutellaria barbata D. Don | 129 | 30.9% |
Astragalus mongholicus Bunge | 93 | 22.3% |
Curcuma longa L. | 72 | 17.3% |
Xiang-Sha-Liu-Jun-Zi-Tang | 68 | 16.3% |
Zhen-Ren-Huo-Ming-Yin | 61 | 14.6% |
Yin-Chen-Wu-Ling-San | 56 | 13.4% |
Paeonia lactiflora Pall. | 50 | 12.0% |
Rheum palmatum L. | 48 | 11.5% |
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Chen, S.-L.; Ho, C.-Y.; Lin, W.-C.; Lee, C.-W.; Chen, Y.-C.; Chen, J.-L.; Chen, H.-Y. The Characteristics and Mortality of Chinese Herbal Medicine Users among Newly Diagnosed Inoperable Huge Hepatocellular Carcinoma (≥10 cm) Patients: A Retrospective Cohort Study with Exploration of Core Herbs. Int. J. Environ. Res. Public Health 2022, 19, 12480. https://doi.org/10.3390/ijerph191912480
Chen S-L, Ho C-Y, Lin W-C, Lee C-W, Chen Y-C, Chen J-L, Chen H-Y. The Characteristics and Mortality of Chinese Herbal Medicine Users among Newly Diagnosed Inoperable Huge Hepatocellular Carcinoma (≥10 cm) Patients: A Retrospective Cohort Study with Exploration of Core Herbs. International Journal of Environmental Research and Public Health. 2022; 19(19):12480. https://doi.org/10.3390/ijerph191912480
Chicago/Turabian StyleChen, Shu-Ling, Chia-Ying Ho, Wei-Chun Lin, Chao-Wei Lee, Yu-Chun Chen, Jiun-Liang Chen, and Hsing-Yu Chen. 2022. "The Characteristics and Mortality of Chinese Herbal Medicine Users among Newly Diagnosed Inoperable Huge Hepatocellular Carcinoma (≥10 cm) Patients: A Retrospective Cohort Study with Exploration of Core Herbs" International Journal of Environmental Research and Public Health 19, no. 19: 12480. https://doi.org/10.3390/ijerph191912480