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: An International Journal of Medicine
The use of adjunctive traditional Chinese medicine therapy and survival outcome in patients with head and neck cancer: a nationwide population-based cohort study
Hung-Che Lin 0 1 2 3 4 5 6 9
Cheng-Li Lin 0 1 2 3 4 5 6 7 8
Wen-Yen Huang 0 1 2 3 4 5 6 13
Wei-Chuan Shangkuan 0 1 2 3 4 5 6 12
Bor-Hwang Kang 0 1 2 3 4 5 6 9
Yueng-Hsiang Chu 0 1 2 3 4 5 6 9
Jih-Chin Lee 0 1 2 3 4 5 6 9 11
Hueng-Chuen Fan 0 1 2 3 4 5 6 10
Chia-Hung Kao 0 1 2 3 4 5 6 14 15
0 Defense Medical Center , Taipei , Taiwan
1 Medicine and PET Center, China Medical University Hospital , Taichung , Taiwan
2 of Medicine, College of Medicine, China Medical University , Taichung , Taiwan
3 National Defense Medical Center , Taipei , Taiwan
4 National Chiao Tung University , Hsinchu , Taiwan
5 Otolaryngology-Head and Neck Surgery, Kaohsiung Veterans General Hospital , Kaohsiung , Taiwan
6 Oncology, Tri-Service General Hospital, National Defense Medical Center , Taipei , Taiwan
7 College of Medicine, China Medical University , Taichung , Taiwan
8 Office for Health Data, China Medical University Hospital , Taichung
9 Department of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital , National
10 Department of Pediatrics, Tri-Service General Hospital
11 Department of Biological Science and Technology, Institute of Bioinformatics and Systems Biology
12 Department of
13 Department of Radiation
14 Department of Nuclear
15 Graduate Institute of Clinical Medical Science and School
Background: Traditional Chinese medicine (TCM) is widely used in the treatment of patients with several types of cancer.
However, no large-scale clinical studies have evaluated whether TCM is associated with better survival in patients with
head and neck cancer (HNC).
Methods: The Taiwan National Health Insurance Research Database was used to conduct a retrospective cohort study of
patients with HNC between 2001 and 2011. The patients with HNC were separated into TCM users and non-users, and Cox
regression models were applied to determine the association between the use of TCM and survival outcome.
Results: The TCM and comparison cohorts comprised data for 2966 and 2670 patients, respectively. The mean age was 51.3
years in the TCM cohort and 51.7 years in the comparison cohort. Multivariate analysis demonstrated that the use of TCM
was significantly associated with lower risk of all-cause mortality by 32% (adjusted hazard ratio, 0.68; 95% confidence
interval, 0.62–0.75). Patients with longer TCM use had a lower mortality rate (P for trend < 0.001).
Conclusions: Our study showed that adjunctive therapy with TCM is associated with higher survival outcome. However,
some limitations exist, such as the lack of information of cancer stage. In addition, causality cannot be assessed with this
retrospective study. A randomized controlled trial to test the effect of adjunctive TCM therapy in HNC patients is needed.
Head and neck cancer (HNC) is an important cause of death and
morbidity worldwide. It is the eighth most frequent type of
cancer in USA with nearly 53 000 new cases diagnosed annually,
accounting for 11 520 deaths.1 More than 550 000 cases of HNC
occur annually worldwide.2 The current treatment modalities
for patients with HNC include surgery, radiotherapy,
chemotherapy and targeted biological therapies.3 However, the
prognosis and 5-year survival rates for patients with HNC remain
poor, particularly when the cancer occurs in the oropharynx
and hypopharynx.1,4 Traditional Chinese medicine (TCM) is one
of the widely used alternative medicine therapies among
patients in China, Hong Kong and Taiwan. Some studies have
proposed that TCM can be beneficial in the treatment of cancer,
including breast cancer, hepatocellular carcinoma, gastric
cancer, lung cancer, colorectal cancer, prostate cancer, superficial
bladder cancer and leukemia.5–11 However, clinical studies on
the therapeutic effects of TCM in patients with HNC are scarce
and have limited sample sizes.11–13 In Taiwan, TCM is a widely
accepted form of medical treatment for many diseases. It is
covered by the Taiwanese National Health Insurance (NHI)
program. Using the population-based National Health Insurance
Research Database (NHIRD), we investigated whether the
combination of TCM and contemporary cancer treatments affected
the survival of patients with HNC.
The NHI program was implemented in 1995 and covers >99% of
the 23.74 million Taiwan residents.14 The NHI program is a
mandatory health insurance program that offers
comprehensive medical care coverage, including outpatient, inpatient,
emergency and TCM services as well as prescription drugs for
all insurants. In the NHI program, insurants with any of the 30
categories of catastrophic illness specified by the Bureau of NHI
(including cancer) can apply for catastrophic illness certificates
[Registry of Catastrophic Illnesses Patient Database (RCIPD)]. If
the insured has major diseases such as cancer, he or she can
apply for a catastrophic illness certificate. To reduce the
financial hardship associated with catastrophic illness, beneficiaries
are exempted from copayments. The issuance of certificates is
validated through careful review of medical records,
pathological reports, and imaging studies by at least two specialists.
The diseases investigated in this study were identified
according to the diagnosis codes in the RCIPD, based on International
Classification of Diseases, Ninth Revision, Clinical Modification
(ICD-9-CM) codes. All personally identifiable information in the
RCIPD is scrambled to conform to the Personal Information
Protection Act. This study was approved by the Institutional
Review Board of China Medical University (CMU-REC-101-012).
Data extracted from the RCIPD were used for this retrospective
cohort study. This study comprised patients aged >20 years
who were diagnosed with primary HNC (ICD-9-CM codes
140149) between 2001 and 2011. Patients diagnosed with HNC who
used TCM for >90 days were defined as TCM users, and those
who used TCM for fewer than 30 days were considered TCM
non-users. The date of the 90th day of TCM treatment was used
as the index date. To assemble a comparison cohort, controls
were randomly selected and frequency matched with patients
in the TCM cohort at a ratio of 1:1, based on age group
(in 10-year span); sex; comorbidities of hypertension, diabetes,
congestive heart failure (CHF), stroke, chronic obstructive
pulmonary disease (COPD) and liver cirrhosis; treatment for HNC;
and index year, using the same exclusion criteria during the
same period (Figure 1).
The study outcome was all-cause mortality during the 11-year
follow-up. The identification of death events was determined
according to the RCIPD. The study patients were followed from
the index date until their deaths, withdrawal from the NHI
program, or the end date of the database (31 December 2011).
Variables of exposure
Premium-based income was categorized into three levels:
<NT$15 000, NT$15 000–19 999 and NT$20 000 (US$1 * NT$30).
The urbanization level was based on the population density of
the residential area, population ratio of elderly people, the
number of agricultural workers, educational level and the number of
physicians per 100 000 people. Urbanization was categorized into
four levels, with Level 1 being the most urbanized and Level 4 the
least urbanized. We also assessed patients who had at least three
claims for ambulatory care or hospitalization visits at the
baseline with principal or secondary diagnoses of hypertension
(ICD9-CM 401-405), diabetes (ICD-9-CM 250), CHF (ICD-9-CM 428),
stroke (ICD-9-CM 430-438), COPD (ICD-9-CM 490-496) or liver
cirrhosis (ICD-9-CM 571), which were identified from the RCIPD as
baseline comorbidities. The treatment of HNC was divided into
six groups, according to the treatment status: (i) surgery alone; (ii)
surgery and adjuvant therapy; (iii) radiotherapy alone; (iv)
chemotherapy alone; (v) radiotherapy and systemic therapy and (vi)
others or no treatment (Table 2).
The distributions of sociodemographic status and comorbidities
were expressed as a frequency (with a percent) or a
mean 6 standard deviation (SD). The categorical variables were
analyzed using a chi-square test, and the continuous variables
of the baseline characteristics of TCM users and non-users were
analyzed using a Student t-test. The Kaplan–Meier method was
used to depict the curves of the event-free rate between the two
cohorts, and the log-rank test was used to examine the
difference between the curves. Univariate and multivariate Cox
proportional hazards regression analyses were used to estimate
the hazard ratio (HR) with a 95% confidence interval (CI) for
mortality. The variables that were significant in the univariate
Cox analysis were included in the multivariable Cox
proportional hazards model to identify the independent
predictors of mortality. To verify the dose–response relationship
between TCM use and mortality, the TCM use category was
treated as a continuous variable to calculate the P value of the
linear trend. The herbal prescription patterns and herbal
formulae were described. The Statistical Analysis System (SAS),
Version 9.3 (SAS Institute, Cary, NC) computer software program
was used to perform all statistical analyses. Comparison results
with a P value of <0.05 were considered statistically significant.
The TCM and comparison cohorts comprised data for 2966 and
2670 patients, respectively. Table 1 shows sociodemographic,
comorbidity and treatment data for the TCM and control
patients. No significant differences in age distribution were found
between the TCM and comparison cohorts (mean age 51.3 6 10.8
vs. 51.7 6 11.2 years, respectively). Approximately 45.6% of
patients in the TCM cohort were <49 years old. Additionally, the
patients with TCM use of 251–550 days and >550 days,
respectively. Therefore, a longer duration of TCM use was associated
with a lower mortality rate (P for trend <0.001).
To our knowledge, this is the first large-scale nationwide cohort
study investigating the association between adjunctive TCM
therapy and the survival of patients with HNC. We found that
TCM user had better survival outcomes (adjusted HR ¼ 0.68). A
longer duration of TCM is associated with a lower mortality rate
(P for trend <0.001). In the multivariable model, increasing age,
male sex, lower income, CHF and stroke were significantly
associated with an increased risk of mortality. Sex was a strong and
independent prognostic factor, and women had higher survival
rates than men did. Our data indicated that higher
socioeconomic status was associated with increased survival. This is
likely attributable to greater exposure to tobacco, alcohol and
betel nuts, which are all established indicators for poor outcomes
in HNC patients, among patients with low socioeconomic than
those with high socioeconomic status.15 In Taiwan, betel-nut
chewing is common and associated with all-cause mortality.16
Approximately 2 million people habitually chew betel nuts in
Taiwan (10% of the population).17 A hospital-based case–control
majority of the patients in the TCM cohort were male (78.6%).
Participants in both cohorts had monthly income levels of
NT$15 000–19 999 and tended to live in more urbanized areas
(57.9 vs. 55.7% for urbanization Levels 1 and 2, respectively).
Patients who were treated with TCM had a higher prevalence
of diabetes, CHF, stroke and COPD than the patients in the
comparison cohort. The mean follow-up time was 3.63
years (SD ¼ 2.51) in the TCM cohort and 3.19 years (SD ¼ 2.54)
in the comparison cohort (data not shown). Figure 2 shows
the survival curve for the two cohorts and indicates that the
incidence curve of mortality was significantly lower in the
TCM cohort than in the comparison cohort (log-rank test,
P < 0.001).
The univariate and multivariate Cox regression analyses
demonstrated a strong association between the use of TCM and lower
mortality (Table 2). Compared with TCM non-users, the mortality
of TCM users was 31% lower (crude HR, 0.69; 95% CI ¼ 0.62–0.75).
After adjustment for sociodemographic variables, comorbidities
and treatment of HNC, TCM users had lower mortality by 32%.
Further analysis demonstrated a dose–response relationship
between TCM use and mortality (Table 3). The adjusted HRs were
0.57 (95% CI ¼ 0.49–0.67) and 0.30 (95% CI ¼ 0.25–0.36) for HNC
study of the incidence of oral cancer was computed to be 123-fold
higher in patients who smoked, drank alcohol and chewed betel
nuts than in non-users in Taiwan.18 Chen et al. reported that the
most prevalent site of oral squamous cell carcinoma (SCC) in
Taiwan was the buccal mucosa (37.4%), which contrasted with
data from other countries, such as USA and Northern Norway.19
Buccal cancer accounted for only 2% of all oral SCC in USA and
14% of all oral SCC in Northern Norway.19–21
TCM users had a higher prevalence of comorbidities than
the control group, but the TCM group had a higher survival rate
than the comparison cohort, reflecting that the superiority of
survival among TCM users relative to the cohort patients might
Treatment modalities also had an impact on the risk of
mortality. Treatment with radiotherapy and systemic therapy was
shown to cause the greatest risk for mortality. This increased
risk for mortality likely occurred among patients using this
combined modality because this combined modality was used
for patients who had advanced unresectable cases. Patients
who were treated with surgery and adjuvant therapy also had
higher risks of mortality. This is likely attributable to the fact
that most of these patients had locally advanced cases. The
lowest risk for mortality occurred among patients who received
radiotherapy alone, which was typically used for early stage
patients for organ preservation, such as early stage cancers of the
larynx, base of tongue or hypopharynx.
The TCM prescribed to treat patients with HNCs according to
the TCM functional classifications are shown in Table 4. In
recent years, research on the use of TCM for cancer treatment has
accelerated with the advancement of molecular biology. TCM
affects cancer treatment by (i) targeting apoptosis pathways in
cancer; (ii) reducing inflammatory and infectious complications
in the tissues surrounding the carcinoma; (iii) enhancing
immunity and body resistance; (iv) improving patients’ general
conditions and qualities of life as well their cancer related
fatigue to prolong their life spans; (v) increasing antioxidant
activities; (vi) targeting the tumor cellular proteasome and nuclear
factor-kappaB (NF-jB) pathway5,10,22–25 TCM often involves
mixtures of several Chinese herbs, and some studies have proposed
that the pharmacological advantages of TCM may be derived
from the potentiating action of these multiple bioactive
components and the advancement of individualized therapy.26,27
The most popular herbal formula of the compound
prescription in our study was Gan-Lou-Yin, which consists of Radix
Rehmanniae, Radix Rehmanniae Preparata, Herba Dendrobii,
Radix Asparagi, Radix Ophiopogonis, Radix Scutellariae, Herba
Artemisiae Scopariae, Fructus Aurantii, Folium Eriobotryae and
Radix Glycyrrhizae Preparata.
Herba Dendrobii has been shown to act as a NF-jB inhibitor.
Radix Glycyrrhizae Preparata has been reported to induce the
autophagy of cancer cells through the suppression of Bcl-2
expression and the mTOR pathway. Radix Scutellariae targets
cancer cells through reactive oxygen species (ROS)-mediated
mechanisms, which can potentiate the cytotoxicity of
anticancer medications by depleting glutathione (GSH). The GSH is
a crucial factor in antioxidant defense. Moreover, Scutellariae
can also inhibit the activities of extracellular signal-regulated
kinases (ERK), serine/thronine kinase (AKT), cyclooxygenase-2
(COX-2) and NF-jB to enable it to arrest tumor cell cycle.5,10,23,28
The most popular herbal formula of the single prescription in
our study was Bai-Hua-She-She-Cao, which can attenuate
toxicity and enhance the efficacy of allopathy, improving
TCM is currently considered effective in treating several
cancers other than HNC. Jiang et al.11 reported that TCM was
beneficial in treating unresectable hepatocellular carcinoma in
combination with transcatheter arterial chemoembolization
(TACE). They revealed improved survival in patients treated
with TCM and TACE. TCM is also effective as an adjuvant
therapy for several cancers, including colorectal cancer, advanced
hepatocellular carcinoma, non-small cell lung cancer (NSCLC),
gastric cancer and advanced breast cancer. TCM can reduce
gastrointestinal toxicity and enhance the tumoricidal effect of
chemotherapy in patients with advanced colorectal cancer.
Additionally, TCM can reduce the adverse effects of cytotoxic
drug capecitabine in patients with advanced hepatocellular
carcinoma and prolong the survival of patients with NSCLC. In
patients with breast cancer, TCM can alleviate bone marrow
inhibition and cellular immunity suppression caused by
chemotherapy and prolong the survival of these cancer patients. TCM
also seemed to prolong the survival of patients with progressive
gastric cancer.5 Ling et al.9 reported that TCM could reduce
tumor recurrence and metastasis in patients with NSCLC,
colorectal cancer, hepatocellular carcinoma, superficial bladder
cancer and gastric cancer. Zhou et al.6 also reported that TCM had
synergistic antitumor effects in patients with leukemia and
The large sample size obtained from our nationwide
database lends statistical strength to our examination of the
association between TCM and survival outcomes in patients with
HNC. The patients in our study displayed a wide range of
demographic characteristics, which might render our results more
applicable to the general population. Moreover, this allowed us
to perform stratified analyses according to age, sex, income and
urbanization level. However, this study has several limitations.
First, the NHI program covers only for TCM prescribed by TCM
physicians; therefore, the NHI data do not include
overthe-counter TCM. In other words, the use of TCM may be
underestimated. Second, the NHIRD is a claims-based database;
therefore, no detailed clinical information regarding cancer
staging or biochemical data are recorded. It is the major
limitation of this study. Besides, there may be some unmeasured
confounder correlates with TCM use that is the causative agent
for better outcomes. Therefore, we recommend a randomized
controlled trial to test the effects of adjunctive TCM therapy in
HNC patients is necessary. In addition, we do not analyze
survival outcomes in different types of TCM. Many participants
had mixed types of TCM at the same time or sequentially used
different types of TCM. This is very common in TCM
prescription. Therefore, we could not compare the effects of different
types of TCM. Finally, the NHIRD documents only the date of
death, not the cause of death. The effect of TCM on
HNCspecific mortality therefore cannot be analyzed.
Our study showed that adjunctive therapy with TCM is
associated with higher survival outcome. However, this finding
should be interpreted with caution. The major limitation is the
lack of information of patient cancer stage. In addition,
causality cannot be assessed with the retrospective design. A
randomized controlled trial to test the effect of adjunctive TCM therapy
in HNC patients is needed.
This study is supported in part by Taiwan Ministry of Health
and Welfare Clinical Trial and Research Center of Excellence
(MOHW104-TDU-B-212-113002); China Medical University
Hospital, Academia Sinica Taiwan Biobank, Stroke
Biosignature Project (BM104010092); NRPB Stroke Clinical
Trial Consortium (MOST 103-2325-B-039-006); Tseng-Lien
Lin Foundation, Taichung, Taiwan; Taiwan Brain Disease
Foundation, Taipei, Taiwan; Katsuzo and Kiyo Aoshima
Memorial Funds, Japan; and Health, and welfare surcharge
of tobacco products, China Medical University Hospital
Cancer Research Center of Excellence
(MOHW104-TDU-B212-124-002, Taiwan), and CMU under the Aim for Top
University Plan of the Ministry of Education, Taiwan. The
funders had no role in study design, data collection and
analysis, decision to publish or preparation of the
Conflict of interest: None declared.
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