Conventional Western Treatment Associated With Chinese Herbal Medicine Ameliorates the Incidence of Head and Neck Cancer Among Patients With Esophageal Cancer

Abstract

Background: Because of advances in medical treatment, the survival of cancer patients is prolonged. In line with the prolonged survival time of cancer the incidence of second primary cancer has increased. There is currently no effective way to prevent the occurrence of secondary primary cancer (SPC). Objectives: The aim of this study is to evaluate whether Chinese Herbal Medicine (CHM) is correlated with reduced occurrence of second primary cancer (SPC) of head and neck (H&N) in patients with esophageal cancer (EC). Method: We identified 15,546 patients who were diagnosed with esophageal cancer between Jan 1, 2000, and Dec 31, 2010. The patients with H&N cancer before receiving CHM were excluded. After the selection and matching process, both CHM and non-CHM cohorts each contained 850 individuals. We compared the cumulative incidence of SPC of H&N with or without CHM treatment in patients with EC by the Kaplan-Meier method. NodeXL is used to run a network analysis of CHM to examine the association between herbs and formulas. Results: Compared with non-CHM users, CHM-users showed a reduced incidence rate of SPC of H&N among the patients with EC. Reduced cumulative incidence of SPC of H&N among patients with EC was noted in the CHM cohort compared to the non-CHM cohort. The most commonly used single herbs and formulas were associated with reducing SPC occurrence. Conclusion: We propose that CHM as an adjuvant therapy may prevent the occurrence of SPC of H&N in patients with EC.

Keywords

secondary primary cancers esophageal cancer head and neck cancer Chinese herbal medicine cohort study

Introduction

Esophageal cancer (EC) is one of the most commonly occurring cancers in the world. There were an estimated 483 000 new cases of EC in 2015, resulting in approximately 439 000 deaths. Globally, it is the sixth leading cause of cancer-related deaths and the seventh leading cause of years of life lost as a result of cancer.¹ There are 2 major histological subtypes: squamous cell carcinoma (SCC) and adenocarcinoma (AC), which have varying regional and ethnic distributions.^2,3 SCC currently has a higher global prevalence rate than AC, whereas approximately 79% of all SCC cases are found in South-Eastern and Central Asia.³ The main geographical distribution areas of AC were in Northern and Western Europe, Northern America, and Oceania, which together accounted for 46% of AC cases globally.³ Current treatments of EC include endoscopic therapy for early stages. Meanwhile, esophagectomy combined with neoadjuvant chemoradiotherapy with carboplatin and paclitaxel, or cisplatin and fluorouracil, is commonly used for patients with medium-grade diagnoses, whereas palliative chemotherapy with cisplatin or oxaliplatin, combined with either fluorouracil or capecitabine, is used for patients with unresectable cancers.⁴ Because of the application of such advanced treatments, survival rates have seen notable increases.^4-6 As reported, the 5-year survival rate increased from 5% from 1975 to 1977, to 20.5% from 2006 to 2012.⁷ Tragically, however, increased survival times lead to EC patients’ increased risk of developing secondary primary cancers (SPCs). Previous reports have indicated that the standardized incidence ratio (SIR) of overall SPCs in EC patients compared with the general population are significantly increased in Taiwan,⁸ whereas Zhu et al⁹ reported that SIR (1.34) was enhanced by 26% according to the SEER database of the US population. Furthermore, Chuang et al¹⁰ reported that SIR (1.15) also increased in 13 population-based cancer registries in Europe, Australia, Canada, and Singapore. All the patients with EC were at increased risk of suffering from head and neck (H&N), lung, stomach, small intestine, and kidney cancer as well as leukemia.^8-11 Among these SPCs, H&N cancer was often noted to be of the highest risk.^8-10 However, current studies on the issue of SPC only suggest close monitoring as a preferred method of early detection, so that SPCs can undergo earlier treatment.^6,11-13 There are currently no more aggressive or effective methods of SPC prevention.

Complementary and alternative medicine (CAM) therapies are commonly applied in many countries. CAM can be classified into various categories, including biological-based therapies, manipulative and body-based therapies, mind-body therapies, alternative medical systems, energy healing therapy, and special diets. Herbal medicine is defined as a category of CAMs.¹⁴ Wu et al¹⁵ have reported that there were about 40.6 million adults who used herbs and supplements, such as ginkgo and ginseng, in 2012, in the United States. It was observed that cancer survivors used more nonvitamin/mineral natural products than cancer-free adults (23.7% vs 18.5%) among the American population in 2012, in total spending approximately $1.2 billion annually on nonvitamin/mineral natural products, with a mean of $285 per cancer survivor.¹⁴ However, only 3.9% reported the primary reason for their CAM use as specifically to treat cancer. This number was notably less than that for other health-related reasons, such as back pain (14.4%), joint pain/stiffness (9.8%), cardiovascular diseases (9.5%), and neck pain (6.6%).¹⁴

Taiwan has been under the current National Health Insurance (NHI) system since 1995. In 1997, the NHI Research Database (NHIRD) was established by the National Health Research Institute to promote research and offer informative insights for the development of national health policies. The NHIRD covers approximately 23 million insurers and is one of the largest nationwide population databases in the world.¹⁶ As of 2015, the NHI covered 99.6% of the population in Taiwan.¹⁷ Chinese herbal medicine (CHM) constitutes a significant category of traditional Chinese medicine (TCM) for CAM therapies. CHM treatments reimbursed by NHI since 1996 were either single-herb or multiherb products, extracted to powder form after water decoction, concentration, and excipient, by Good Manufacturing Practice–certified pharmaceutical companies.¹⁸ In Taiwan, patients often use CHM to treat or relieve the symptoms and signs of endocrine disorders, nutritional and metabolic diseases, immunity disorders (23.2%), and genitourinary system diseases (16.6%).¹⁷ CHM treatment may help relieve symptoms of discomfort associated with cancer or those induced by chemotherapy and/or radiotherapy.^19-21 Moreover, some studies have demonstrated that CHM has anticancer effects.^22,23

The aim of the present study is to clarify whether CHM is associated with reduced risk of SPC of the H&N in patients with EC, which could provide an additional treatment option for patients to not only ameliorate the side effects, but also to decrease the secondary cancer recurrence rate.

Methods

Data Source

Participants of this retrospective cohort study consist entirely of Taiwan residents. We used the Registry for Catastrophic Illness Patient Database (RCIPD), a sub–data set of NHIRD, which records the medical care information of Taiwan’s catastrophic illness patients. Those patients enrolled in RCIPD correspond to various pathological categories. The catchment population for the NHIRD is estimated to be more than 99% of the total population of Taiwan. Specific disease identification in the NHIRD was recorded according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code. The medical care information recorded in the NHIRD includes, among others, medical category, drug use, and surgery undergone.

Study Population and Covariates

Patients newly diagnosed with EC in the RCIPD during the years 2000 to 2010 were qualified for inclusion in this study. The patients with EC were divided into 2 groups, classified as CHM and non-CHM cohorts. The definition of CHM users included patients having TCM clinical visits with EC ICD-9-CM code after diagnosis of EC. The non-CHM users were the population without any record of TCM clinical visit after diagnosis of EC. The index date was defined as the TCM-received date. Only individuals whose index date occurred between the years 2000 and 2010 were enrolled in this study. Those patients with H&N cancer (ICD-9-CM: 140, 141, 143-418, and 161) before the index date were excluded.

The occurrence of H&N cancer as SPC was identified among EC patients during the years 2000 to 2011. History of alcohol-related illness (ICD-9-CM: 291, 303, 305, 571.0, 571.1, 571.2, 571.3, 790.3, and V11.3), cirrhosis (ICD-9-CM: 571), anemia (ICD-9-CM: 280-285), asthma (ICD-9-CM: 493), chronic obstructive pulmonary disease (COPD; ICD-9-CM: 491, 492, 493 and 496), diabetes mellitus (ICD-9-CM: 250), hypertension (ICD-9-CM: 401-405), coronary artery disease (CAD; ICD-9-CM: 410-414), rheumatoid arthritis (ICD-9-CM: 714), systemic lupus erythematosus (ICD-9-CM: 710.0), stroke (ICD-9-CM: 430-438), esophagus ulcer (ICD-9-CM: 530.2), and esophagitis (ICD-9-CM: 530.1) before the index date were the baseline comorbidities. Surgery, chemotherapy, and radiotherapy were also considered to be variables. The job types of participants were included in the categories of office workers, manual workers, and others. In this study, we also investigated the specific usage patterns of CHMs among patients with EC.

Statistical Analysis

The final study population was recruited after propensity score match.²⁴ Sex, age, index year, and diagnosis year of EC were the criteria for the propensity score matching. Each CHM user was matched with a non-CHM user at a 1:1 ratio, according to the propensity score calculated. We tested the association of baseline demographics in patients with and without CHMs using χ² tests. χ² Tests were also used to compare comorbidity and treatment modality. We used the Fisher exact test instead of the χ² test when the cell was insufficient. The difference of mean age between CHM users and non-CHM users was evaluated using the Student t-test. Our study used the Kaplan-Meier method to estimate the cumulative incidence of H&N cancer during the study period. The log-rank test was conducted to compare the difference in cumulative incidence of H&N cancer between CHM and non-CHM cohorts. The effect of variables was examined in Cox proportional hazards models. This study utilized mortality to adjust Cox proportional hazards models to calculate subhazard ratio (SHR) and 95% CI. We classified the CHM receiving duration group by median CHM treatment days. NodeXL is an open-source freeware used to run a network analysis of CHM, which can be found at http://nodexl.codeplex.com/. P values less than .05 indicated statistical significance in this study. We performed analyses (except network analysis) with the statistical software package, SAS, version 9.4 (SAS Institute, Inc, Cary, NC).

Results

Demographic Characteristics

We identified 15 546 patients who were diagnosed with EC between January 1, 2000, and Decemeber 31, 2010 (Figure 1). There were 1261 and 12 173 participants in the CHM group and non-CHM groups, respectively. After selection by the exclusion criteria and matching process, both CHM and non-CHM cohorts each contained 850 individuals.

Figure 1.

Flow chart of CHM and non-CHM cases from Registry for Catastrophic Illness Patient Database (RCIPD) in Taiwan during 2000-2010.

In terms of the demographic characteristics of the patients with EC, both the CHM and non-CHM cohorts consisted mainly of male participants (Table 1). There were 516 (60.7%) and 493 (58%) CHM and non-CHM users, aged 40 to 59 years, respectively, whereas the average ages of the CHM and non-CHM cohorts were 57.2 and 58.0 years, respectively. Although the job-type distribution of patients differed between the CHM cohort and non-CHM cohort (P = .001), manual workers made up approximately half of both groups; cirrhosis, hypertension, COPD, and esophagitis were the primary baseline comorbidities in the 2 cohorts. Moreover, the study found a significant difference between patients receiving chemotherapy and/or radiotherapy between the CHM and non-CHM cohorts (P = .01 for chemotherapy; P < .001 for radiotherapy). The mean induction times between CHM users and non-CHM users were 2.41 (2.02) and 2.15 (1.20) years, respectively (t-test P = .61). This indicates that there was no statistically significant difference in the mean induction time of subsequent H&N cancer after the diagnosis of EC between groups.

Table 1.

Demographic Characteristics of the Patients Newly Diagnosed With Esophageal Cancer in Taiwan in 2000-2010.

Variable	Non-CHM, n = 850, 50.00%		CHM, n = 850, 50.00%		P Value
Variable	n	Percentage	n	Percentage	P Value
Sex					.63
Female	35	4.12	39	4.59
Male	815	95.9	811	95.4
Age at baseline (years)					.33
20-39	40	4.71	30	3.53
40-59	493	58.0	516	60.7
≥60	317	37.3	304	35.8
Mean (SD)^a	58.0(12.5)		57.2(11.2)		.17
Job type					.001
Office worker	161	18.9	187	22.0
Manual worker	423	49.8	463	54.5
Others	266	31.3	200	23.5
Baseline comorbidity
Alcohol-related illness	192	22.6	197	23.2	.77
Cirrhosis	313	36.8	351	41.3	.06
Anemia	140	16.5	128	15.1	.42
Asthma	81	9.53	71	8.35	.40
Chronic obstructive pulmonary disease	253	29.8	248	29.2	.79
Diabetes mellitus	121	14.2	137	16.1	.28
Hypertension	299	35.2	284	33.4	.44
Coronary artery disease	137	16.1	163	19.2	.10
Rheumatoid arthritis	1	0.12	0	0
Systemic lupus erythematosus	0	0	0	0
Stroke	95	11.2	88	10.4	.58
Esophagus ulcer	98	11.5	117	13.8	.17
Esophagitis	260	30.6	288	33.9	.15
Treatment
Surgery	77	9.06	74	8.71	.80
Chemotherapy	627	73.8	671	78.9	.01
Radiotherapy	688	80.9	748	88.0	<.001
Target therapy^b	3	0.35	1	0.12	.62
Mean follow-up period (median), year	1.38 (0.73)		1.63 (0.89)
Mean induction time (median), year^a	2.41 (2.02)		2.15 (1.2)		.61
Mean CHM duration^c (median), year			0.54 (0.31)

Abbreviation: CHM, Chinese herbal medicine.

Student t-test.

Fisher exact test.

Duration is the period between esophageal cancer diagnosis date and index date.

The Cause-Specific Hazard Ratio and 5-Year Cumulative Incidence of H&N Cancer

The study reveals that compared with non-CHM users, CHM users presented a reduced incidence risk of H&N cancer among patients with EC (adjusted SHR = 0.58, 95% CI = 0.34-0.98, P = .04; Table 2). Of note, during the study period, the cumulative incidence of H&N cancer was significantly higher among non-CHM users as compared with CHM users (Figure 2). We initially defined EC patients who took CHM for ≤7 days as the low-dose CHM cohort, in contrast to CHM >7 days as the high-dose CHM cohort. The crude SHRs between low- and high-dose cohorts were 0.39 (95% CI = −0.17 to 0.88; P = .02) and showed statistical significance. Our results demonstrated that there was no statistical significance in the dose response of CHM after adjustment (SHR = 0.48; 95% CI = −0.2 to 1.12; P = .09), as shown in Supplementary Table 1. We believed that the high-dose CHM cohort might show a trend to decreased incidence of SPC of H&N cancer compared with the low-dose CHM cohort with a larger number of patients. After dividing the population into 4 subgroups, on the other hand (Table 2), we found that the risk of H&N cancer among the CHM cohort that received CHM for a period of more than 28 days was significantly lower than that among the non-CHM cohort (adjusted SHR = 0.45; 95% CI = 0.21-0.97; P = .04).

Table 2.

Cox Model–Measured Hazard Ratio and 95% CIs of Head and Neck Cancer Associated With CHM Use and Covariates Among Esophageal Cancer Patients.

Characteristics	Event Number (n = 58)	Crude			Adjusted^a
Characteristics	Event Number (n = 58)	HR	(95% CI)	P Value	HR	(95% CI)	P Value
CHM
No	35	1	Reference		1	Reference
Yes	23	0.62	(0.37-1.04)	.07	0.58	(0.34-0.98)	.04
CHM duration
Nonuser	35	1	Reference		1	Reference
<14 Days	11	1	(0.51-1.96)	.99	0.86	(0.44-1.67)	.66
14-27	3	0.38	(0.12-1.22)	.10	0.4	(0.13-1.27)	.12
≥28 Days	9	0.49	(0.24-1.02)	.06	0.45	(0.21-0.97)	.04
Sex
Women	0	1	Reference		1	Reference
Men	58
Age, years
20-39	2	1	Reference		1	Reference
40-59	45	1.61	(0.39-6.59)	.51	1.82	(0.42-7.89)	.42
≥60	11	0.63	(0.14-2.82)	.55	0.98	(0.2-4.82)	.98
Job type
Office worker	17	1	Reference		1	Reference
Manual worker	31	0.7	(0.39-1.26)	.24	0.77	(0.42-1.41)	.40
Others	10	0.41	(0.19-0.9)	.03	0.63	(0.28-1.4)	.26
Baseline comorbidity (yes vs no)
Alcohol-related illness	20	1.86	(1.09-3.19)	.02	1.19	(0.63-2.22)	.60
Cirrhosis	31	1.83	(1.1-3.06)	.02	1.57	(0.88-2.79)	.13
Anemia	7	0.71	(0.33-1.57)	.40	0.8	(0.37-1.76)	.59
Asthma	2	0.35	(0.09-1.43)	.14	0.09	(0.02-0.32)	<.001
Chronic obstructive pulmonary disease	15	0.86	(0.48-1.54)	.60	1.46	(0.79-2.71)	.23
Diabetes mellitus	7	0.78	(0.35-1.71)	.53	1.03	(0.42-2.53)	.94
Hypertension	18	0.87	(0.5-1.51)	.62	1.52	(0.81-2.88)	.20
Coronary artery disease	3	0.25	(0.08-0.79)	.02	0.27	(0.09-0.84)	.02
Rheumatoid arthritis	0
Systemic lupus erythematosus	0
Stroke	1	0.15	(0.02-1.06)	.06	0.2	(0.03-1.66)	.14
Esophagus ulcer	9	1.25	(0.61-2.53)	.54	1.25	(0.6-2.62)	.55
Esophagitis	18	0.97	(0.56-1.69)	.91	0.93	(0.53-1.65)	.81
Treatment (yes vs no)
Surgery	10	2.53	(1.28-4.99)	.01	2.32	(1.14-4.73)	.02
Chemotherapy	49	1.71	(0.85-3.47)	.14	0.84	(0.4-1.79)	.66
Radiotherapy	56	5.08	(1.25-20.67)	.02	4.78	(1.04-21.89)	.04

Abbreviations: CHM, Chinese herbal medicine; HR, hazard ratio.

Adjusted HR: adjusted for sex, age, job type, all comorbidities, and all treatments in Cox proportional hazards regression.

Figure 2.

Kaplan-Meier analysis of cumulative incidence of head and neck cancer between esophageal cancer patients with and without Chinese herbal medicine (CHM) use. The cumulative incidence of head and neck cancer was significantly higher among non-CHM users as compared with CHM users in the patients with esophageal cancer (log-rank test, P = .02).

Patients with a comorbidity of asthma or CAD presented a lower incidence of H&N cancer (adjusted SHR = 0.09, 95% CI = 0.02-0.32, P value <.001 for asthma; adjusted SHR = 0.27, 95% CI = 0.09-0.84, P value = .02 for CAD; Table 2). Because there were only 2 events of asthma and 3 events of CAD in all EC patients associated with H&N cancer, it is difficult to conclude that CHM really had the effect of ameliorating the incidence of SPC (H&N cancer) in the EC patients with asthma and CAD. Among the study population, surgery and radiotherapy enhanced the recurrence probability of head and neck cancer (adjusted SHR = 2.32, 95% CI = 1.14-4.73, P value = .02 for surgery; adjusted SHR = 4.78, 95% CI = 1.04-21.89, P value = .04 for radiotherapy; Table 2). Furthermore, patients receiving surgery and/or radiotherapy treatment demonstrated an increased incidence rate of H&N cancer compared with those not having undergone such treatments. To further investigate the effect of CHM on the incidence rates of H&N cancer with and without CHM use in patients with EC in different treatment stratifications, we found that the CHM cohort demonstrated a decreased incidence rate of H&N cancer in patients receiving chemotherapy and/or radiotherapy rather than surgery, compared with the non-CHM cohort (adjusted SHR = 0.47, 95% CI = 0.26-0.85, P < .05 for chemotherapy; adjusted SHR = 0.56, 95% CI = 0.32-0.95, P < .05 for radiotherapy). This indicates that CHM reduced the risk of SPC of H&N cancer occurrence caused by chemotherapy and/or radiotherapy, as shown in Table 3. The overall incidence of SPC of H&N cancer in the CHM cohort was lower than that of the non-CHM cohort. More specifically, after stratification of the follow-up period, the adjusted SHR was 0.45 (95% CI = −0.21 to 0.94) in the CHM cohort within the follow-up period of less than 2 years, as shown in Table 3.

Table 3.

Incidence Rates, Hazard Ratio, and CIs of Head and Neck Cancer With and Without CHM Among Esophageal Cancer Patients in Different Treatment and Follow-up Period Stratifications.

	CHM						CHM vs Non-CHM
	No (n = 850)			Yes (n = 850)			Crude SHR (95% CI)	Adjusted SHR (95% CI)
	Event	Person-years	IR	Event	Person-years	IR	Crude SHR (95% CI)	Adjusted SHR (95% CI)
Treatment
Surgery	5	117	42.7	5	140	35.7	0.83 (0.24-2.82)	0.69 (0.13-3.53)
Chemotherapy	31	812	38.2	18	1038	17.4	0.51 (0.29-0.9)*	0.47 (0.26-0.85)*
Radiotherapy	34	874	38.9	22	1127	19.5	0.56 (0.33-0.96)*	0.56 (0.32-0.95)*
Follow-up period (years)
<2	20	779	25.7	11	879	12.5	0.53 (0.25-1.1)	0.45 (0.21-0.94)*
2-3	10	228	43.9	8	289	27.7	0.63 (0.25-1.6)	0.66 (0.24-1.77)
≥4	5	165	30.3	4	222	18.1	0.64 (0.17-2.47)	1.07 (0.2-5.66)

Abbreviations: CHM, Chinese herbal medicine; SHR, subhazard ratio; IR, incidence rate.

Single Herbs and Formulas Commonly Prescribed in TCM Clinical Practice

The most popular herbal prescription for patients with EC was Hedyotidis Diffusae Herba (Table 4). The second and third most frequently prescribed herbs were Fritillaria thunbergii and Scutellariae Barbatae Herba, respectively. The top 3 formulas prescribed for patients with EC were Xiang-Sha-Liu-Jun-Zi-Tang, Ban-Xia-Xie-Xin-Tang, and Shen-Ling-Bai-Zhu–San, respectively (Table 5). The composition of the 10 most common formulas is shown in Supplementary Table 2. For each treatment involving patients with EC, 32.22% of the CHM prescriptions consisted of 5 or 6 individual combinations of single herbs and/or formulas (Supplementary Figure 1), whereas prescriptions with 7 or 8 CHM combinations made up 27.26%. The prescriptions of Hedyotidis Diffusae Herba along with Scutellariae Barbatae Herba and F thunbergii were the most frequent CHM combinations prescribed by TCM practitioners (Figure 3).

Table 4.

The 10 Most Common Single Herbs Prescribed for Patients With Esophageal Cancer.

Prescription Name (in Chinese)	Frequency	Number of Person-days, Frequency	Average Daily Dose (g)	Average Duration for Prescription (days)
Bai-Hua-She-She-Cao [Hedyotis diffusa]	1967	23 052	1.5	11.7
Bei-Mu [Fritillaria thunbergii]	1110	13 274	1.2	12
Ban-Zhi-Lian [Scutellaria barbata D Don]	1030	12 267	2.1	11.9
Dan-Shen [Salvia miltiorrhiza]	819	10 991	1.4	13.4
Huang-Qi [Astragalus membranaceus]	854	10 950	1.6	12.8
Hai-Piao-Xiao [Os Sepiae]	613	8583	1.6	14
Hou-Po [Magnolia officinalis]	740	8342	1.2	11.3
Mai-Men-Dong [Radix Ophiopogon japonicus]	605	6838	1.4	11.3
Bai-Zhu [Atractylodes macrocephala]	587	6610	1.4	11.3
Huang-Qin [Scutellaria baicalensis]	534	6371	1.2	11.9

Table 5.

The 10 Most Common Formulas Prescribed for Patients With Esophageal Cancer.

Prescription Name (in Chinese)	Frequency	Number of Person-days, Frequency	Average Daily Dose (g)	Average Duration for Prescription (days)
Xiang-Sha-Liu-Jun-Zi-Tang	951	12 999	4.8	13.7
Ban-Xia-Xie-Xin-Tang	743	9884	5	13.3
Shen-Ling-Bai-Zhu-San	658	8601	6.1	13.1
Bu-Zhong-Yi-Qi-Tang	640	7292	6	11.4
Pao-Ho-Wan	486	6629	3.9	13.6
Gan-Lu-Yin	578	6113	6.2	10.6
Xuan-Fu-Dai-Zhe- Shi-Tang	443	5462	4.1	12.3
Ping-Wei-San	422	4844	3.8	11.5
Jia-Wei-Xiao-Yao-San	362	4641	3.9	12.8
Liu-Wei-Di-Huang-Wan	399	4510	4.7	11.3

Figure 3.

Network analyses of the most frequently used 50 herb and formula combinations for all patients with esophageal cancer. The size of the spot indicates the frequency of Chinese herbal product prescribed, and the width of the line indicates the frequency of association between 2 Chinese herbal products.

Discussion

This is the first report using the NHIRD to compare the risk of SPC of the H&N among patients diagnosed with EC with and without CHM treatment. In a recent study, Chen et al⁸ reported that the cumulative incidence of H&N cancer remained significantly high within a follow-up time of more than 10 years among patients with EC. Notably, this study reveals that the cumulative incidence of H&N cancer in EC patients with CHM treatment is 15% of the total cumulative incidence rate, within a follow-up time of 8 years. In contrast, the incidence in patients without CHM use rose to approximately 30% of the cumulative incidence rate during the 8-year follow-up period. These findings indicate that patients with EC using CHM demonstrate a decreased risk of developing H&N cancer over a longer-term follow-up period. The decreased incidence rate in the CHM cohort within the follow-up period of less than 2 years suggests that CHM treatment as early as possible may have a protective effect against incidence of SPCs.

The association of EC with SPC, especially for H&N cancers, was first identified by the connection to the field cancerization effect in 1953 by Slaughter et al.²⁵ It has been reported that smoking, drinking, and heat damage are high-risk factors for developing SCC.^3,26-28 The carcinogenic effects of tobacco and alcohol may concurrently influence other parts of the aerodigestive tract. The affected epithelium of the aerodigestive tract may be activated in more than one location within the body, leading to a process of irreversible change, eventually resulting in carcinogenesis. Finally, these carcinogens, exposed in sufficient intensity for a period of time, will trigger the development of multiple independent primary cancers.^9,10,25 In addition to smoking and drinking, betel nut is also an addictive substance commonly used in the Asian region.²⁹ As reported, betel nut has been found to cause cancers in the upper aerodigestive tract, including oral SCC and SCC of the pharynx, esophagus, and larynx.³⁰ Betel nut and betel nut extract exert carcinogenicity, mutagenicity, and genotoxicity to result in tumor production by many mechanisms.³¹ Chewing betel nut causes mucosal exposure to 4 N-nitrosamines formed by areca alkaloids, 2 of which are carcinogenic,³² through reactive oxygen species activation. Because of reactive oxygen species attacking salivary glands and the oral mucosa, the structural change of oral mucosa facilitates penetration by the betel nut ingredients and environmental toxicants. We consider that the mucosa change induced by a variety of carcinogens such as cigarettes and betel nut will increase the risk of H&N cancer among patients with EC. In Taiwan, it has been reported that SCC accounts for about 95.5% of all ECs.³³ Chen et al⁸ have reported that major surgery (HR = 1.24; 95% CI = 1.06-1.44; P = .006) is an independent risk factor of subsequent development of SPC. In this study, we found a similar result, specifically that surgery increased the risk of SPC H&N cancer. Based on the observations of this study, we can propose that CHM can interrupt the process of field cancerization via adjusting the constitution of patients with EC. Clinical CHM prescriptions are composed of several natural products, each containing numerous chemical compounds and each exerting its specific therapeutic functions on multiple targets within the human body. As tumorigenesis and metastasis involve multiple signaling pathways, inhibitors that affect a single pathway may not fully counter the disease progression and may even cause resistance.³⁴ CHM prescriptions, causing relatively fewer side effects and offering a multitargeted approach, may play an important role in the treatment of both original cancers and SPCs.

According to TCM theory, the formation of individual constitutions results from congenital inheritance and lifestyle influences, including environmental conditions and dietary habits. The specific constitution causes the body’s susceptibility to particular pathogenic factors and determines the trend of syndrome changes.³⁵ It has been shown that the frequent use of tobacco and alcohol leads to the development of phlegm-dampness and dampness-heat constitutions.³⁶ Patients with such a phlegm-dampness constitution are known to be particularly susceptible to metabolic syndromes, such as hyperlipidemia, diabetes, obesity, and hypertension,³⁷ which are also associated with H&N cancer.^38,39 As reported, the risk for oral cancers in male individuals increased 15%, in parallel with the standard deviation metabolic risk score increment.³⁹ In addition, the heat effect of dampness-heat constitution contributes to chronic inflammation resulting from increased oxidative stress and has been suggested as the mechanism responsible for increased susceptibility to cancer.^40,41 This study reveals the 10 most commonly prescribed formulas for patients with EC. Among them, Xiang-Sha-Liu-Jun-Zi-Tang is clinically applied to those with the phlegm-dampness constitution to relieve various symptoms associated with the digestive tract, such as chemotherapy-induced nausea and vomiting as well as anorexia-cachexia syndrome.⁴² It has been demonstrated that Liu-Jun-Zi-Tang exhibited both anti-inflammatory and antioxidative protective effects on mice exposed to cigarette smoke through enhanced activities of antioxidant enzymes and by attenuating the levels of lipid oxidative production through inhibiting phosphorylation of IκB-α and NF-κB.⁴³ Additionally, Liu-Jun-Zi-Tang has been shown to regulate insulin secretion and ameliorate metabolic syndromes,³⁹ which are beneficial for the prevention of SPC initiation.^44,45

Here, we found that radiotherapy increased the risk of SPC of the H&N in patients with EC, in line with a report by Zhu et al.⁹ As we know, radiation therapy for primary cancers is highly associated with an increased risk of developing SPC in nearby organs.⁹ It is biologically plausible that DNA damage resulting from radiotherapy is a potential mechanism leading to the occurrence of SPC in the irradiated H&N area.^46,47 Based on the observations of this study, we can propose that CHM could prevent the development of SPC of the H&N via protecting against radiotherapy-induced DNA damage. Ban-Xia-Xie-Xin-Tang (BXXXT) is commonly used for treatment of chemotherapy- and radiotherapy-induced mucositis in patients with EC. BXXXT simultaneously decreases DNA damage induced by radiotherapy through multiple mechanisms, including by inhibiting COX2 activity and PGE2 production and by restraining MAPK upregulation to reduce stable free radicals and prevent reactive oxygen species formation.^21,48 Furthermore, Gan-Lu-Yin (GLY) is frequently used for the treatment of oral ulcers after chemotherapy and/or radiotherapy in patients with H&N cancer. GLY decreases the level of TNF-α release via inhibiting the NF-κB–, AKT-, and ERK-dependent pathways.⁴⁹ Based on this, we propose that this protective effect may also be applied to the prevention of SPC occurrence of H&N in patients with EC. Moreover, CHM is associated with immune modulation in patients with EC to avoid the development of SPC of the H&N. Notably, Bu-Zhong-Yi-Qi-Tang has been shown to relieve cancer-related fatigue⁵⁰ by enhancing interleukin-18 to induce cell-mediated immunity and improve the host’s defensive capabilities.⁵¹ In addition, Jia-Wei-Xiao-Yao-San can rehabilitate paclitaxel-induced axonal involvement and promote recovery from paclitaxel-induced neuropathy via increasing the proportion of phosphorylated ERK1/2 and phosphorylated AKT to promote neurite outgrowth with NGF.⁵² As a result of Jia-Wei-Xiao-Yao-San use, quality of life can be improved, allowing patients to accept a more complete treatment of chemotherapy.

The prescription of CHM, in combination with numerous single herbs or formulas, aims to potentiate therapeutic efficacy and mitigate side effects.⁵³ As such, Figure 3 illustrates network analyses of the most frequent herbs and formula combinations for patients diagnosed with EC. We found that Hedyotidis Diffusae Herba, Scutellariae Barbatae Herba, and Fritillaria thunbergii can be combined in clinical prescription, which may result in enhanced anticancer effects.^53,54 Significantly, Magnolia officinalis and Scutellaria baicalensis were reported to induce apoptosis both in esophageal and H&N cancers, which could contribute to clinical anticancer effects.^22,23,55,56 The biological anticancer activities and possible mechanisms of the most common single herbs are illustrated in Supplementary Table 3.^{22,23,34,54-66}

The data used for the present study were extracted from the NHIRD; however, there inevitably exist some limitations and flaws. The NHI does not provide patient specifics, including laboratory data, images, pathology reports, disease stage, metastasis status, or lifestyle details. Therefore, we could not confirm preliminary histological subtypes of EC patients. Because of a lack of data, we also could not evaluate whether CHM influenced risk factors such as exposure to tobacco and/or alcohol. Moreover, some cancer patients may take supplements or medications from pharmacies instead of hospitals, the data of which were not recorded by the NHI. Additionally, the NHI only reimburses prescriptions of CHM by licensed TCM practitioners who register the data; therefore, data from those doctors who do not participate in the NHI program (fewer than 10%) will be excluded.¹⁷

Conclusion

In conclusion, this study demonstrates that CHM, which has been shown to relieve symptoms of discomfort associated with cancer and cancer treatment, is also associated with reduced incidence of SPC of the H&N in EC patients. This effect may result from the multicomponent compositions, multitargeted mechanisms, and presence of fewer side effects. CHM may also reduce cancer-promoting side effects of conventional treatments such as radiotherapy. However, it is necessary to further validate the relationship between CHM and the reduced incidence rate of SPC of the H&N by conducting a prospective clinical trial involving patients with EC in the near future.

Supplemental Material

Supplementary_Table_and_Figure-R2_EDITS – Supplemental material for Conventional Western Treatment Associated With Chinese Herbal Medicine Ameliorates the Incidence of Head and Neck Cancer Among Patients With Esophageal Cancer

Supplemental material, Supplementary_Table_and_Figure-R2_EDITS for Conventional Western Treatment Associated With Chinese Herbal Medicine Ameliorates the Incidence of Head and Neck Cancer Among Patients With Esophageal Cancer by Chia-Chen Chang, Kuo-Wei Bi, Hung-Jen Lin, Yuan-Chih Su, Wen-Ling Wang, Chen-Yuan Lin, Chun-Fu Ting, Mao-Feng Sun and Sheng-Teng Huang in Integrative Cancer Therapies

Footnotes

Acknowledgements

The authors would like to thank James Waddell for the critical reading and revision of our manuscript.

Authors’ Note

C-CC and K-WB wrote the manuscript, interpreted the data, and contributed equally to this work. Y-CS collected, assembled, and analyzed the data. H-JL, W-LW, C-YL, C-FT and M-FS provided and checked the data. S-TH designed and conceived the study, and amended the manuscript. C-CC, K-WB, H-JL, Y-CS, W-LW, C-YL, C-FT, M-FS, and S-TH approved the final manuscript. The Review Board and Ethics Committee of China Medical University Hospital, Taiwan, approved the data used for this research (CMUH104-REC2-115(CR-3)). All information of patients was decoded in the database from NHIRD, and informed consent was not needed.

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 work was supported and funded by National Research Institute of Chinese Medicine, Ministry of Health and Welfare (MOHW106-NRICM-C-104-000002), Taipei Chinese Medical Association (TPCMA2018-Research02), Health and welfare surcharge of tobacco products, China Medical University Hospital Cancer Research Center of Excellence (MOHW107-TDU-B-212-114024), China Medical University Hospital (DMR-107-164, DMR-107-192 and CRS-106-001), and Chinese Medicine Research Center, China Medical University under the Higher Education Sprout Project, Ministry of Education (CMRC-CHM-1) in Taiwan. This study was also supported in part by the Ministry of Health and Welfare, Taiwan (MOHW107-TDU-B-212-123004), Academia Sinica Stroke Biosignature Project (BM10701010021), MOST Clinical Trial Consortium for Stroke (MOST 106-2321-B-039-005), Tseng-Lien Lin Foundation, Taichung, Taiwan, and Katsuzo and Kiyo Aoshima Memorial Funds, Japan.

ORCID iD

Sheng-Teng Huang, .

Supplemental Material

Supplemental material for this article is available online.

References

Global Burden of Disease Cancer Collaboration; Fitzmaurice

Allen

et al . Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the Global Burden of Disease Study. JAMA Oncol. 2017;3:524-548.

Abbas

Krasna

Overview of esophageal cancer. Ann Cardiothorac Surg. 2017;6:131-136.

Arnold

Soerjomataram

Ferlay

Forman

Global incidence of oesophageal cancer by histological subtype in 2012. Gut. 2015;64:381-387.

Rustgi

El-Serag

HB.

Esophageal carcinoma. N Engl J Med. 2014;371:2499-2509.

Kleinberg

Knisely

Heitmiller

et al . Mature survival results with preoperative cisplatin, protracted infusion 5-fluorouracil, and 44-Gy radiotherapy for esophageal cancer. Int J Radiat Oncol Biol Phys. 2003;56:328-334.

Ghaly

Kamel

Nasar

et al . Locally advanced esophageal cancer: what becomes of 5-year survivors? J Thorac Cardiovasc Surg. 2016;151:726-732.

Jemal

Ward

Johnson

et al . Annual Report to the Nation on the Status of Cancer, 1975-2014, featuring survival. J Natl Cancer Inst. 2017;109(9). doi:10.1093/jnci/djx030

Chen

Teng

et al . Secondary primary malignancy risk among patients with esophageal cancer in Taiwan: a nationwide population-based study. PLoS One. 2015;10:e0116384.

Zhu

Chen

Zhu

et al . Risk of second primary cancer after treatment for esophageal cancer: a pooled analysis of nine cancer registries. Dis Esophagus. 2012;25:505-511.

10.

Chuang

Hashibe

Scelo

et al . Risk of second primary cancer among esophageal cancer patients: a pooled analysis of 13 cancer registries. Cancer Epidemiol Biomarkers Prev. 2008;17:1543-1549.

11.

Nandy

Dasanu

CA.

Incidence of second primary malignancies in patients with esophageal cancer: a comprehensive review. Curr Med Res Opin. 2013;29:1055-1065.

12.

Morimoto

Yano

Yoda

et al . Clinical impact of surveillance for head and neck cancer in patients with esophageal squamous cell carcinoma. World J Gastroenterol. 2017;23:1051-1058.

13.

Otowa

Nakamura

Takiguchi

et al . Safety and benefit of curative surgical resection for esophageal squamous cell cancer associated with multiple primary cancers. Eur J Surg Oncol. 2016;42:407-411.

14.

John

Hershman

Falci

Shi

Tsai

Greenlee

Complementary and alternative medicine use among US cancer survivors. J Cancer Surviv. 2016;10:850-864.

15.

Wang

Tsai

Huang

Kennedy

Trend and pattern of herb and supplement use in the United States: results from the 2002, 2007, and 2012 National Health Interview Surveys. Evid Based Complement Alternat Med. 2014;2014:872320.

16.

Hsing

Ioannidis

JP.

Nationwide population science: lessons From the Taiwan National Health Insurance Research Database. JAMA Intern Med. 2015;175:1527-1529.

17.

Kuo

Chang

Muo

et al . Use of complementary traditional Chinese medicines by adult cancer patients in Taiwan: a nationwide population-based study. Integr Cancer Ther. 2018;17:531-541.

18.

Fleischer

Chang

Chiang

Chang

Hsieh

Yen

HR.

Adjunctive Chinese herbal medicine therapy improves survival of patients with chronic myeloid leukemia: a nationwide population-based cohort study. Cancer Med. 2016;5:640-648.

19.

Suzuki

Asakawa

Amitani

Fujitsuka

Nakamura

Inui

Cancer cachexia pathophysiology and translational aspect of herbal medicine. Jpn J Clin Oncol. 2013;43:695-705.

20.

Seike

Sawada

Kawakita

et al . A new candidate supporting drug, Rikkunshito, for the QOL in advanced esophageal cancer patients with chemotherapy using docetaxel/5-FU/CDDP. Int J Surg Oncol. 2011;2011:715623.

21.

Kamide

Yamashita

Araki

Tomifuji

Shiotani

Hangeshashinto (TJ-14) prevents radiation-induced mucositis by suppressing cyclooxygenase-2 expression and chemotaxis of inflammatory cells. Clin Transl Oncol. 2017;19:1329-1336.

22.

Singh

Gupta

Prasad

Velu

Katiyar

SK.

Honokiol inhibits the growth of head and neck squamous cell carcinoma by targeting epidermal growth factor receptor. Oncotarget. 2015;6:21268-21282.

23.

Zhang

Guo

Zhang

Meng

XY.

Baicalein induces apoptosis in esophageal squamous cell carcinoma cells through modulation of the PI3K/Akt pathway. Oncol Lett. 2013;5:722-728.

24.

D’Agostino

Jr.

Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med. 1998;17:2265-2281.

25.

Slaughter

Southwick

Smejkal

Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer. 1953;6:963-968.

26.

Castro

Peleteiro

Lunet

Modifiable factors and esophageal cancer: a systematic review of published meta-analyses. J Gastroenterol. 2018;53:37-51.

27.

Andrici

Eslick

GD.

Hot food and beverage consumption and the risk of esophageal cancer: a meta-analysis. Am J Prev Med. 2015;49:952-960.

28.

Maghsudlu

Yazd

EF.

Heat-induced inflammation and its role in esophageal cancer. J Dig Dis. 2017;18:431-444.

29.

Gupta

Warnakulasuriya

Global epidemiology of areca nut usage. Addict Biol. 2002;7:77-83.

30.

Lee

Fang

et al . The neoplastic impact of tobacco-free betel-quid on the histological type and the anatomical site of aerodigestive tract cancers. Int J Cancer. 2012;131:E733-E743.

31.

Jeng

Chang

Hahn

LJ.

Role of areca nut in betel quid-associated chemical carcinogenesis: current awareness and future perspectives. Oral Oncol. 2001;37:477-492.

32.

Hoffmann

Brunnemann

Prokopczyk

Djordjevic

MV.

Tobacco-specific N-nitrosamines and Areca-derived N-nitrosamines: chemistry, biochemistry, carcinogenicity, and relevance to humans. J Toxicol Environ Health. 1994;41:1-52.

33.

Chen

Chan

Chao

Yen

TC.

Detection of synchronous cancers by fluorodeoxyglucose positron emission tomography/computed tomography during primary staging workup for esophageal squamous cell carcinoma in Taiwan. PLoS One. 2013;8:e82812.

34.

Lin

Wei

Hong

Liu

Peng

Effect of Hedyotis diffusa Willd extract on tumor angiogenesis. Mol Med Rep. 2011;4:1283-1288.

35.

Wang

. Identification of Chinese medicine constitution in public health services [published online December 27, 2016]. Chin J Integr Med. doi:10.1007/s11655-016-2740-6

36.

Wang

Zhu

Lin

Correlation between tobacco and alcohol use and traditional Chinese medicine constitutions: an analysis based on a sample from general population of China. J Tradit Chin Med. 2013;33:642-646.

37.

Wang

et al . Phlegm-dampness constitution: genomics, susceptibility, adjustment and treatment with traditional Chinese medicine. Am J Chin Med. 2013;41:253-262.

38.

Chang

Lin

Chen

Jane

Chen

MY.

Metabolic syndrome and health-related behaviours associated with pre-oral cancerous lesions among adults aged 20-80 years in Yunlin County, Taiwan: a cross-sectional study. BMJ Open. 2015;5:e008788.

39.

Stocks

Bjorge

Ulmer

et al . Metabolic risk score and cancer risk: pooled analysis of seven cohorts. Int J Epidemiol. 2015;44:1353-1363.

40.

Kawanishi

Ohnishi

Hiraku

Oikawa

Murata

Nitrative and oxidative DNA damage in infection-related carcinogenesis in relation to cancer stem cells. Genes Environ. 2016;38:26.

41.

Arimilli

Schmidt

Damratoski

Prasad

GL.

Role of oxidative stress in the suppression of immune responses in peripheral blood mononuclear cells exposed to combustible tobacco product preparation. Inflammation. 2017;40:1622-1630.

42.

Fujitsuka

Uezono

Rikkunshito, a ghrelin potentiator, ameliorates anorexia-cachexia syndrome. Front Pharmacol. 2014;5:271.

43.

Zhou

Luo

Lei

et al . Liujunzi Tang, a famous traditional Chinese medicine, ameliorates cigarette smoke-induced mouse model of COPD. J Ethnopharmacol. 2016;193:643-651.

44.

Tanaka

Urita

Nara

Miura

Sugimoto

Effects of the traditional Japanese medicine Rikkunshito on postprandial glucose and lipid metabolism. Hepatogastroenterology. 2011;58:1112-1118.

45.

Gong

Wei

Pan

Type 2 diabetes mellitus and risk of oral cancer and precancerous lesions: a meta-analysis of observational studies. Oral Oncol. 2015;51:332-340.

46.

Rusin

Walczak

Zwierzchlejska

et al . DNA damage and repair of head and neck cancer cells after radio- and chemotherapy. Z Naturforsch C. 2009;64:601-610.

47.

Patel

See

Williamson

Archer

Evans

PH.

Radiation induced sarcoma of the head and neck. Head Neck. 1999;21:346-354.

48.

Matsumoto

Sekine-Suzuki

Nyui

et al . Analysis of the antioxidative function of the radioprotective Japanese traditional (Kampo) medicine, hangeshashinto, in an aqueous phase. J Radiat Res. 2015;56:669-677.

49.

Yang

Lee

et al . Suppression of the TNF-alpha level is mediated by Gan-Lu-Yin (traditional Chinese medicine) in human oral cancer cells through the NF-kappa B, AKT, and ERK-dependent pathways. Environ Toxicol. 2016;31:1196-1205.

50.

Jeong

Ryu

Kim

Park

Choi

Yoon

SW.

Bojungikki-tang for cancer-related fatigue: a pilot randomized clinical trial. Integr Cancer Ther. 2010;9:331-338.

51.

Tamura

Takahashi

Xue

et al . Enhanced effects of combined bu-zhong-yi-qi-tang (TJ-41) and interleukin-18 on the production of tumour necrosis factor-alpha and interferon-gamma in human peripheral blood mononuclear cells. J Int Med Res. 2004;32:25-32.

52.

Konaka

Moriyama

Sakurada

et al . Kamishoyosan and Shakuyakukanzoto promote recovery from paclitaxel-induced neurite retraction in PC12 cells. J Pharm Health Care Sci. 2017;3:20.

53.

Tao

Balunas

MJ.

Current therapeutic role and medicinal potential of Scutellaria barbata in traditional Chinese medicine and Western research. J Ethnopharmacol. 2016;182:170-180.

54.

Zheng

Zhang

et al . Peiminine inhibits colorectal cancer cell proliferation by inducing apoptosis and autophagy and modulating key metabolic pathways. Oncotarget. 2017;8:47619-47631.

55.

Chen

Izzo

Demizu

et al . Different redox states in malignant and nonmalignant esophageal epithelial cells and differential cytotoxic responses to bile acid and honokiol. Antioxid Redox Signal. 2009;11:1083-1095.

56.

Choi

Park

Kim

Hong

Kim

GC.

Scutellariae radix induces apoptosis in chemoresistant SCC-25 human tongue squamous carcinoma cells. Am J Chin Med. 2015;43:167-181.

57.

Chen

Tong

Tang

Liu

. The Hedyotis diffusa Willd. (Rubiaceae): a review on phytochemistry, pharmacology, quality control and pharmacokinetics. Molecules. 2016;21:E710.

58.

Lin

Chen

Lin

Lai

Peng

Hedyotis diffusa Willd extract suppresses proliferation and induces apoptosis via IL-6-inducible STAT3 pathway inactivation in human colorectal cancer cells. Oncol Lett. 2015;9:1962-1970.

59.

Gong

Wang

Yuan

et al . Inhibition of tumor growth and immunomodulatory effects of flavonoids and scutebarbatines of Scutellaria barbata D Don in Lewis-bearing C57BL/6 mice. Evid Based Complement Alternat Med. 2015;2015:630760.

60.

Hung

Pan

WL.

Roles of reactive oxygen species in anticancer therapy with Salvia miltiorrhiza bunge. Oxid Med Cell Longev. 2016;2016:5293284.

61.

Lin

Lee

Huang

et al . Danshen improves survival of patients with colon cancer and dihydroisotanshinone I inhibit the proliferation of colon cancer cells via apoptosis and skp2 signaling pathway. J Ethnopharmacol. 2017;209:305-316.

62.

Bian

Yue

Jin

Hong

Shu

Selenium-dependent antitumor immunomodulating activity of polysaccharides from roots of

A membranaceus. Int J Biol Macromol. 2014;69:64-72.

63.

Cho

Jeon

Park

et al . Multifunctional effects of honokiol as an anti-inflammatory and anti-cancer drug in human oral squamous cancer cells and xenograft. Biomaterials. 2015;53:274-284.

64.

Chen

Guo

Zhao

et al . Ophiopogonin B induces apoptosis, mitotic catastrophe and autophagy in A549 cells. Int J Oncol. 2016;49:316-324.

65.

Long

Wang

Jia

et al . Anti-tumor effects of Atractylenolide-I on human ovarian cancer cells. Med Sci Monit. 2017;23:571-579.

66.

Zhang

et al . Inhibition of cancer cell proliferation and prostaglandin E2 synthesis by Scutellaria baicalensis. Cancer Res. 2003;63:4037-4043.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.64 MB