The use of Chinese herbal products for nasopharyngeal carcinoma in Taiwan : A population-based study

In most countries, the incidence of nasopharyngeal carcinoma (NPC) is no more than 1 per 100,000 for both men and women; however, it is much higher for men and women in Taiwan. The use of traditional Chinese medicine (TCM) as complementary and alternative medicine for the treatment of NPC and its treatment-related side effects has been increasing. The National Health Insurance (NHI) covers 99.6% of Taiwan’s residents. In the present population-based cohort study, we aimed to investigate the pattern of utilization of Chinese herbal products (CHPs) for NPC from 2001 through 2011 in Taiwan. We identified a total of 30294 patients with newly diagnosed NPC from the Registry for Catastrophic Illnesses Patient Database (RCIPD). Descriptive statistics and multiple logistic regression analysis were employed to estimate the adjusted odds ratios (aORs) for CHP utilization. From 2001 through 2011, 17816 patients aged ≥20 years were newly diagnosed with NPC. Of these, 4749 patients used TCM outpatient services for NPC treatment. TCM users were more likely to be women, young, residents of Central Taiwan, and white-collar workers. The most commonly prescribed formula CHP was Gan-Lu-Yin, followed by Xin-Yi-Qing Fei-Tang and Shan-Shen-Mai-Men-Dong-Tang. The most commonly prescribed single CHP was Hedyotis diffusa, followed by Radix Scrophulariae and Radix Ophiopogonis. These findings provide information regarding personalized therapies for NPC and can Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 26 September 2018 doi:10.20944/preprints201809.0498.v1


Introduction
Nasopharyngeal carcinoma (NPC) is a malignancy arising from the nasopharynx, most commonly the posterolateral nasopharynx, pharyngeal recess, or fossa of Rosenmüller.The most common presentation is a palpable neck lump, with approximately 60% patients seeking medical attention when this occurs.Such lumps develop because of metastatic disease in the cervical lymph nodes.In endemic regions such as China, Hong Kong, and Singapore, a Chinese adult man seen with large, bulky bilateral nodes is generally considered to have NPC or lymphoma.Although 60% patients with NPC initially present with a neck lump caused by nodal metastasis, at least 80% patients are diagnosed with positive nodes (N1, N2, or N3) [1].Men are two to three times more likely to develop NPC than are women, and the peak age of occurrence is between 50 and 60 years [2].The graph shows that newly diagnosed cases of NPC accounted for approximately 2% of all malignancy cases each year.
The incidence of NPC is reportedly less than 1 per 100,000 for both men and women in most countries; however, it is 20-30 per 100,000 men and 15-20 per 100,000 women in Hong Kong [3].NPC is an infection-related cancer that is strongly driven by the Epstein-Barr virus.The occurrence of this infection is strongly associated with genetics, particularly in South China, Hong Kong, and Taiwan [4,5].
From 2001 through 2011, approximately 1300-1600 individuals were newly diagnosed with NPC in Taiwan (Figure 1a), with NPC accounting for approximately 2% of all cases of malignancies (Figure 1b) during this period.In fact, NPC is the tenth most common cancer among men in Taiwan [6,7].
Interest in complementary and alternative medicine (CAM) is increasing among not only patients looking for help but also healthcare providers studying the effectiveness of various therapies and management techniques.Up to 52% cancer patients use one or more CAM treatments, and over 80% patients use CAM concurrently with chemotherapeutic agents during the initial phases of cancer treatment [8][9][10].

Study population
We identified 30294 patients with newly diagnosed NPC (ICD-9-CM 147) from RCIPD.Patients with missing information on age or sex (n = 14), those diagnosed with NPC before the end of 1999 (n = 12302), and those aged <20 years (n = 162) were excluded.Eventually, 17816 patients were included in the study and further divided into TCM users (n = 9577) and TCM nonusers (n = 8239; Figure 2).The former were defined as individuals who used TCM outpatient services at least once during the study period, while the latter were defined as individuals who never visited TCM clinics after the first NPC diagnosis.Evaluated demographic factors included sex, age (20-29, 30-39, 40-49, 50-59, and ≥60 years), occupational status (white collar, blue collar, and others), and residential areas area (northern Taiwan, central Taiwan, southern Taiwan, and eastern Taiwan and offshore islands).

Statistical analysis
Descriptive statistics for the TCM users and TCM nonusers are presented as means and standard deviations (SD) for continuous variables and numbers and percentages for categorical variables.Differences in the distribution of these statistics between the two groups were assessed using Student's t-test for continuous variables and Pearson's chi-square test for categorical variables.Multiple logistic regression analysis was performed to determine the correlation between demographic data (sex, age, occupational status, and residential area) and TCM use.The logistic regression model produced odds ratios (ORs) and corresponding 95% confidence intervals (CIs).
Adjusted ORs (aORs) were used to predict patients with higher odds of using TCM.
All statistical analyses were performed using SAS software, version 9.4 (SAS Institute, Cary, NC, USA).All P-values were derived from two-sided tests, with the significance level set at 0.05.

Results
The patient recruitment flowchart is presented in Figure 2. In total, 17816 patients aged ≥20 years were newly diagnosed with NPC from 2001 through 2011.
White-collar workers are generally richer than blue-collar workers, so they are able to afford additional treatments.Our results were in accordance with a previous study of TCM use by adult patients with cancer [22].The demographic characteristics of NPC patients reported in this study may help public health policymakers and clinicians in making informed decisions regarding the distribution of TCM supplements in the different regions in Taiwan.
Conventional treatments for NPC include surgery, radiation therapy (RT), and chemotherapy or target therapy.Currently, RT is the mainstay of treatment for NPC because the primary tumor is not easily amenable to surgical resection in most cases [23].Our data from NHI (shown in Figure 4) also showed that RT was the most common treatment strategy used for patients with NPC from 2001 through 2011 in Taiwan.However, RT often causes several side effects such as mucositis, xerostomia, dysphagia, dermatitis, weight loss, and malnutrition.Among these, xerostomia is one of the most common acute and long-term side effects that is primarily induced by RT and is dependent on the cumulative radiation doses to the head and neck region [1].In recent years, the use of TCM in combination with conventional cancer therapy has become more widespread.NPC patients receiving conventional anticancer therapies combined with TCM treatment reportedly exhibited increased survival rates, enhanced tumor responses, an improved Karnofsky performance status, lower side effect rates, and better immunostimulation [24] Because NPC and its treatment can cause many complications, the goal of TCM is to not only try and cure the cancer but also prevent unwanted complications during conventional treatments.The graph shows that radiotherapy was the most common treatment modality throughout the study period, with an increase in the number of patients over time.In addition, the number of patients with no treatment can be seen to decrease over time.Gan-Lu-Yin can be used as an adjuvant treatment to not only reduce RT-related side effects but also cure the cancer.
Xin-Yi-Qing-Fei-Tang, the second most commonly prescribed formula CHP in our study, clears heat from the lungs and stomach and unblocks the nasal orifices.In TCM practice, Xin-Yi-Qing-Fei-Tang is often appropriate for patients with yellow sputum; a stuffy nose; and thick, sticky, and yellow nasal discharge due to upper respiratory tract infection or allergies [31].It is also the most common herbal formula used for children with allergic rhinitis and adults with chronic rhinosinusitis [31,32].
NPC patients often exhibit yellow, thick, and sticky mucus due to upper respiratory tract infection or inflammation while receiving anticancer treatment.This could be the reason why Xin-Yi-Qing-Fei-Tang was such a commonly prescribed combination in our study.
Shan-Shen-Mai-Men-Dong-Tang is used to clear and nourish the lungs and stomach, engender fluid, repair damaged cells, and control the symptoms of dryness associated with cancer treatment [13].One study by Sung and Dong (2001) in China also showed that Shan-Shen-Mai-Men-Dong-Tang could improve oral dryness and interleukin-1β expression in a concentration-dependent manner while promoting the expression of inducible hemoxygenase and peroxisome proliferator-activated receptor gamma (PPAR-γ).The anti-inflammatory effects of Hedyotis diffusa are most likely facilitated by its inhibitory effects on the c-Jun N-terminal kinase (JNK) signaling pathway [16].
Radix Scrophulariae (Xuan Shen) is used to clear heat and cool the blood, nourish yin, and relieve toxicity.It is often used for the treatment of fever, swelling, neuritis, laryngitis, constipation, and inflammatory diseases [41].The constituents of Radix Scrophulariae were reported to show antioxidant, antibacterial, anti-inflammatory, neuroprotective, antidiabetic, cytotoxic, and antimicrobial activities [17,42].In addition, the anti-inflammatory effects of this drug were associated with the NF-κB signaling pathway [43].In another study, Radix Scrophulariae combined with Viticis Fructus was shown to decrease cell adhesion, alter the cell morphology to a round shape, and induce cell death in cancer cells [18].
Radix Ophiopogonis is capable of tonifying yin, engendering fluid, moistening the lungs, and clearing the heart; accordingly, it is often used for the treatment of dry cough, dry mouth, throat impediment and pain, vexation and insomnia, and constipation [44].It has been shown to exert cardiovascular protection and anti-inflammatory, antidiabetic, anticancer, antioxidative, and immunomodulatory activities in previous studies [45,46].The anti-inflammatory activity could be attributed to a decrease in IL-6 production [21].In addition, this herb was found to induce apoptosis of prostate cancer cells via a receptor interacting serine/threonine kinase 1 (RIPK1)-related pathway both in vitro and in vivo [20].
We found that Gan-Lun-Yin and Zhi-Bai-Di-Huang-Wan were most commonly prescribed together, with Gan-Lun-Yin expected to nourish yin and clear heat and Zhi-Bai-Di-Huang-Wan expected to nourish the kidney and liver yin and clear heat [47,48].Both these CHPs clear heat and nourish yin, thus reducing the side effects of RT.
The second most common combination was Gan-Lun-Yin and Xin-Yi-Qing-Fei-Tang; the former clears heat while the latter treats upper airway symptoms.With regard to single CHPs, Scutellariae Barbatae and Hedyotis diffusa were most commonly prescribed in combination.Both herbs can clear heat and show anticancer activities.
The second most common combination was Radix Scrophulariae and Radix Ophiopogonis, both of which strengthen yin and reduce the side effects of RT.In summary, all these CHPs are generally prescribed in combination to enhance their efficacy, minimize toxicity, and tailor the treatment according to individual needs [49].
The top three formula CHPs and single CHPs in the present study share a common function of clearing heat, and most of them can nourish yin.The main treatment for NPC is RT, the side effects of which include mucositis, xerostomia, dysphagia, and dermatitis.All these side effects are a part of the heat syndrome as per TCM theory.
Therefore, herbs that can clear heat and nourish yin are generally used to minimize RT-associated side effects.Although our findings were in accordance with TCM theory, well-designed clinical trials are required to further clarify our findings.At present, there is one prospective pilot study demonstrating that Gan-Lu-Yin can be used to treat dry mouth during RT for head and neck cancer, consistent with our findings [50].
This study has several limitations.First, we did not evaluate the efficacy and adverse effects of the CHPs.Although NHIRD has extensive prescription data, we did not have access to other chart-level records such as laboratory data and physician notes.Therefore, the usefulness of the treatments could not be assessed [49,51].
Second, TCM is not fully covered by the NHI program in Taiwan.Moreover, visits to clinics not contracted with the NHI program were not included in the present study.In Taiwan, approximately 5% TCM clinics are not contracted with the NHI program; therefore, TCM use may have been underestimated [25].Third, patients with NPC

Fig. 1a
Fig. 1a Annual incidence of newly diagnosed nasopharyngeal carcinoma (NPC) from 2000 through 2011 in Taiwan.The graph shows that approximately 1300-1600 individuals were diagnosed with NPC each year.Fig. 1b Proportion of newly diagnosed NPC cases among all cases of malignancy each year from 2000 through 2011 in Taiwan Chinese medicine (TCM) is the most common CAM in our clinical practice.Considering that different stages of NPC are characterized by various clinical features and complications before and after conventional treatments, TCM doctors typically provide treatment using different combinations of Chinese herbs.In Taiwan, Chinese herbal products (CHPs) have been listed under the National Health Insurance (NHI) program since 1995.NHI covers 99.6% of Taiwan's residents.However, there is a lack of large-scale statistical data on the clinical usage of TCM in NPC.Therefore, we aimed to investigate the utilization of CHPs for NPC from 2001 through 2011 in Taiwan by exploring the demographic characteristics of patients and the patterns of CHP prescriptions.While demographic data can provide relevant information for clinical pharmaceutical and epidemiological studies, data regarding prescription patterns can provide information regarding the monitoring, evaluation, and modification of medical services and facilitate the establishment of reference data concerning individualized therapies for NPC.Methods Data sources The National Health Insurance (NHI) program of Taiwan is a universal insurance program established in 1995, reforming from 13 insurance-related systems and providing coverage for 99.9% Taiwanese citizens by the end of 2014.The NHI Research Database (NHIRD) has been managed, maintained, and released by the National Health Research Institute (NHRI) in Taiwan.In this population-based cohort study, we obtained data from the Registry for Catastrophic Illnesses Patient Database (RCIPD), which is a part of NHIRD.RCIPD contains claims data from insurers diagnosed with one of 30 categories of major diseases (cancer, chronic mental illness, end-stage renal disease, several autoimmune diseases, etc.) who require long-term care and are exempted from co-payment.Registered data include demographic data, the date of visit or hospitalization, drug prescriptions, and diagnoses coded in the format of the International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM).For the protection of insurer privacy, all potentially identifying information was encrypted.The study was approved by the Ethics Review Board of China Medical University (CMUH1O4-REC2-115).

Figure 2 .
Figure 2. Flowchart of recruitment of subjects from Catastrophic Illnesses Patient Database during 2000-2011 in Taiwan.Abbreviation: TCM, traditional Chinese medicine.

Figure 3 .
Figure 3. Distribution of the number CHP in one prescription.The most common prescriptions of CHP combinations or single Chinese herbs contained 5 to 7 herbs.There was an average of 6.56 Chinese herbs in a single prescription for patients with nasopharyngeal carcinoma.Abbreviation: CHP, Chinese herb products.
-Ren-Wan, Zhu-Ling-Tang, and Long-Dan-Xie-Gan-Tang 144 (0.03) Shu-Jing-Huo-Xue-Tang, Dang-Gui-Nian-Tong-Tang, and Du-Huo-Ji-Sheng-Tang 103 (0.02) Chai-Ge-Jie-Ji-Tang, Shu-Jing-Huo-Xue-Tang, and Dang-Gui-Nian-Tong-Tang 73 (0.02) Liu-Wei-Di-Huang-Wan, Tian-Wang-Bu-Xin-Dan, and Suan-Zao-Ren-Tang 72 (0.02) Chai-Ge-Jie-Ji-Tang, Shu-Jing-Huo-Xue-Tang, and Du-Huo-Ji-Sheng-Tang 72 (0.02) CHPs, Chinese herbal products Discussion In this nationwide cohort study of CHP use for NPC treatment from 2001 through 2011 in Taiwan, we observed that women were more likely to use TCM than were men.Moreover, TCM users were younger than nonusers, probably because younger patients readily accept a variety of treatments.Patients in central Taiwan showed a higher OR for TCM use than did those in southern and Taiwan and northern Taiwan, possibly because central Taiwan has the highest density of TCM clinics in Taiwan.Therefore, TCM services are easily available for residents of central Taiwan.The allocation of TCM services could have affected the TCM-seeking behavior of patients.

Figure 4 .
Figure 4. Distribution of treatment modalities for nasopharyngeal carcinoma (NPC) from 2000 through 2011 in Taiwan show several different symptoms, and those in different stages and receiving different treatments develop variable complications[52].Typically, TCM physician prescribe one or two formulae combined with several single herbs in one prescription based on the patient's symptoms.In the present study, however, we were unable to confirm the stage of cancer and treatments during CHP use.Therefore, further studies should evaluate the pattern of utilization of CHPs during different stages and treatments for cancer.ConclusionsIn conclusion, our findings suggest that CHPs are widely used for the management of NPC and its treatment-related side effects in Taiwan.TCM users with NPC are more likely to be women, younger individuals, white-collar workers, and residents of Central Taiwan.The most frequently prescribed CHPs for NPC are Gan-Lu-Yin and Hedyotis diffusa.These findings provide information regarding personalized therapies and can promote further clinical experiments and pharmacological research on CHPs for NPC treatment in Taiwan.Further well-designed, randomized, double-blind, placebo-controlled studies and basic mechanistic studies and clinical trials are needed to assess the safety and effectiveness of the prominent CHPs used for NPC management in Taiwan.

Table 2 .
Possible mechanisms of action or effects of frequently used formula or single CHPs for nasopharyngeal carcinoma in Taiwan (2001 through 2011)

Table 3 .
Top ten formula and single CHPs prescribed by TCM physicians for the treatment of nasopharyngeal carcinoma in Taiwan (2001 through 2011; total number of CHPs, n = 423545) comprising three formula CHPs are shown in Table5.Preprints (www.preprints.org)| NOT PEER-REVIEWED |

Table 5 .
Top five combinations comprising three formula CHPs prescribed for nasopharyngeal carcinoma in Taiwan (2001 through 2011; total number of CHPs, n =