Skip to main content
NCBI home page
Integrative Cancer Therapies logoLink to Integrative Cancer Therapies
. 2020 Jun 19;19:1534735420915275. doi: 10.1177/1534735420915275

Effects and Relative Factors of Adjunctive Chinese Medicine Therapy on Survival of Hepatocellular Carcinoma Patients: A Retrospective Cohort Study in Taiwan

Yu-Pei Liao 1,*, Pei-Tseng Kung 2,3,*, Yueh-Hsin Wang 1, Yeong-Ruey Chu 1, Shung-Te Kao 4, Wen-Chen Tsai 1,✉
PMCID: PMC7307484  PMID: 32552053

Abstract

Some patients with cancer use adjunctive Chinese medicine, which might improve the quality of life. This study aims to investigate the effects and relative factors of adjunctive Chinese medicine on survival of hepatocellular carcinoma patients at different stages. The study population was 23 581 newly diagnosed hepatocellular carcinoma patients and received surgery from 2004 to 2010 in Taiwan. After propensity score matching with a ratio of 1:10, this study included 1339 hepatocellular carcinoma patients who used adjunctive Chinese medicine and 13 390 hepatocellular carcinoma patients who used only Western medicine treatment. All patients were observed until the end of 2012. Kaplan-Meier method and Cox proportional hazards model was applied to find the relative risk of death between these 2 groups. The study results show that the relative risk of death was lower for patients with adjunctive Chinese medicine treatment than patients with only Western medicine treatment (hazard ratio = 0.68; 95% confidence interval = 0.62-0.74). The survival rates of patients with adjunctive Chinese medicine or Western medicine treatment were as follows: 1-year survival rate: 83% versus 72%; 3-year survival rate: 53% versus 44%; and 5-year survival rate: 40% versus 31%. The factors associated with survival of hepatocellular carcinoma patients included treatment, demographic characteristics, cancer stage, health status, physician characteristics, and characteristics of primary medical institution. Moreover, stage I and stage II hepatocellular carcinoma patients had better survival outcome than stage III patients by using adjunctive Chinese medicine therapy. The effect of adjunctive Chinese medicine was better on early-stage disease.

Keywords: hepatocellular carcinoma, treatment of cancer, adjunctive Chinese medicine therapy, surgery, survival analysis

Introduction

With the incidence of cancer increasing annually, this disease has become one of the most prominent health issues affecting humans worldwide. According to the World Health Organization,1 approximately 780 000 new cases of liver cancer were reported worldwide in 2012. The incidence rate was 10.1 per 100 000 people, and the mortality rate was 5.1 per 100 000, the latter of which was ranked second among deaths caused by cancer. The incidence and mortality rates of liver cancer in Taiwan are higher than the global average; in 2011, the number of confirmed cases of liver cancer in Taiwan was approximately 11 292, and the incidence and mortality rates were 35.79 and 24.95 per 100 000 people, respectively. Liver cancer was ranked second among all deaths caused by cancer in Taiwan.2 Currently, 3 methods are available for cancer treatment: Western medicine treatment, Chinese medicine treatment, and combined Chinese-Western medicine treatment (ie, adjunctive Chinese medicine treatment). Many cancer patients who receive Western medicine treatment also seek and use Chinese medicine treatment as adjunctive therapy. The use of Chinese medicine treatment in Taiwan has increased among patients with liver cancer, and the ratio of Chinese medicine treatment users remains high (18.89%).3 A previous study showed that the use of Chinese medicine treatment by cancer patients significantly improved their overall quality of life and body functions.4 In addition, the use of adjunctive Chinese medicine treatment significantly elevated the survival rate of lung cancer patients as well as their prognostic results.5 The mortality rate from liver cancer is higher among men compared with their female counterparts,6 and the risk increases with age.7,8 Furthermore, low socioeconomic status or family income, severity of comorbidity, and liver cancer stage increase the risk of death.6,9-12 Other related factors influencing the survival rate of cancer patients include medical institution characteristics,13,14 physician service volume, and physician age.14,15

Previous studies5,16 have shown that adjunctive Chinese medicine treatment can significantly improve the survival rates of patients with cancer (eg, breast cancer patients and lung cancer patients). However, few studies have investigated the difference in the survival rates of liver cancer patients between Western medicine treatment and adjunctive Chinese medicine treatment. Therefore, this study was conducted to investigate the effect of adjunctive Chinese medicine treatment on the survival rate of patients with liver cancer.

Materials and Methods

Research Database

This retrospective cohort study examined the Taiwan Cancer Registry for the 2004 to 2010 period, the National Health Insurance Research Database (NHIRD) for the 2002 to 2012 period, and the Cause of Death Data for the 2004 to 2012 period. The cancer registry data were obtained from the Health Promotion Administration, and the other data were obtained from the Ministry of Health and Welfare. The Taiwan Cancer Registry contains information on numerous cancer cases as well as relevant information such as patients’ cancer stage. Diagnosis of cancer is confirmed according to the International Classification of Diseases for Oncology, 3rd edition (ICD-O-3), which identifies cancer categories according to primary site, histology, behavioral code, and classification/differentiation. In determining the cancer stage according to diagnostic results, the Taiwan Cancer Registry assesses the severity of cancer clinically, surgically, and pathologically in accordance with the tumor-node-metastasis (TNM) staging system of the American Joint Committee on Cancer (AJCC).17 The NHIRD contains comprehensive health care–related information such as the characteristics of Taiwan’s health care providers and patients’ demographic information and all medical records including Western medicine and Chinese medicine. As of 2013, 23 462 863 people were enrolled in the National Health Insurance (NHI) program, accounting for approximately 99.6% of people living in Taiwan.18

Study Population

In this study, patients whose liver cancer (ICD-O-3 codes C22.0-C22.1) was newly diagnosed with a stage I, II, or III and also received a surgery treatment between 2004 and 2010 were selected as the study participants, and they were followed up until December 31, 2012. Patients were excluded if they had carcinoma in situ (n = 6541), did not receive any treatment within the past 6 months (n = 5446), received only palliative care (n = 48), died within 3 months of diagnosis (n = 12 557), received only Chinese medicine treatment (n = 1972), or did not receive liver surgery (n = 5451; Figure 1). In the present study, the 2 treatments were defined according to Lee et al,16 as follows:

Figure 1.

Figure 1.

Open in a new tab

Flowchart for the selection of study participants.

  1. Western medicine treatment: patients who received Western medicine treatment within 1 year of diagnosis and <30 days of Chinese medicine treatment.

  2. Adjunctive Chinese medicine treatment: patients who received Western medicine treatment and ≥30 days of Chinese medicine treatment within 1 year of diagnosis.

All liver cancer patients were enrolled in the NHI program and had high accessibility to Western Medicine. All cancer patients were exempted from payments for cancer treatments under the NHI. Western Medicine was the primary treatment for all patients in our study. The exposure of Western Medicine was comparable in the 2 cohorts.

To facilitate a more accurate comparison of the survival rates between the patients who underwent Western medicine treatment and those who underwent adjunctive Chinese medicine treatment, this study adopted the propensity score matching (PSM) with the greedy matching by digit without replacement method to eliminate characteristic differences between the 2 groups with a ratio of 1:10.19 It was the conditional probability of the patients receiving adjunctive Chinese medicine treatment, and its calculation was based on the variables that are given in Table 1. Using the multivariate logistic regression model, the probability of the patients receiving adjunctive Chinese medicine treatment was estimated for matching between the 2 groups. The groups were matched by sex, age, monthly salary, urbanization level of residence location, other catastrophic illnesses or injuries, severity of comorbidity hepatitis B virus, hepatitis C virus, cirrhosis, cancer stage, and treatment methods.

Table 1.

Differences Between the Variables Prior to and After Propensity Score Matching for Patients Who Received Western Medicine Treatment and Those Who Received Adjunctive Chinese Medicine Treatment (2004-2010).

Variables Before Propensity Score Matching
 After Propensity Score Matching
Total Western Medicine Adjunctive Chinese Medicine P Total Western Medicine Adjunctive Chinese Medicine P
N % n1 % n2 % N % n1 % n2 %
Total number 23 581 100.00 22 209 94.18 1372 5.82 14 729 100.00 13 390 90.91 1339 9.09
Gender .068 .998
 Male 16 709 70.86 15 707 94.00 1002 6.00 10 675 72.48 9704 90.90 971 9.10
 Female 6872 29.14 6502 94.62 370 5.38 4054 27.52 3686 90.92 368 9.08
Age <.001 .321
 ≤40 1052 4.46 969 92.11 83 7.89 784 5.32 709 90.43 75 9.57
 41-50 2791 11.84 2590 92.80 201 7.20 1948 13.23 1755 90.09 193 9.91
 51-60 5807 24.63 5415 93.25 392 6.75 4009 27.22 3634 90.65 375 9.35
 ≥61 13 931 59.08 13 235 95.00 696 5.00 7988 54.23 7292 91.29 696 8.71
Monthly salary (NTD) <.001 .901
 Low-income household 186 0.79 178 95.70 8 4.30 85 0.58 77 90.59 8 9.41
 ≤17 280 1059 4.49 996 94.05 63 5.95 644 4.37 581 90.22 63 9.78
 17 280-22 800 13 259 56.23 12 573 94.83 686 5.17 7797 52.94 7111 91.20 686 8.80
 22 801-28,800 3308 14.03 3130 94.62 178 5.38 1999 13.57 1821 91.10 178 8.90
 28 801-36 300 1580 6.70 1469 92.97 111 7.03 1126 7.64 1017 90.32 109 9.68
 36 301-45 800 2002 8.49 1857 92.76 145 7.24 1442 9.79 1307 90.64 135 9.36
 45 801-57 800 854 3.62 792 92.74 62 7.26 604 4.10 545 90.23 59 9.77
 ≥57 801 1333 5.65 1214 91.07 119 8.93 1032 7.01 931 90.21 101 9.79
Urbanization level of residence location .004 .999
 Level 1 5901 25.02 5532 93.75 369 6.25 3898 26.46 3539 90.79 359 9.21
 Level 2 6807 28.87 6396 93.96 411 6.04 4393 29.83 3995 90.94 398 9.06
 Level 3 3431 14.55 3225 94.00 206 6.00 2151 14.60 1953 90.79 198 9.21
 Level 4 4010 17.01 3796 94.66 214 5.34 2405 16.33 2193 91.19 212 8.81
 Level 5 966 4.10 933 96.58 33 3.42 371 2.52 338 91.11 33 8.89
 Level 6 1364 5.78 1275 93.48 89 6.52 954 6.48 865 90.67 89 9.33
 Level 7 1102 4.67 1052 95.46 50 4.54 557 3.78 507 91.02 50 8.98
Other catastrophic illnesses or injuries <.001 1.000
 No 21 317 90.40 20 024 93.93 1293 6.07 13 855 94.07 12 595 90.91 1260 9.09
 Yes 2264 9.60 2185 96.51 79 3.49 874 5.93 795 90.96 79 9.04
Charlson Comorbidity Index .010 .961
 ≤3 20 250 85.87 19 034 94.00 1216 6.00 13 050 88.60 11 866 90.93 1184 9.07
 4-6 2634 11.17 2513 95.41 121 4.59 1290 8.76 1170 90.70 120 9.30
 ≥7 697 2.96 662 94.98 35 5.02 389 2.64 354 91.00 35 9.00
Hepatitis B virus <.001 .792
 No 12 992 55.10 12 310 94.75 682 5.25 7525 51.09 6846 90.98 679 9.02
 Yes 10 589 44.90 9899 93.48 690 6.52 7204 48.91 6544 90.84 660 9.16
Hepatitis C virus .012 .660
 No 14 448 61.27 13 563 93.87 885 6.13 9296 63.11 8443 90.82 853 9.18
 Yes 9133 38.73 8646 94.67 487 5.33 5433 36.89 4947 91.05 486 8.95
Cirrhosis <.001 .317
 No 6272 26.60 5851 93.29 421 6.71 4199 28.51 3801 90.52 398 9.48
 Yes 17 309 73.40 16 358 94.51 951 5.49 10 530 71.49 9589 91.06 941 8.94
Cancer stage <.001 .424
 Stage I 9527 40.40 8899 93.41 628 6.59 6350 43.11 5751 90.57 599 9.43
 Stage II 6384 27.07 6028 94.42 356 5.58 3931 26.69 3579 91.05 352 8.95
 Stage III 7670 32.53 7282 94.94 388 5.06 4448 30.20 4060 91.28 388 8.72
Treatment methods <.001 .330
 OP + CH + TACE 5517 23.40 5268 95.49 249 4.51 3032 20.59 2783 91.79 249 8.21
 OP 4723 20.03 4296 90.96 427 9.04 3921 26.62 3527 89.95 394 10.05
 OP + CH + RT + TACE 2787 11.82 2619 93.97 168 6.03 1926 13.08 1758 91.28 168 8.72
 OP + RT 2531 10.73 2408 95.14 123 4.86 1413 9.59 1290 91.30 123 8.70
 OP + TACE 2318 9.83 2215 95.56 103 4.44 1164 7.90 1061 91.15 103 8.85
 OP + CH 1665 7.06 1553 93.27 112 6.73 1120 7.60 1008 90.00 112 10.00
 OP + RFA 1730 7.34 1660 95.95 70 4.05 799 5.42 729 91.24 70 8.76
 OP + CH + RT 1300 5.51 1228 94.46 72 5.54 814 5.53 742 91.15 72 8.85
Open in a new tab

Abbreviations: NTD, New Taiwan dollar; OP, surgery; CH, chemotherapy; TACE, embolization; RT, radiography; RFA, radiofrequency ablation.

Statistical Analysis

The data were processed and analyzed using SAS Version 9.4. Descriptive and inferential statistical analyses were conducted with the level of significance set at α = .05.

Cancer stage was defined according to the TNM staging system of the AJCC (ie, stages I-III).20 Area of residence was divided into 7 categories according to the degree of urbanization, with a value of 1 indicating the highest degree of urbanization. To evaluate the severity of comorbidities, primary and secondary diagnosis codes from the International Classification of Diseases, Ninth Revision, Clinical Modification, were converted into weighted scores. The weighted scores were subsequently summed to obtain the Charlson Comorbidity Index (CCI),21 which was then applied to calculate the comorbidity scores. These scores, which represented the severity of the comorbidities, were divided into 3 levels (≤3, 4-6, and ≥7). Patients were considered to have other catastrophic illnesses or injuries only if other catastrophic illnesses or injuries had been diagnosed prior to their liver cancer diagnosis. Primary medical institution was determined according to the type of health care facility that the patients frequented the most for treatment during the observation period. The service volume of hospitals or physicians was defined as the number of liver cancer patients who were treated in a given year by the hospital or physician. The service volume of hospitals or physicians was divided into 3 levels by interquartile range: low (≤25%), median (25% to 75%), and high (≥75%).

After the study population was divided into Western and adjunctive Chinese medicine treatment groups, the χ2 test was applied to identify any differences in the demographic information, liver cancer stage, and health status of the 2 groups before and after conducting the PSM with a 1:10 matching ratio by using greedy matching by digit without replacement. Cox proportional hazards models were employed to examine related factors influencing the survival rate of the patients with liver cancer, and the patients’ survival period was measured in years. The independent variables in the analysis were cancer treatment method, demographic characteristics, liver cancer stage, health status, physician characteristics, and characteristics of primary medical institution. The dependent variable was whether the patients survived. Last, patient survival was analyzed and calculated using the Kaplan-Meier method according to 1-, 3-, and 5-year survival rates. The results were employed to plot the survival curves for both of the treatment methods (for all patients and stratified by cancer stage). The log-rank test was then used to test the differences in the patient survival rates. This study has been approved by the research ethics committee in China Medical University (Institutional Review Board No. CMU-REC-101-012).

Results

Characteristics of Liver Cancer Patients Prior to and After PSM

Table 1 shows that prior to PSM, the sex, age, monthly salary, urbanization level of residence location, other catastrophic illnesses or injuries, severity of comorbidity, whether or not the liver cancer patients had hepatitis B virus, whether or not the liver cancer patients had hepatitis C virus, whether or not the liver cancer patients had cirrhosis, cancer stage, and treatment methods of liver cancer patients who underwent Western medicine treatment differed significantly from those who underwent adjunctive Chinese medicine treatment (P < .05). PSM was subsequently employed, and liver cancer patients who received adjunctive Chinese medicine treatment (n = 1339) were matched with those who received Western medicine treatment (n = 13 390). The patients who underwent adjunctive Chinese medicine treatment were mostly men (9.10%). The largest groups of patients who had received adjunctive Chinese medicine treatment were patients ≥61 years of age (8.71%), monthly salary in 17 280 to 22 800 NTD (New Taiwan dollar; 8.80%), urbanization level of residence location with level 2 (9.06%), without other catastrophic illnesses or injuries (9.09%), a low severity of comorbidities (9.07%), without hepatitis B virus (9.02%), without hepatitis C virus (9.18%), with cirrhosis (8.94%), stage I liver cancer patients (9.43%), and those who received the treatment method of only operation (10.05%). Among the patients who underwent adjunctive Chinese medicine treatment, the mean, median, minimum, and maximum number of days of treatment in the first year after diagnosis was 110, 84, 30, and 365 days, respectively. Subsequently, the χ2 test was employed to analyze whether the characteristics of the liver cancer patients who received Western medicine treatment differed from those who received adjunctive Chinese medicine treatment. The results show that according to the sex, age, monthly salary, urbanization level of residence location, other catastrophic illnesses or injuries, severity of comorbidity, whether or not the liver cancer patients had hepatitis B virus, whether or not the liver cancer patients had hepatitis C virus, whether or not the liver cancer patients had cirrhosis, cancer stage, and treatment methods, the differences between the 2 groups were nonsignificant (P > .05).

The Effect of Adjunctive Chinese Medicine Treatment on the Survival Rate of Liver Cancer Patients and Related Factors

After performing the PSM for the patients who received adjunctive Chinese medicine treatment and those who received Western medicine treatment, Cox proportional hazards models were employed to conduct an analysis, the results of which showed that the liver cancer patients who received adjunctive Chinese medicine treatment exhibited a hazard ratio (HR) of 0.68 compared with those who received Western medicine treatment (95% confidence interval [CI] = 0.62-0.74; Table 2). Subsequently, all of the related variables were controlled, and the survival curves for both patient groups were plotted (Figure 2). The curves show that compared with those who received Western medicine treatment, the patients who received adjunctive Chinese medicine treatment exhibited higher 1-year (83% vs 72%), 3-year (53% vs 44%), and 5-year (40% vs 31%) survival rates.

Table 2.

Effect of Adjunctive Chinese Medicine Treatment on the Survival Rate of Liver Cancer Patients and Related Factors.

Variables Survival
 Death
 P Adjusted HR 95% CI P
N % N %
Total number 4930 33.47 9799 66.53
Treatment <.001
 Western medicine (ref) 4403 32.88 8987 67.12
 Adjunctive Chinese medicine 527 39.36 812 60.64 0.68 0.62-0.74 <.001
Gender <.001
 Male (ref) 3523 33.00 7152 67.00
 Female 1407 34.71 2647 65.29 1.00 0.96-1.05 .937
Age <.001
 ≤40 (ref) 287 36.61 497 63.39
 41-50 655 33.62 1293 66.38 1.08 0.97-1.20 .142
 51-60 1481 36.94 2528 63.06 1.09 0.98-1.20 .102
 ≥61 2507 31.38 5481 68.62 1.25 1.13-1.37 <.001
Average age (mean ± SD) 60.51 ± 12.14 62.32 ± 12.79 <.001
Monthly salary (NTD) <.001
 Low-income household (ref) 30 35.29 55 64.71
 ≤17 280 208 32.30 436 67.70 0.94 0.71-1.25 .677
 17 280-22 800 2311 29.64 5486 70.36 0.96 0.73-1.25 .754
 22 801-28 800 735 36.77 1264 63.23 0.91 0.69-1.19 .475
 28 801-36 300 426 37.83 700 62.17 0.87 0.66-1.14 .301
 36 301-45 800 560 38.83 882 61.17 0.82 0.63-1.08 .161
 45 801-57 800 237 39.24 367 60.76 0.83 0.62-1.10 .188
 ≥57 801 423 40.99 609 59.01 0.75 0.57-0.99 .045
Urbanization level of residence location <.001
 Level 1 (ref) 1406 36.07 2492 63.93
 Level 2 1548 35.24 2845 64.76 0.97 0.92-1.03 .287
 Level 3 669 31.10 1482 68.90 1.11 1.04-1.19 .001
 Level 4 751 31.23 1654 68.77 1.01 0.94-1.07 .870
 Level 5 120 32.35 251 67.65 1.02 0.89-1.16 .801
 Level 6 257 26.94 697 73.06 1.12 1.03-1.22 .012
 Level 7 179 32.14 378 67.86 1.02 0.92-1.14 .685
Other catastrophic illnesses or injuries <.001
 No (ref) 4693 33.87 9162 66.13
 Yes 237 27.12 637 72.88 1.30 1.20-1.41 <.001
Charlson Comorbidity Index <.001
 ≤3 (ref) 4476 34.30 8574 65.70
 4-6 362 28.06 928 71.94 1.16 1.08-1.24 <.001
 ≥7 92 23.65 297 76.35 1.28 1.14-1.44 <.001
Hepatitis B virus .086
 No (ref) 2500 33.22 5025 66.78
 Yes 2430 33.73 4774 66.27 0.95 0.91-1.00 .033
Hepatitis C virus <.001
 No (ref) 3106 33.41 6190 66.59
 Yes 1824 33.57 3609 66.43 0.89 0.85-0.94 <.001
Cirrhosis <.001
 No (ref) 1901 45.27 2298 54.73
 Yes 3029 28.77 7501 71.23 1.56 1.48-1.63 <.001
Cancer stage <.001
 Stage I (ref) 3136 49.39 3214 50.61
 Stage II 1292 32.87 2639 67.13 1.40 1.32-1.47 <.001
 Stage III 502 11.29 3946 88.71 3.42 3.25-3.59 <.001
Treatment methods <.001
 OP + CH + TACE (ref) 886 29.22 2146 70.78
 OP 1809 46.14 2112 53.86 0.90 0.84-0.96 .001
 OP + CH + RT + TACE 341 17.71 1585 82.29 1.30 1.22-1.39 <.001
 OP + RT 549 38.85 864 61.15 1.08 0.99-1.17 .082
 OP + TACE 339 29.12 825 70.88 0.94 0.86-1.02 .109
 OP + CH 289 25.80 831 74.20 1.33 1.23-1.45 <.001
 OP + RFA 479 59.95 320 40.05 0.61 0.54-0.69 <.001
 OP + CH + RT 105 12.90 709 87.10 1.83 1.68-2.00 <.001
 OP + CH + TACE 133 24.63 407 75.37 1.11 1.00-1.23 .061
Level of hospital <.001
 Medical center (ref) 3289 34.70 6190 65.30
 Regional hospital 1091 31.05 2423 68.95 1.13 1.07-1.19 <.001
 District hospital 368 29.39 884 70.61 1.18 1.10-1.28 <.001
 Physician Clinics 182 37.60 302 62.40 1.17 0.99-1.38 .074
Ownership of hospital <.001
 Public (ref) 1712 35.58 3100 64.42
 Nonpublic 3218 32.45 6699 67.55 1.00 0.96-1.05 .856
Service volume of hospitals .185
 Low (ref) 28 31.82 60 68.18
 Median 63 37.50 105 62.50 1.09 0.78-1.52 .624
 High 4839 33.43 9634 66.57 1.11 0.83-1.48 .490
Service volume of physician .185
 Low (ref) 62 24.51 191 75.49
 Median 162 28.98 397 71.02 0.87 0.73-1.04 .135
 High 4706 33.81 9211 66.19 0.70 0.59-0.81 <.001
Age of physician <.001
 ≤40 (ref) 1365 28.86 3365 71.14
 41-50 2278 34.56 4313 65.44 0.90 0.86-0.95 <.001
 51-60 1120 36.95 1911 63.05 0.83 0.78-0.88 <.001
 ≥61 167 44.30 210 55.70 0.82 0.71-0.94 .005
Open in a new tab

Abbreviations: HR, hazard ratio; CI, confidence interval; NTD, New Taiwan dollar; OP, surgery; CH, chemotherapy; TACE, embolization; RT, radiography; RFA, radiofrequency ablation.

Figure 2.

Figure 2.

Open in a new tab

Survival curves of liver cancer patients were performed by the Cox proportional hazard model, in which 1 group received Western medicine treatment (n1 = 13 390) and another group received adjunctive Chinese medicine treatment (n2 = 1339).

When stratified by cancer stage (Figure 3), significant differences were observed between the 2 groups (P < .05). The 5-year survival rate of patients with stage I liver cancer who received adjunctive Chinese medicine treatment (56%) was higher than that of those who received Western medicine treatment (48%). Similarly, the 5-year survival rate of the patients with stage II liver cancer patients who received adjunctive Chinese medicine treatment (41%) was higher than that of those who received Western medicine treatment (30%).

Figure 3.

Figure 3.

Open in a new tab

Survival curves of liver cancer patients performed by the Cox proportional hazard model are displayed by cancer stage, in which one group received Western medicine treatment (n1 = 13 390) and another group received adjunctive Chinese medicine treatment (n2 = 1339).

Related Factors Influencing Liver Cancer Patients Survival

Table 2 shows that the risk of death was equal between women and men (HR = 1.00; 95% CI = 0.96-1.05). Furthermore, the risk increased with age: liver cancer patients ≥61 years exhibited a significantly higher risk of death compared with those aged ≤40 years (HR = 1.25; 95% CI = 1.13-1.37). The risk of death of the patients with the highest monthly salaries was 0.75 times that of low-income earners (95% CI = 0.57-0.99). Regarding urbanization level of residence location, the risk of death of the patients who lived in the areas with lowest degree of urbanization was 1.02 times that of those living in the areas with the highest degree of urbanization (95% CI = 0.92-1.14). The patients with other catastrophic illnesses or injuries exhibited a risk of death that was significantly higher than those without other catastrophic illnesses or injuries (HR = 1.30; 95% CI = 1.20-1.41). Regarding the health status of the liver cancer patients, the more severe their comorbidities were, the higher the risk of death became; those with a CCI of ≥7 exhibited 1.28 times risk of death compared with those with a CCI of ≤3 (95% CI = 1.14-1.44). Moreover, the risk of death of the liver cancer patients with hepatitis C virus did not increase compared with those without hepatitis C virus (HR = 0.89; 95% CI = 0.85-0.94), but the risk of death of patients with cirrhosis was significantly higher than those without cirrhosis (HR = 1.56; 95% CI = 1.48-1.63). And the risk also increased with cancer stage, with that of stage III liver cancer patients (HR = 3.42; 95% CI = 3.25-3.59) significantly exceeding that of the stage I liver cancer patients. Regarding the primary medical institution characteristics, the lower the level of the medical institution was, the greater the risk of death became; the risk of death among the patients who received treatment at district hospitals were significantly higher than that of those who were treated at medical centers (HR = 1.18; 95% CI = 1.10-1.28). Concerning the ownership of the medical institutions, the risk of death for patients who received treatment at private medical institutions was similar with those who were treated at public medical institutions (HR = 1.00; 95% CI = 0.96-1.05), and the risk of death for patients who received treatments at hospitals with a different service volume was not significantly different. Finally, regarding physician age, the patients who received treatment primarily from physicians aged ≥61 years exhibited the lowest risk of death (HR = 0.82; 95% CI = 0.71-0.94).

Table 3 shows that for the patients who received adjunctive Chinese medicine treatment, the most frequently used traditional Chinese medicine regimen comprised 6 single-herb medicine and 4 herbal formulas. For single-herb medicines, the most frequently used medicines were bai hua she she cao (24.9%), ban zhi lian (12.1%), dan shen (10.8%), yin chen hao (6.9%), bie jia (6.5%), and ye jiao teng (5.6%); for herbal formulas, the 4 most frequently used formulas were jia wei xiao yao san (11.3%), xiao chai hu tang (10.9%), xiang sha liu jun zi tang (8.3%), and yin chen wu ling san (6.2%).

Table 3.

Top 10 Traditional Chinese Medicine Used by Patients Who Received Adjunctive Chinese Medicine Treatment.

Name of Traditional Chinese Medicine Ingredient %
Bai Hua She She Cao Hedyotis diffusa 24.9
Ban Zhi Lian Scutellaria barbata 12.1
Jia Wei Xiao Yao San Angelica sinensis, Poria, Gardenia jasminoides, Menthae, Paeonia lactiflora, Bupleurum chinense DC, Glycyrrhiza uralensis, Atractylodes macrocephala, Moutan Radicis Cortex, Ginger 11.3
Xiao Chai Hu Tang Bupleurum chinense DC, Scutellaria baicalensis Georgi, Talinum, Glycyrrhiza uralensis, Pinellia ternata, Ginger, Ziziphus jujuba 10.9
Dan Shen Salvia miltiorrhiza Bge 10.8
Xiang Sha Liu Jun Zi Tang Rosa banksiae, Fructus amomi, Pericarpium Citri Reticulatae, Pinellia ternata, Codonopsis pilosula, Poria, Glycyrrhiza uralensis, Ginger, Ziziphus jujuba 8.3
Yin Chen Hao Artemisia capillaris 6.9
Bie Jia Carapax trionycis 6.5
Yin Chen Wu Ling San Artemisia capillaris, Alisma plantago-aquatica, Atractylodes macrocephala, Poria, Polyporus umbellatus, Ramulus cinnamomi 6.2
Ye Jiao Teng Polygonum multiflorum Thunb 5.6
Open in a new tab

Discussion

In this study, PSM was adopted to reduce selection bias, the results of which show that when all other related factors were controlled, the risk of death for the patients who received adjunctive Chinese medicine treatment was significantly lower than that of those who received Western medicine treatment (HR = 0.68). This indicates that adjunctive Chinese medicine treatment can improve the survival rate of patients with liver cancer, which supports the findings of previous studies investigating the effectiveness of adjunctive Chinese medicine treatment on improving the survival rate of patients with different types of cancer (ie, liver, lung, breast, and head and neck cancer)5,16,22-24; however, in these studies, the patients were not stratified according to their cancer stage. Some studies have shown that combining Chinese medicine treatment with chemotherapy can significantly extend the survival period of patients with late-stage lung or colon cancer.25,26 Meta-analyses have confirmed that compared with Western medicine treatment, adjunctive Chinese medicine treatment is more effective in elevating the survival period of patients with mid- to late-stage liver or lung cancer.27,28 Cancer patients who received adjunctive Chinese medicine treatment exhibited increased suppression of cancer cells, which lowers the risk of death. In addition, Chinese medicine treatment eases the adverse reactions that patients experience during chemotherapy and radiation therapy.5,26 Therefore, when patients with cancer elect to receive adjunctive Chinese medicine treatment, their clinical symptoms and quality of life can be improved and their survival can be extended.24,26 The 10 traditional Chinese medicines used by the liver cancer patients who received adjunctive Chinese medicine treatment in the present study are similar to those reported in previous studies, indicating that the most common traditional Chinese medicines used by patients with liver cancer are jia wei xiao yao san, xiao chai hu tang, and xiang sha liu jun zi tang.29 Other studies have indicated that jia wei xiao yao san, bai hua she she cao, ban zhi lian, and dan shen are traditional Chinese medicines that are commonly used to treat breast cancer.16 Because no study has explored the effectiveness of adjunctive Chinese medicine for treating stage I to III liver cancer,29,30 this study addressed this research gap and found that adjunctive Chinese medicine treatment exhibited more favorable treatment results on stage I and II liver cancer than on stage III liver cancer. This may be attributable to patients with stage I or II cancer having milder conditions that were easier to treat.

The results of this study support those reported by previous studies that have shown that the risk of death was lower for women than for men,6,7,31,32 higher for older age groups and patients with a lower socioeconomic status,6-8,10,11,33-35 higher with increasing severity of comorbidities,36,37 and higher at later cancer stages.12,35,38,39 In the present study, the risk of death increased with age; lower income; greater severity of comorbidities, catastrophic illnesses or injuries; and at later cancer stages. The results of previous studies have showed that the patients having hepatitis C virus may increase the risk of developing liver cancer.40,41 This study adopted the PSM that included the variable of hepatitis C; since all patients have developed a liver cancer, the mortality risk of patients with liver cancer having hepatitis C was not significant.

For the patients who were treated at hospitals, the outcome of their treatment might have differed because of differences in the treatment provided by the hospitals due to different hospital characteristics. The results of this study were supported by previous studies and indicated that the postsurgery mortality rate of patients with a liver cancer is significantly lower in medical centers than nonmedical centers (including regional, district hospitals, and physician clinics).42 Regarding ownership of hospitals, nonpublic hospitals (including private hospitals) showed a higher mortality rate than that of public hospitals,42 but this study did not indicate the same outcome. The present study shows that the risk of death for patients with liver cancer increased significantly when treatment was received through lower level medical institutions, nonpublic institutions, and physicians with low service volumes, which accords with the results of previous studies.43-45 Health behavior and lifestyle, which include smoking, drinking alcohol, exercise, and diet, may affect the survival of cancer patients. Previous studies have indicated that the risk of death was higher for cancer patients who have the habit of smoking and drinking alcohol.46,47 In contrast, cancer patients who perform regular exercise and take a nutritional diet may have improved survival.48,49 Although we could not include these health behaviors and lifestyle factors in the analysis model, we believe that these factors might have similar impacts on these 2 groups of patients.

Research Limitations

This study was not a randomized clinical trial and used medical claim data compiled by the NHI Administration for analysis. The survival curves (Figure 3) indicated that there was a significant association between the patients receiving adjunctive Chinese medicine treatment and the patients having better survival rate, but a cause and effect relationship could not be determined from these data. In addition, patients might have self-selected for medical treatment, leading to bias in the study. Although the NHI covers the most portion of the cost of both traditional Chinese and Western medical regimens, some patients may be required to pay for traditional Chinese medicines not covered by the NHI. Consequently, it remains unclear how such medical expenses incurred may have resulted in a possible underestimation of the number of patients who received adjunctive Chinese medicine treatment. In addition, the study was unable to determine whether the number of liver cancer patient deaths from the data reflects the actual number of deaths from liver cancer because the patients could have died from other causes. Finally, the external validity of this study results for other countries with different health care delivery systems is limited.

Conclusions

After PSM was applied to reduce selection bias, the study results revealed that compared with those who received only Western medicine treatment, patients who received adjunctive Chinese medicine treatment exhibited a lower risk of death and increased survival rates. Related factors influencing the survival rate of liver cancer patients included demographic characteristics (ie, sex, age), income, area of residence, cancer stage, health status (ie, severity of comorbidities), catastrophic illness or injury status, cirrhosis, treatment methods, primary medical institution characteristics (ie, hospital level and ownership structure), and primary physician characteristics (ie, age). In addition, the effects of adjunctive Chinese medicine treatment on liver cancer patients differed among the patients according to cancer stage, in which the survival rate of the patients with stage I or II cancer was higher than that of patients with stage III or IV cancer.

According to the results of this study, we recommend that government or physicians should further conduct focused preclinical studies as well as well-designed and controlled prospective clinical trials. Future studies should consider investigating the underlying mechanisms of the medicines used in adjunctive Chinese medicine treatment to determine which type of traditional Chinese medicine or treatment is the most effective for improving the survival rate of patients with liver cancer.

Acknowledgments

We appreciate the use of the National Health Insurance Research Database and the Cancer Register Files provided by Statistic Center of Ministry of Health and Welfare. We are also grateful to Health Data Science Center, China Medical University Hospital, for providing administrative, technical and funding support.

Footnotes

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by Grant ASIA107-CMUH-15 from Asia University and China Medical University. We are also grateful to Health Data Science Center, China Medical University Hospital, for providing administrative, technical, and funding support.

References

  • 1. World Health Organization. GLOBOCAN 2012: estimated incidence, mortality and prevalence worldwide in 2012. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed June 6, 2015.
  • 2. Health Promotion Administration ROC. Taiwan Cancer Registry Report in 2011. http://www.hpa.gov.tw/BHPNet/Web/Stat/StatisticsShow.aspx?No=201404160001. Accessed June 6, 2015.
  • 3. Liao YH, Lin CC, Li TC, Lin JG. Utilization pattern of traditional Chinese medicine for liver cancer patients in Taiwan. BMC Complement Altern Med. 2012;12:146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. Xu W, Towers AD, Li P, Collet JP. Traditional Chinese medicine in cancer care: perspectives and experiences of patients and professionals in China. Eur J Cancer Care (Engl). 2006;15:397-403. [DOI] [PubMed] [Google Scholar]
  • 5. Lin G, Li Y, Chen S, Jiang H. Integrated Chinese-western therapy versus western therapy alone on survival rate in patients with non-small-cell lung cancer at middle-late stage. J Tradit Chin Med. 2013;33:433-438. [DOI] [PubMed] [Google Scholar]
  • 6. Artinyan A, Mailey B, Sanchez-Luege N, et al. Race, ethnicity, and socioeconomic status influence the survival of patients with hepatocellular carcinoma in the United States. Cancer. 2010;116:1367-1377. [DOI] [PubMed] [Google Scholar]
  • 7. Bowker SL, Majumdar SR, Veugelers P, Johnson JA. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin: response to Farooki and Schneider. Diabetes Care. 2006;29:1990-1991. [DOI] [PubMed] [Google Scholar]
  • 8. Jembere N, Campitelli MA, Sherman M, et al. Influence of socioeconomic status on survival of hepatocellular carcinoma in the Ontario population; a population-based study, 1990-2009. PLoS One. 2012;7:e40917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. El-Serag HB, Siegel AB, Davila JA, et al. Treatment and outcomes of treating of hepatocellular carcinoma among Medicare recipients in the United States: a population-based study. J Hepatol. 2006;44:158-166. [DOI] [PubMed] [Google Scholar]
  • 10. Kemmer N, Neff G, Secic M, Zacharias V, Kaiser T, Buell J. Ethnic differences in hepatocellular carcinoma: implications for liver transplantation. Dig Dis Sci. 2008;53:551-555. [DOI] [PubMed] [Google Scholar]
  • 11. Kwong SL, Stewart SL, Aoki CA, Chen MS., Jr. Disparities in hepatocellular carcinoma survival among Californians of Asian ancestry, 1988 to 2007. Cancer Epidemiol Biomarkers Prev. 2010;19:2747-2757. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Minagawa M, Ikai I, Matsuyama Y, Yamaoka Y, Makuuchi M. Staging of hepatocellular carcinoma: assessment of the Japanese TNM and AJCC/UICC TNM systems in a cohort of 13,772 patients in Japan. Ann Surg. 2007;245:909-922. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. Chaudhry R, Goel V, Sawka C. Breast cancer survival by teaching status of the initial treating hospital. CMAJ. 2001;164:183-188. [PMC free article] [PubMed] [Google Scholar]
  • 14. Wang YH, Kung PT, Tsai WC, Tai CJ, Liu SA, Tsai MH. Effects of multidisciplinary care on the survival of patients with oral cavity cancer in Taiwan. Oral Oncol. 2012;48:803-810. [DOI] [PubMed] [Google Scholar]
  • 15. Halm EA, Lee C, Chassin MR. Is volume related to outcome in health care? A systematic review and methodologic critique of the literature. Ann Intern Med. 2002;137:511-520. [DOI] [PubMed] [Google Scholar]
  • 16. Lee YW, Chen TL, Shih YR, et al. Adjunctive traditional Chinese medicine therapy improves survival in patients with advanced breast cancer: a population-based study. Cancer. 2014;120:1338-1344. [DOI] [PubMed] [Google Scholar]
  • 17. Health Promotion Administration. Taiwan Cancer Registry Coding Manual. Long Form in 2011. http://tcr.cph.ntu.edu.tw/uploadimages/Longform%20Manual_Official%20version_20171204_W.pdf. Accessed March 20, 2020.
  • 18. Central Health Insurance Department of the Ministry of Health and Welfare. The National Health Insurance Statistics in 2013. http://www.nhi.gov.tw/Resource/webdata/28507_1_%E5%85%A8%E6%B0%91%E5%81%A5%E5%BA%B7%E4%BF%9D%E9%9A%AA%E7%B5%B1%E8%A8%88%E5%8B%95%E5%90%91-2013%E5%B9%B4.pdf. Accessed June 6, 2015.
  • 19. Parsons LS. Performing a 1: N case-control match on propensity score. Paper presented at: Proceedings of the 29th Annual SAS Users Group International Conference; 2004; Montreal, Canada. [Google Scholar]
  • 20. American Cancer Society. Liver cancer stages. http://www.cancer.org/cancer/livercancer/detailedguide/liver-cancer-staging. Published 2015. Accessed June 6, 2015.
  • 21. Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol. 1992;45:613-619. [DOI] [PubMed] [Google Scholar]
  • 22. Lin HC, Lin CL, Huang WY, et al. The use of adjunctive traditional Chinese medicine therapy and survival outcome in patients with head and neck cancer: a nationwide population-based cohort study. QJM. 2015;108:959-965. [DOI] [PubMed] [Google Scholar]
  • 23. Yang Y, Wu Y, Yao C. Exploration on TCM clinical study on non-small cell lung cancer. Chin J Integr Tradit West Med. 2003;23:147-149. [Google Scholar]
  • 24. Chen S, Flower A, Ritchie A, et al. Oral Chinese herbal medicine (CHM) as an adjuvant treatment during chemotherapy for non-small cell lung cancer: a systematic review. Lung Cancer. 2010;68:137-145. [DOI] [PubMed] [Google Scholar]
  • 25. Xu ZY, Jin CJ, Zhou CC, et al. Treatment of advanced non-small-cell lung cancer with Chinese herbal medicine by stages combined with chemotherapy. J Cancer Res Clin Oncol. 2011;137:1117-1122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. Zhou LY, Shan ZZ, You JL. Clinical observation on treatment of colonic cancer with combined treatment of chemotherapy and Chinese herbal medicine. Chin J Integr Med. 2009;15:107-111. [DOI] [PubMed] [Google Scholar]
  • 27. Shu X, McCulloch M, Xiao H, Broffman M, Gao J. Chinese herbal medicine and chemotherapy in the treatment of hepatocellular carcinoma: a meta-analysis of randomized controlled trials. Integr Cancer Ther. 2005;4:219-229. [DOI] [PubMed] [Google Scholar]
  • 28. Yang S, Cui M, Li HY, Zhao YK, Gao YH, Zhu HY. Meta-analysis of the effectiveness of Chinese and Western integrative medicine on medium and advanced lung cancer. Chin J Integr Med. 2012;18:862-867. [DOI] [PubMed] [Google Scholar]
  • 29. Liao YH, Lin CC, Lai HC, Chiang JH, Lin JG, Li TC. Adjunctive traditional Chinese medicine therapy improves survival of liver cancer patients. Liver Int. 2015;35:2595-2602. [DOI] [PubMed] [Google Scholar]
  • 30. Tsai FJ, Liu X, Chen CJ, et al. Chinese herbal medicine therapy and the risk of overall mortality for patients with liver cancer who underwent surgical resection in Taiwan. Complement Ther Med. 2019;47:102213. [DOI] [PubMed] [Google Scholar]
  • 31. Cook MB, McGlynn KA, Devesa SS, Freedman ND, Anderson WF. Sex disparities in cancer mortality and survival. Cancer Epidemiol Biomarkers Prev. 2011;20:1629-1637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. Yang D, Hanna DL, Usher J, et al. Impact of sex on the survival of patients with hepatocellular carcinoma: a Surveillance, Epidemiology, and End Results analysis. Cancer. 2014;120:3707-3716. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33. Janssen-Heijnen ML, Houterman S, Lemmens VE, Louwman MW, Maas HA, Coebergh JW. Prognostic impact of increasing age and co-morbidity in cancer patients: a population-based approach. Crit Rev Oncol Hematol. 2005;55:231-240. [DOI] [PubMed] [Google Scholar]
  • 34. Kim WR, Gores GJ, Benson JT, Therneau TM, Melton LJ., 3rd Mortality and hospital utilization for hepatocellular carcinoma in the United States. Gastroenterology. 2005;129:486-493. [DOI] [PubMed] [Google Scholar]
  • 35. Xu LB, Wang J, Liu C, et al. Staging systems for predicting survival of patients with hepatocellular carcinoma after surgery. World J Gastroenterol. 2010;16:5257-5262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. Lee SH, Choi HC, Jeong SH, et al. Hepatocellular carcinoma in older adults: clinical features, treatments, and survival. J Am Geriatr Soc. 2011;59:241-250. [DOI] [PubMed] [Google Scholar]
  • 37. Shau WY, Shao YY, Yeh YC, et al. Diabetes mellitus is associated with increased mortality in patients receiving curative therapy for hepatocellular carcinoma. Oncologist. 2012;17:856-862. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38. Gomaa AI, Hashim MS, Waked I. Comparing staging systems for predicting prognosis and survival in patients with hepatocellular carcinoma in Egypt. PLoS One. 2014;9:e90929. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39. Toyoda H, Kumada T, Kiriyama S, et al. Changes in the characteristics and survival rate of hepatocellular carcinoma from 1976 to 2000: analysis of 1365 patients in a single institution in Japan. Cancer. 2004;100:2415-2421. [DOI] [PubMed] [Google Scholar]
  • 40. Saito I, Miyamura T, Ohbayashi A, et al. Hepatitis C virus infection is associated with the development of hepatocellular carcinoma. Proc Natl Acad Sci U S A. 1990;87:6547-6549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41. International Agency for Research on Cancer. Hepatitis Viruses. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Lyon, France: International Agency for Research on Cancer; 1994. [Google Scholar]
  • 42. Siemerink EJ, Schaapveld M, Plukker JT, Mulder NH, Hospers GA. Effect of hospital characteristics on outcome of patients with gastric cancer: a population based study in north-east Netherlands. Eur J Surg Oncol. 2010;36:449-455. [DOI] [PubMed] [Google Scholar]
  • 43. Chen TM, Chang TM, Huang PT, et al. Management and patient survival in hepatocellular carcinoma: does the physician’s level of experience matter? J Gastroenterol Hepatol. 2008;23(7 pt 2):e179-e188. [DOI] [PubMed] [Google Scholar]
  • 44. Kuo RN, Chung KP, Lai MS. Re-examining the significance of surgical volume to breast cancer survival and recurrence versus process quality of care in Taiwan. Health Serv Res. 2013;48:26-46. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45. Lin HC, Lin CC. Surgeon volume is predictive of 5-year survival in patients with hepatocellular carcinoma after resection: a population-based study. J Gastrointest Surg. 2009;13:2284-2291. [DOI] [PubMed] [Google Scholar]
  • 46. Shih WL, Chang HC, Liaw YF, et al. Influences of tobacco and alcohol use on hepatocellular carcinoma survival. Int J Cancer. 2012;131:2612-2621. [DOI] [PubMed] [Google Scholar]
  • 47. Chiang CH, Lu CW, Han HC, et al. The relationship of diabetes and smoking status to hepatocellular carcinoma mortality. Medicine (Baltimore). 2016;95:e2699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48. Park SM, Lim MK, Shin SA, Yun YH. Impact of prediagnosis smoking, alcohol, obesity, and insulin resistance on survival in male cancer patients: National Health Insurance Corporation Study. J Clin Oncol. 2006;24:5017-5024. [DOI] [PubMed] [Google Scholar]
  • 49. Irwin ML, Mayne ST. Impact of nutrition and exercise on cancer survival. Cancer J. 2008;14:435-441. [DOI] [PubMed] [Google Scholar]

Articles from Integrative Cancer Therapies are provided here courtesy of SAGE Publications

RESOURCES