Accepted Manuscript

A systematic review on Chinese herbal treatment for radiotherapy-induced xerostomiain head and neck cancer patients

Wan Najbah Nik Nabil, Ren Jye Lim, Si Yan Chan, Nai Ming Lai, Ai Ch'i Liew

PII: S1744-3881(17)30370-5

DOI: 10.1016/j.ctcp.2017.10.004

Reference: CTCP 774

To appear in: Complementary Therapies in Clinical Practice

Received Date: 17 August 2017

Revised Date: 5 October 2017

Accepted Date: 12 October 2017

Please cite this article as: Nik Nabil WN, Lim RJ, Chan SY, Lai NM, Liew AiCh', A systematic reviewon Chinese herbal treatment for radiotherapy-induced xerostomia in head and neck cancer patients,Complementary Therapies in Clinical Practice (2017), doi: 10.1016/j.ctcp.2017.10.004.

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https://doi.org/10.1016/j.ctcp.2017.10.004

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A systematic review on Chinese herbal treatment for radiotherapy-induced

xerostomia in head and neck cancer patients

Running title: Review of Chinese herbs for xerostomia

Wan Najbah Nik Nabil a,b, #

, Ren Jye Lim b, Si Yan Chan

a,b, Nai Ming Lai

c, Ai Ch’i Liew

d

a Pharmacy Department, National Cancer Institute, Prescint 7, 62250 Putrajaya, Putrajaya,

Malaysia.

b Traditional & Complementary Medicine (T&CM) Unit, National Cancer Institute, Prescint 7,

62250 Putrajaya, Putrajaya, Malaysia.

c School of Medicine, Faculty of Health and Medical Sciences, Taylor’s University, No. 1,

Jalan Taylor’s, 47500 Subang Jaya, Selangor, Malaysia.

d Traditional and Complementary Medicine (T&CM) Unit, Hospital Kepala Batas, Jalan

Bertam 2, 13200 Kepala Batas, Pulau Pinang, Malaysia.

# Corresponding author

Email addresses:

WNNN: pfnajbah@nci.gov.my RJL: drrjlim@nci.gov.my

SYC: siyanchan.pharm@gmail.com NML: lainm123@gmail.com

ACL: aichiliew81@gmail.com

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Author contributions:

Study design Wan Najbah Nik Nabil, Dr Lim Ren Jye

Data acquisition Wan Najbah Nik Nabil, Liew Ai Ch’i

Quality control of data Wan Najbah Nik Nabil, Chan Si Yan

Data analysis and interpretation Wan Najbah Nik Nabil, Dr Lim Ren Jye, Dr Lai Nai

Ming

Manuscript preparation Wan Najbah Nik Nabil, Dr Lim Ren Jye

Manuscript editing Dr Lai Nai Ming

Acknowledgement: The authors would like to thank the Director of Health Malaysia for

permission to publish this paper. We thank the Director of National Cancer Institute,

Malaysia for supporting this research. We appreciate the database support provided by

Institute Medical Research (IMR), Malaysia, Dr Te Kian Kong and Mr Wong Zhi Hang. This

review did not receive any specific grant from funding agencies in the public, commercial, or

not-for-profit sectors.

Conflict of Interest: None

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A systematic review on Chinese herbal treatment for radiotherapy-induced

xerostomia in head and neck cancer patients

Running title: Review of Chinese herbs for xerostomia

Abstract

Background: Over 80% of head and neck cancer patients suffer from radiotherapy-induced

xerostomia (dry mouth). Xerostomia affects cancer patients’ quality of life, and xerostomia

sometimes persists throughout the patients’ lifetime. This review aimed to evaluate the

effectiveness and safety of Chinese herbs in relieving radiotherapy induced xerostomia.

Methods: Systematic searches were conducted on 6 databases (English and Chinese). Studies

published up till May 2017 were considered for inclusion.

Results: A final 14 RCTs (total 994 head and neck cancer patients undergoing radiotherapy)

compared Chinese herbs with no herbs, were included in analysis. Very low to moderate quality

of evidence found Chinese herbal treatment may relief radiotherapy-induced xerostomia and

other related complications (such as oral mucositis and loss of appetite) in head and neck

cancer patients.

Conclusion: There is limited evidence that Chinese herbal treatment may relief radiotherapy-

induced xerostomia and other related complications in head and neck cancer patients.

Word count: 148 words

Keywords: Chinese herbal drugs; xerostomia; radiotherapy; head and neck neoplasms; meta-

analysis

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1. Introduction

Over 80% of head and neck cancer patients who have received radiotherapy suffer

from radiotherapy-induced xerostomia (dry mouth) [1]. Xerostomia affects cancer

patients’ quality of life by altering their taste which leads to loss of appetite [1],

interrupting their sleep (due to the frequent need of drinking water) [2, 3] and makes

routine activities such as chewing and swallowing a laborious task [1, 3]. Often,

xerostomia persists well beyond radiotherapy and sometimes throughout the patients’

lifetime [3].

Pharmacologic treatment such as pilocarpine has been shown to transiently

improve xerostomia symptoms [4, 5]. Moreover, pilocarpine causes some adverse

effects such as sweating, headache, urinary frequency, and worsening cardiac and

respiratory functions in patients with cardiovascular and respiratory diseases [4, 6].

Available non-pharmacologic interventions, namely oral lubricants/saliva substitutes are

reported to provide only transient and partial relief for xerostomia symptoms [4].

Complementary therapy, such as acupuncture and Chinese herbal medicine, have

been used variably in the management of radiotherapy-induced xerostomia. Guideline

developers such as the National Comprehensive Cancer Network [7] and the Chinese

Medical Association [8] have respectively included acupuncture and Chinese herbal

medicine as part of the management recommendations. Controlled trials [9, 10]

suggested that Chinese herbs can alleviate radiotherapy induced xerostomia, but to-

date there is no systematic review to synthesise the findings of these trials to better

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inform practice and direct future research. This systematic review aimed to evaluate the

effectiveness and safety of Chinese herbs in relieving radiotherapy-induced xerostomia.

2. Methods

2.1 Literature search strategy

We performed a systematic search in May 2017 to identify studies using Chinese herbs

to alleviate radiotherapy-induced xerostomia. The 6 databases – PubMed, Cochrane

Central Register of Controlled Trials (CENTRAL), EMBASE, AMED, CINAHL and China

National Knowledge Infrastructure (CNKI) – and ongoing clinical trials (www.controlled-

trials.com and clinicaltrials.gov) were searched from inception onwards. We contacted

expert for guidance on review development and search terms. We did not contact any

expert to identify additional trials that were potentially eligible. The following

combination of MeSH terms and keywords were used: (‘xerostomia’ or ‘dry mouth’ or

‘asialia’ or ‘salivary gland hypofunction’ or ‘radioxerosomia’) and (‘drugs Chinese herbal’

or ‘Medicine Chinese Traditional’ or ‘plants medicinal’ or ‘plant extracts’ or ‘Chinese

herbal medicine’ or ‘Chinese herbal drug’ or ‘Chinese drug plant’ or ‘medicinal plant’ or

‘plant preparation’ or ‘plant extract’ or ‘materia medica’) and (‘neoplasm’ or ‘tumor’ or

‘neoplasia’ or ‘cancer’). English and Chinese language journals were considered for this

review.

2.2 Inclusion and exclusion criteria

Studies that satisfied the following criteria were included: i) randomized controlled

trials, ii) Population: patients diagnosed with head and neck cancer, having received

radiotherapy with/without chemotherapy, iii) Intervention: oral Chinese herbs either

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alone or in combination with other treatment, iv) Outcome: severity of radiotherapy-

induced xerostomia, evaluated by any means. We excluded the following types of

studies: i) non-randomised controlled trials, animal studies and in-vitro studies, ii)

studies that evaluated xerostomia caused by other conditions (e.g. Sjogren’s Syndrome),

iii) Chinese herbs used to manage other cancer related symptoms and not xerostomia,

iv) studies that were otherwise relevant but without including severity of radiotherapy-

induced xerostomia as an outcome.

Primary outcomes were both acute (occur < 90 days after started radiotherapy)

and late xerostomia effects (occur ≥ 90 days after radiotherapy started) [11].

Xerostomia may be evaluated using validated measurement scale (such as Toxicity

Criteria of Radiation Therapy Oncology Group (RTOG), World Health Organization

(WHO)), visual analog scale (VAS), measuring salivary flow or study participants

subjective self-assessment of the treatment progress (i.e. improved, no change or worse

than baseline). Secondary outcome was the effect of herbs on other radiotherapy’s

adverse effects, study participants’ Quality of Life (QoL) or their tumour response

following herbal treatment.

2.3 Data Extraction

Duplicated search results were first removed. Two authors independently screened

through title and abstracts for relevant studies. Two authors screened the full text of the

identified relevant studies, extracted data of the included studies and determined their

risk of bias. The extracted data included: study characteristics, information relating to

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the risks of bias and data for each outcome. The extracted data were cross-checked by

another co-author for accuracy. Any disagreement was resolved by discussion. When

there were two or more studies that were sufficiently similar in terms of patient

characteristics, intervention, comparison and outcomes, meta-analysis was performed

using the Review Manager (RevMan 5.3) software. Two authors rated the quality of

evidence for each major outcome via the GRADE approach [12] using the online

GRADEPRO platform. We displayed the quality of evidence using the “Summary of

Findings” table [13].

3. Results

The search yielded a total of 1,202 studies as in Figure 1. Screening through title and

abstracts shortlisted 28 studies. Though full text review included 20 eligible studies,

however data from 5 studies were not included in the analysis. A final total of 15 studies

were included for analysis.

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Figure 1. Study flow diagram.

3.1 Included studies

Included studies were published between 2004 and 2016 and all evaluated herbs as an

adjunctive treatment in alleviating the radiotherapy-induced xerostomia, except for 1

study [14] which compared the effect of 2 herbs in relieving the xerostomia (Ma 2012;

Table 1). Thirteen studies recruited predominantly or solely patients with

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nasopharyngeal (NPC) cancer and 2 studies did not specify the cancer type of the

population. With regards to the staging of cancer, 4 studies [15-18] recruited Stage III

and IV cancer patients (Hu 2011, Huang 2013, Wei 2009 and Yang 2014) and staging

information had not been provided in the other studies. Across the included studies,

only Huang 2013 [16] and Wei 2009 [17] used the same herbal intervention (i.e. Zhong

Jie Feng). Study participants’ xerostomia was mainly assessed using the Visual Analog

Scale (VAS; 4 studies) and the RTOG grading (4 studies)Table 1.

The included studies mostly used Mai Men Dong (Tuber Ophiopogonis Japonici;

11 studies), Dang Shen (Radix Codonopsitis Pilosulae; 8 studies), Sheng Di Huang (Radix

Rehmaniae; 7 studies) and Xuan Shen (Radix Scrophulariae Ningpoensis; 7 studies).

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Table 1. Characteristic of studies included in the systematic review.

First

author

Year of

publica

-tion

Type of

head and

neck cancer

Cancer

staging

Radio-

therapy

dose

(Gy)

Intervention Xerostomia

assessment tool

Other outcome assessed

Adverse event

from

radiotherapy

QoL Tumor

Response

1. Hao, Q. [19]

2016 Nasopharyn

geal (NPC),

oral, tongue,

throat, sinus

Unspecifi

ed

60 - 68 Yu Nu Jian formula, OD

taken from radiotherapy

started till ended

Wang Zhong He and

Guo Gao 2012

grading

Oral mucositis --- ---

2. Hu, Y.R. [20]

2004 NPC, tonsil,

tongue

I-IV 36 - 70 Shen Qi Fang Hou

formula, BD, taken from

radiotherapy started till

ended

Researcher own

grading

Hardening of

neck muscle

--- ---

3. Hu, X.M.

[15]

2011 NPC, oral,

larynx,

hypopharynx

, nasal and

sinus

III – IV 40 - 75 Yang Yin Jie Du Tang

formula, BD during

radiotherapy

Presence of

xerostomia

Nausea and

vomiting,

fatigue,

leukopenia, loss

of appetite

√ √

4. Huang, D.N.

[16]

2013 NPC III - IV 56-66

Zhong Jie Feng , OD,

taken from 3 day pre-

radiotherapy till

radiotherapy ended

RTOG grading Oral mucositis,

dermatitis at

neck

--- √

5. Jiang, Z.X. [21]

2005 NPC, oral,

tonsil,

parotid,

metastasis

to neck

(unknown

origin)

Unspecifi

ed

60 - 70 Tian Men Dong, Mai Men

Dong, Dang Shen, Sha

Shen, Yuan Shen, Dan

Sen, Sheng Di Huang,

taken 60 ml TDS.

Administration time was

unspecified

Researcher own

grading

--- --- ---

6. Jiang, Z.X. [22]

2006 NPC, tonsil Unspecifi

ed

60 - 70 Sheng Jin formula, TDS,

taken from radiotherapy

started till ended

Salivary flow (time

needed to wet the

filter paper)

--- --- ---

7. Li, H. 2009 NPC, oral, Unspecifi 60 - 70 Xuan Mai Zeng Ye Hua Du Salivary flow (time --- --- ---

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[23] tonsil,

parotid

ed Tang formula, TDS, taken

from radiotherapy started

for 30 days

needed to wet filter

paper), VAS grading

8. Liu, Y.H. [24]

2016 Unspecified II-IV 50 - 75 Qing Re Yang Yin Sheng

Jin formula/ Jian Pi Hua

Shi formula/ Zi Bu Shen

Yin formula/ Wen Bu

Shen Yang formula/ Yi Qi

Yang Yin formula were

given based on Chinese

medicine diagnosis, OD

for 10 days (1 course),

and treated for 3 courses.

RTOG grading,

salivary flow in 10

min

Oral mucositis,

leukopenia, loss

of appetite

--- ---

9. Ma, X.Y. [14]

2012 NPC Unspecifi

ed

64 - 72 Qing Fei Yang Wei

formula, TDS, taken from

radiotherapy started till

ended

Wang Zhong He and

Guo Gao 2012

grading tool.

--- --- ---

10. Wei, B. [17]

2009 NPC III - IV 36 - 74 Zhong Jie Feng, OD, taken

from 3 days pre-

radiotherapy till

radiotherapy ended

RTOG grading Oral mucositis,

leukopenia, loss

of appetite

--- ---

11. Wu, X. [25]

2014 NPC, tonsil,

tongue, gum

II - III 70 Kang Fu Xin Ye, TDS,

taken from radiotherapy

started till 30 days post-

radiotherapy

LENTSOMA grading,

salivary volume

Oral mucositis --- ---

12. Yang, H. Q. [18]

2014 NPC, oral,

larynx,

hypopharynx

III - IV 50 - 75 Zi Yin Jie Du herbs, TDS,

taken during

radiotherapy

Presence of

xerostomia

Nausea and

vomiting,

fatigue,

leukopenia,

drowsy

√ √

13. Yin, L.H. [26]

2009 Unspecified Unspecifi

ed

65 - 75 Bai Ying Tang formula,

BD, taken from

radiotherapy started till 4

weeks post-radiotherapy

VAS grading Oral mucositis √ √

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14. Zhang, C.Y. [27]

2011 NPC I-IV 45 - 75 Qing Re Yang Yin formula,

Jian Pi Yang Yin formula,

Zi Shen Yang Yin formula

were given based on

Chinese medicine

diagnosis. Taken from

radiotherapy started for 6

months

RTOG grading, VAS

grading, presence of

xerostomia

--- --- ---

15. Zhang, Y.X. [28]

2012 NPC, oral,

tonsil,

tongue,

sinus,

waldeyer's

ring

lymphoma

II-III 60 - 70 Yang Yin Sheng Jin Tang

formula, BD, taken from

radiotherapy started till

ended

VAS grading, salivary

flow in 30 minutes

--- --- ---

***All studies compared the effect between Chinese herbs and without Chinese herbs; except for Ma 2012 compared between 2 Chinese herbs

(i.e. Qing Fei Yang Wei formula and Kang Fu Xin Ye)

OD = Once Daily, BD= Twice daily, TDS=Thrice daily

Table 2. Study design of the included studies.

Study Number of

participants

Study design Study duration Assessed time point

of xerostomia

Intervention Control treatment

1. Hao, Q. [19]

51

(27 CH, 24 control)

RCT Whole RT course

(49 days)

Week 2, 4, 6 during RT

and post-RT

RT + Oral CH RT

2. Hu, Y.R. (2004) [20]

83

(42 CH, 41 control)

RCT Whole RT course

(35-38 days)

During RT RT + Oral CH RT

3. Hu, X.M. (2011) [15]

102

(52 CH, 50 control)

RCT Unspecified Post-RT RT + Oral CH (during RT) RT

4. Huang, D.N. [16]

100

(50 CH, 50 control)

RCT 3 days pre-RT till

RT ended

Post-RT CT + RT + Oral CH CT + RT

5. Jiang, Z.X. 108 RCT, placebo 6 months to 1 year Post-RT RT + Oral CH (during RT) RT + Drink mineral

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(2005) [21] (78 CH, 30 control) control post-RT water daily

6. Jiang, Z.X. (2006) [22]

33

(16 CH, 17 control)

RCT Whole RT course Pre-RT, at RT dose

20Gy, 40Gy, 60Gy

RT + Oral CH RT

7. Li, H. [23] 40 (20 CH, 20 control)

RCT, placebo

control

Unspecified Pre-RT, at RT dose

20Gy, 40Gy, 60Gy,

70Gy

RT + Oral CH (during RT) RT + Drink mineral

water daily

8. Liu, Y.H. [24]

80

(40 CH, 40 control)

RCT 1 year Pre-RT, post-RT, 1

year post-RT

RT + Nursing intervention

+ Oral CH (for 30 days)

RT

9. Ma, X.Y. [14]

60

(30 CH, 30 control)

RCT Whole RT course Week 2, 4, 6 during RT

and post-RT

RT + Oral CH RT + Oral Kang Fu

Xin Ye

10. Wei, B. [17]

46

(21 CH, 25 control)

RCT 3 days pre-RT till

RT ended

Post-RT CT + RT + Oral CH CT + RT

11. Wu, X. [25] 64 (32 CH, 32 control)

RCT 1st

day RT till 30

days post-RT

RT dose 40Gy, 70Gy,

30 days post-RT

RT + Oral vitamin C 1g +

Oral CH

RT

12. Yang, H. Q. [18]

82

(41 CH, 41 control)

RCT Unspecified During RT RT +Oral CH RT

13. Yin, L.H. [26]

60

(30 CH, 30 control)

RCT, placebo

control

1st

day RT till 28

days post-RT

Once weekly since

started RT

RT + Oral CH RT + Drink mineral

water daily

14. Zhang, C.Y. (2011) [27]

65

(33 CH, 32 control)

RCT 1st

day RT till 6

months post-RT

Unspecified RT + Oral CH RT

15. Zhang, Y.X. (2012) [28]

80

(40 CH, 40 control)

RCT Whole RT course Pre-RT, at RT dose

10Gy, 20Gy, 40Gy,

60Gy

RT + Oral CH RT

Placebo (i.e. mineral water) were used in 3 studies and blinding were unspecified in all the studies.

CH = Chinese herbal, CT = Chemotherapy, RCT=Randomised control trial, RT = Radiotherapy

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3.2 Risk of bias among the included studies

All of the studies included in this review had at least one criterion with unclear or high risk of

bias (Figure 2). As for performance bias, only Jiang 2006 scored low risk of bias while the

remaining studies had high risk of bias (Figure 3).

Figure 2. Risk of bias graph: review authors’ assessment on each risk of bias item across all included

studies (presented as percentage).

Figure 3. Risk of bias summary: review authors’ assessment on each risk of bias item.

Random sequence generation (selection bias)

Allocation concealment (selection bias)

Blinding of participants and personnel (performance bias)

Blinding of outcome assessment (detection bias)

Incomplete outcome data (attrition bias)

Selective reporting (reporting bias)

Other bias

0% 25% 50% 75% 100%

Low risk of bias Unclear risk of bias High risk of bias

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Hu 2004 ?

Hu 2011 ?

Huang 2013 +

Jiang 2005 ?

Jiang 2006 ?

Li Hua 2009 ?

Liu 2016 +

Ma 2012 +

Wei Bo 2009 +

Wu 2014 ?

Yang 2014 ?

Yin 2009 ?

Zhang 2011 ?

Zhang 2012 ?

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3.3 Analyses findings

Though all 20 included studies assessed xerostomia as the primary end-point, results of some

studies were not included in the qualitative analysis for the following reasons: i). Unextractable

or unsuitable data to be pooled: 2 studies [9, 29]; ii). The use of non-validated method of

assessing salivary flow: 1 study [30]; iii). Head to head comparisons between 2 herbs: 1 study

[14]; iv) secondary publication of earlier studies: 2 studies [10, 31].

Chinese herbs improved the salivary flow more than no herbs (MD -14.40, 95% CI -

25.73, -3.07; I2=71%, P=0.07, quality of evidence: moderate) based on data on 73 participants

from 2 studies. As the heterogeneity was substantial, the results were analysed using random-

effect model and the quality of evidence was downgraded for the same reason (Table 2).

Fewer participants who received Chinese herbs had severe xerostomia post-radiotherapy (RR

0.42, 95% CI 0.32, 0.56; I2=21%, P=0.28, quality of evidence: moderate) based on data on 404

participants from 6 studies (Table 2).

Table 3. Summary of findings for the main outcome.

Chinese herbs compared with no herbs for xerostomia symptoms and other radiotherapy side effects

Population: Patients with head and neck cancer undergoing radiotherapy

Settings: Outpatients and inpatients

Intervention: Chinese herbs

Comparison: No herbs

Outcomes Relative effect

(95% CI)

No. of participants

(studies)

Quality of the

evidence (GRADE)

Salivary flow (time needed to wet the filter

paper in seconds, assessed at 20Gy)

MD -14.40

(-25.73, -3.07)

73 (2 RCTs) ⨁⨁⨁◯ Moderate

1

Severe xerostomia different scales

(during radiotherapy)

RR 0.60

(0.21 to 1.73)

115

(2 RCTs)

⨁◯◯◯ Very Low

2

Severe xerostomia different scales

(post-radiotherapy)

RR 0.42

(0.32 to 0.56)

404

(6 RCTs)

⨁⨁⨁◯ Moderate

3

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Severe oral mucositis different scales

(post-radiotherapy)

RR 0.34

(0.25 to 0.45)

431

(6 RCTs)

⨁⨁⨁◯ Moderate3

Severe loss of appetite assessed with CTCAE

grading (post-radiotherapy)

RR 0.17

(0.07 to 0.42)

126

(2 RCTs)

⨁⨁⨁◯ Moderate

3

CI: Confidence interval; MD: Mean difference; RR: Risk ratio

GRADE Working Group grade of evidence

High: It is very likely that the effect will be close to what was found in the research.

Moderate: It is likely that the effect will be close to what was found in the research, but there is a

possibility that will be substantially different.

Low: It is likely that the effect will be substantially different from what was found in the research, but

the research provides an indication of what might be expected.

Very low: The anticipated effect is very uncertain and the research does not provide a reliable indication

of what might be expected. 1 Quality of body evidence is downgraded due to substantial heterogeneity (I

2 =71%).

2 Quality of body evidence is downgraded due to imprecision (confidence interval included the null

effect) and risk of bias (high risk of performance bias). 3 Quality of body evidence is downgraded due to risk of bias (high risk of performance bias).

4. Discussion

A final 14 studies (total 994 participants undergoing radiotherapy) compared Chinese herbs

with no herbs, and 6 studies reported outcome data at similar assessment time-point and thus

were suitable for meta-analysis. Though this review only included RCTs, the randomization

method, measures to achieve allocation concealment and blinding of outcome assessment

were not clearly stated in the studies. Consequently, all included studies had unclear risk of

selection bias; and almost all had unclear risk of detection bias. Only Jiang (2006) scored low

risk of performance bias as the xerostomia was assessed with salivary flow rate which was

unaffected by the unblinded participants and personnel, while the remaining studies had high

risk of bias.

The quality of evidence ranged from moderate to very low across the outcomes. The

major factor that led to downgrading of quality of evidence was the risk of bias issues in the

conduct of the study, in particular, unblinded participants and personnel, which was likely to

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bias the assessment of subjective outcome (such as participants self-assessed

absence/presence of xerostomia and grading their xerostomia severity using RTOG, VAS scale).

Chinese herbal medicine has been used in managing radiotherapy-induced

complications, particularly xerostomia. Hospitals in China [32] and Taiwan [33] provide Chinese

herbal to patients pre-, concurrent, and/or post-radiotherapy to prevent/reduce the side

effects of xerostomia. The included studies mainly used Mai Men Dong (Tuber Ophiopogonis

Japonici) in line with findings of an animal study of improved salivary secretion. The proposed

mechanism of action is Mai Men Dong stimulates the transcelullar fluid movement and

secretion at secretory acinar cells [34]. Based on Chinese medicine concept, practitioners

prescribe herb according to pattern differentiation (i.e. focusing certain pattern instead of a

disease or a symptom) [32, 35]. Considering the differed characteristics of Chinese medicine

than Western medicine, Liu et al have outlined the method in planning good quality Chinese

medicine RCTs. For example, as herb are prescribed based on pattern differentiation, though it

is difficult to blind the practitioners, detection bias can be minimized by blinding the outcome

assessors and data analyzer [35].

The occurrence of radiation-induced xerostomia is multifactorial, depending on

concurrent chronic conditions (e.g. Sjogren’s syndrome, sarcoidosis) [36], concurrent medicine

[36], cancer staging [37], and radiation therapy (e.g. radiation dose, radiotherapy modalities)

[1]. Though all included studies stated the total radiotherapy dose, we suggest that future

studies on radiotherapy-induced xerostomia should describe the radiotherapy dose given to the

major salivary gland (i.e. parotid gland) and types of radiotherapy modalities (e.g. Intensity-

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modulated radiotherapy (IMRT), conventional radiotherapy). Patients who received lower

radiotherapy dose to their major salivary glands (e.g. lower radiotherapy dose to the parotid

gland, had parotid-sparing IMRT intervention), had less severe xerostomia [4, 38, 39].

Earlier reviews had: i). Focused on xerostomia resulting from non-cancer condition (e.g.

Sjogren’s syndrome [40]; ii). Reviewed general management of radiotherapy-induced

xerostomia [37, 42]. For example, Mercadante (2017) review on general management of

radiotherapy-induced xerostomia was based on English databases and included one herbal

study, i.e. Ameri et al (2016). Ameri et al (2016) examined the efficacy of the traditional Persian

herbal and artificial saliva in relieving the xerostomia symptom [42]. Comparatively, this

current review focused on radiotherapy-induced xerostomia, excluded studies using non-

Chinese herbal medicine (e.g. Ameri 2016 [43]) and extended the searches to the Chinese

database.

We searched for RCT at several electronic databases and included English and Chinese

published studies. However, non-inclusion of the following studies may limit the scope of this

review and generalizability of the pooled findings: i). Studies that used different measurement

of xerostomia severity than other studies (such as assessing xerostomia using Uptake Rate and

Excretion Rate [9]); ii). Studies with unextractable data/unsuitable data to be pooled; iii).

Studies that used herbs that were not based on Chinese medicine concept (e.g. comparing

ginger extract and placebo on post-radiotherapy head and neck cancer patients [44]. Another

limitation of this review was hand searching for relevant symposia, conference proceedings was

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not performed, although we believed that having searched the published literature extensively,

the likelihood of having substantial additional evidence through hand-searching is low.

5. Conclusion

In conclusion, there is limited evidence that Chinese herbal treatment may relief radiotherapy-

induced xerostomia and other related complications (such as oral mucositis and loss of

appetite) in head and neck cancer patients.

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A systematic review on Chinese herbal treatment for radiotherapy-induced

xerostomia in head and neck cancer patients

Highlights:

• A systematic review and meta-analysis of 14 randomised controlled trials.

• Chinese herbs were evaluated as an adjunct for head and neck cancer patients.

• Low-to-moderate quality evidence showing modest benefits in relieving xerostomia.

Character count with spaces for “Highlights”:

• 1st: 75

• 2nd: 79

• 3rd: 83