Traditional Herbal Medicine as Adjunctive Therapy for Nasopharyngeal Cancer

Abstract

The effectiveness of traditional herbal medicine (THM) as treatment for nasopharyngeal cancer (NPC) has not been clearly demonstrated. The aim of this study is to assess the effectiveness of THM as adjunctive therapies for NPC using the results of randomized controlled trials (RCTs). Five electronic databases, including English and Chinese databases, were systematically searched up to February 2014. All RCTs involving traditional herbal medicine in combination with conventional cancer therapy for NPC were included. Twenty-two RCTs involving 2,298 NPC patients were systematically reviewed. Of these 22 studies, 15 on 1482 patients reported a significant increase in the number surviving patients with survivals of more than 1, 3, or 5 years. Seven studies on 595 patients reported a significant increase in immediate tumor response, and three studies on 505 patients reported a significant decrease in distant metastasis. This meta-analysis of 22 studies suggests that THM combined with conventional therapy can provide an effective adjunctive therapy for NPC. More research and well-designed, rigorous, large clinical trials are required to address these issues

Introduction

Nasopharyngeal carcinoma (NPC) is a disease in which malignant cells form in the tissues of the nasopharynx. Rare in most parts of the world, the cancer is an Epstein-Barr virus–associated malignancy with a remarkable racial and geographical distribution. ¹

Nasopharyngeal carcinoma is rare in Western countries but relatively common in southern Asia. The World Health Organization (WHO) estimated 80 043 new cases per year worldwide. ² However, higher incidences of NPC can be found in areas such as, Southeast Asia, Greenland, and Alaska, and among Arab populations of North Africa and parts of the Middle East, as also in southern China. ³ Furthermore, the 5-year survival rate of NPC is ~60% in adults and children. ⁴ Although localized primary disease is often successfully treated by a combination of drugs and radiation therapy, advanced or recurrent malignancy is rarely cured, and toxicity from therapy is often severe and prolonged. ⁵

At present, radiotherapy and surgery are mainly used in early NPC, but because of its anatomical location adjacent to the skull, most treatments rely on chemotherapy or radiotherapy. ⁶ However, radiotherapy and chemotherapy have adverse effects (AEs) that last beyond treatment. The development of intensity-modulated radiotherapy (IMRT) has reduced AEs but they remain problematic. Therefore, it is important that new therapeutic concomitant therapeutic agents be developed to lessen the effects of AEs and to increase the effectiveness of radiotherapy and nasopharyngeal therapy.

Traditional herbal medicine (THM) has been reported to alleviate chemotherapy-induced nausea and vomiting ⁷ and also peripheral neuropathy. ⁸ Furthermore, THM have been shown to possess immunopharmaceutical effects by modulating lymphocyte functions and immune effector cells. ⁹ Some traditional herbal components have also been shown to have antitumor effects by improving immune functions in vitro and in vivo.^10,11

Recently, much research is being conducted to determine the effect of THM on cancer, and several articles have already been published demonstrating the effects of THM on a variety of cancers.^12-15 In addition, several randomized controlled trials (RCTs) have reported that THM are effective in NPC. After a recent systematic review, ² which included non-RCTs and RCTs, we conducted this meta-analysis on the findings of RCTs that focused on the effectiveness of THM on NPC.

Materials and Methods

Search Strategy

The following sources were used in the literature review up to of February 2014: The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Allied and Complementary Medicine Database (AMED), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL).

Reference lists of articles were checked for latest relevant publications, and a manual search was conducted for relevant journals, symposia, and conference proceedings. All identified publications were cross-referenced. When necessary authors were contacted to request additional data.

The search terms used were “Nasopharyngeal Neoplasms”[MeSH] OR NPC[TIAB] OR ((Nasopharynx[MeSH]OR Nasophrynx[TIAB] OR Nasopharynges[TIAB] OR Nasopharynxes[TIAB] OR Rhinopharynx[TIAB] OR Rhinopharynges[TIAB] OR Rhinopharynxes[TIAB] OR Nasopharyngeal[TIAB] OR NPC[TIAB] OR nasophar*[TIAB] OR rhinophar*[TIAB] OR naso-phar*[TIAB]) AND (Neoplasms[MeSH] OR Neoplasms*[TI] OR Cancer*[TI] OR Tumor*[TI] OR Tumour*[TI] OR Carcinoma[MeSH] OR Carcinoma*[TI] OR Adenocarcinoma[MeSH] OR Adenocarcinoma*[TI] OR adenomatous[TI] OR Lymphoma[MeSH] OR lymphom*[TI] OR lymphedema*[TI] OR Sarcoma[MeSH] OR Sarcoma*[TI] OR “Antineoplastic agents”[MeSH] OR antineoplas*[TI] OR ((adenom*[TI] OR adenopath*[TI]) AND malignant*[TI]))). Since all of the databases searched for this review possessed their own subject headings, each database was searched independently. No language restrictions were imposed. (Figure 1).

Figure 1.

Flow diagram showing the number of studies included and excluded from the systematic review and meta-analysis.

Study Selection

We only selected RCT articles; quasi-randomized and nonrandomized trials were excluded. We also excluded involving animal experiments or in vivo experiments. Articles with nonorally administrated THM were also excluded.

Studies on THM combined with conventional cancer therapy as treatment were included. Regarding control groups, 18 articles with radiotherapy or chemotherapy ¹⁶ or chemoradiotherapy ¹⁷ and 4 other studies^18-21 using different standard regimens were included. Wang et al ¹⁸ used radiotherapy with Dobell’s solution 5 to 8 times a day, lysozyme and vitamin B complex taken orally 3 times a day. In the studies of Zou et al ¹⁹ and Huang et al, ²⁰ patients were prescribed Dobell’s solution 5 to 8 times a day with chemotherapy and chemoradiotherpy respectively. Bao et al ²¹ included patients who did not undergo chemotherapy or radiotherapy as control group, and instead used placebo capsules filled with microcrystalline cellulose and colored to the same color as the Yunzhi-Danshen capsule used in the treatment group.

Quality Assessment

The quality assessment of all studies was performed in accord with category descriptions in the Cochrane Handbook of Systematic Reviews of Interventions. ²² Each study identified was assessed with respect to the inclusion criteria by one of two reviewers. When there was uncertainty regarding eligibility, the second reviewer also assessed the study and a decision was reached by discussion and consensus. Both reviewers independently assessed whether studies met the inclusion criteria and disagreements were resolved by discussion. Further information was sought from authors when papers contained insufficient information to make a decision about eligibility. The following questions were assessed and answered by the reviewers: (a) Was the allocation sequence adequately generated? (b) Was allocation adequately concealed? (c) Was knowledge of the allocated interventions adequately prevented during the study? (d) Was the blinding of the outcome assessment adequate? (e) Were incomplete outcome data adequately addressed? (f) Were the results of the study free of the suggestion of selective outcome reporting? (g) Was the study apparently free of other problems that could put it at risk of bias? This review used “Y, U, N” as keys of the judgments for each question assessed. An answer of “Yes” indicated a low risk of bias (Y), “Unclear” indicated an uncertain risk of bias (U), and “No” indicated a high risk of bias (N) (Table 1).

Table 1.

Randomized Control Trials on the Effect of Traditional Herbal Medicine (THM) on Conventional Nasopharyngeal Carcinoma Therapies.

Study	No. of Participants	TNM Stage	Control Group Intervention	THM Formula	Assessment Outcome	Quality Assessment a
Xu et al (1989)	188	I-IV	Radiotherapy	Destagnation decoction	Survival rate, distant metastasis	U-N-N-N-Y-Y-Y
Hu et al (1995)	57	II-IV	Radiotherapy	Decoction	3 and 5 years survival rate	U-U-N-N-Y-Y-Y
Gan et al (1999)	171	I-IV	Radiotherapy	Re qing jie du decoction	3 and 5 years survival rate	U-U-N-N-U-Y-Y
Yuan et al (2000)	163	I-IVa	Radiotherapy	Sheng chen decoction	3 and 5 years survival rate	U-U-N-N-Y-N-Y
Li (2000)	60	I-IV	Radiotherapy	Yiyiren recipe decoction	1 year survival rate, complete and partial recession	U-U-N-N-Y-Y-Y
Xie et al (2001)	89	II-IV	Radiotherapy	Antike capsule	oral mucositis, nausea and vomiting (II+III+IV)	U-U-N-N-Y-Y-Y
Li et al (2002)	180	I-IV	Radiotherapy	Huaxie huayu decoction	5 years survival rate	U-U-N-N-Y-Y-Y
Liu et al (2002)	100	I-IV	Radiotherapy	Yangying huaxie decoction	1 year survival rate,oral mucositis (II+III+IV)	U-U-N-N-Y-Y-Y
Wen et al (2002)	142	II-IV	Radiotherapy	Zishen Huaxie decoction	1 and 3 years survival rate, oral mucositis(II+III+IV), nausea and vomiting (II+III+IV)	U-U-N-N-Y-Y-Y
Xu et al (2003)	35	I-IV	Radiotherapy	Jingmin recipe decoction	Latent time of evoked potential of upper and lower visual field	U-U-N-N-Y-Y-Y
Wu et al (2003)	76	II-III	Radiotherapy	Replenishing qi and nourishing yin decoction	3 and 5 years survival rate	U-U-N-N-Y-Y-Y
Huang et al (2003)	101	III-IVa	Chemotherapy	Shashen recipe decoction	Oral mucositis (II + III + IV)	Y-Y-N-N-Y-Y-Y
			Radiotherapy
			Dobell’s solution
Huang et al (2003)	119	II-IV	Radiotherapy	Shuichi capsule	5 years survival rate	U-U-N-N-Y-Y-Y
Wen et al (2003)	115	I-IVa	Radiotherapy	Yiqi yangyin huayu decoction	Complete or partial response, 1-, 3-, and 5-year survival rate	U-U-N-N-Y-Y-Y
Wang et al (2005)	86	I-IV	Radiotherapy	Xuan can recipe decoction	Significant difference in total response rate	U-U-N-N-Y-Y-Y
			Dobell’s solution
			Vitamin B, Lysozyme taken orally
Zou et al (2005)	120	I-IV	Radiotherapy Dobell’s solution	Huaxiehuayu decoction	Oral mucositis	U-U-N-N-N-Y-Y
					Partial and complete recession data missing
Yang et al (2005)	60	III-IVa	Radiotherapy	Dihuang yingzi deccotion	1-year survival rate, total response rate	U-U-N-N-Y-Y-Y
Su et al (2005)	60	I-IV	Radiotherapy chemotherapy	Puji jianye decoction	Oral mucositis (II + III + IV), 1-year survival rate	U-U-N-N-Y-Y-Y
Bao et al (2006)	27	I	Placebo capsule	Yunzhi-Danshen capsule	Absolute count of T cells (CD3+), count of Th cells (CD3+ CD4+), count of B cells (CD19+)	U-U-Y-Y-Y-Y-Y
Liang and Cai (2006)	62	III-IV	Chemotherapy	Taizishen recipe decoction	1-year survival rate, complete and partial recession, nausea, and vomiting (II + III + IV)	U-U-N-N-Y-Y-Y
Zhang et al (2006)	92	III-IVa	Radiotherapy	Jiedu shengjin decoction	3-year survival rate, complete and partial recession	U-U-N-N-Y-Y-Y
Song et al (2007)	195	I-IV	Radiotherapy	Qing re sheng jin decoction based on syndrome differentiation	oral mucositis (II + III + IV)	U-U-N-N-Y-Y-Y

a

The following questions were assessed and answered: (a) Was the allocation sequence adequately generated? (b) Was allocation adequately concealed? (c) Was knowledge of the allocated interventions adequately prevented during the study? (d) Was the blinding of outcome assessment adequate? (e) Were incomplete outcome data adequately addressed? (f) Were the results of the study free of suggestion of selective outcome reporting? (g) Was the study apparently free of other problems that could put it at a risk of bias? Answer key: Y, yes; U, unclear; N, no.

Statistical Analysis

Study data were summarized using basic statistics using simple counts and means. The main purpose of the analyses was to quantify and compare the effect of controlled THM trials plus conventional cancer therapy (treatment group) versus the effect of only conventional cancer therapy (control group) in NPC patients. Statistical analysis was conducted using Review Manager 5.1 for Windows (The Nordic Cochrane Center). The odds ratio (OR) of survival period, immediate tumor response, reduction in therapy toxicity, distant metastasis, and response rate, with 95% confidence intervals (CIs), were presented individually for each trial. In the present study, an OR of <1 indicates a lower risk in the treatment group than in the control group, and an OR of >1 indicates a greater risk in the treatment group than in the control group.

Results

Study Description

An initial search identified 96 potentially relevant articles, but only 22 studies met our inclusion criteria and were subjected to systematic review. Two articles were in English and 20 articles were in Chinese.

The total number of subjects evaluated was 2298. A total of 76 articles were initially excluded because they did not meet our inclusion criteria. Of these 76 articles, 55 were excluded because they duplicated other articles or had irrelevant titles, and 21 were excluded after abstract review because they did not match the study criteria. Subsequently, 14 additional articles were included after reference review. More detailed evaluation of each article, resulted in the exclusion of 12 more articles; of these 6 were not randomized controlled trials and 6 failed to match our inclusion criteria.

Survival

The survival findings of 15 studies for 1482 NPC patients with follow-ups ranging between 1 and 5 years were assessed. The survival rate for more than 1 year in treatment groups (n = 317) in 7 studies was 90% (287/317) and in control groups (n = 282) was 80% (228/282). These results showed that THM therapy significantly affected the 1-year survival rate, in favor of the treatment group (OR = 2.50, 95% CI = 1.52-4.11) (Figure 2A). The survival rate for more than 3 years in the treatment groups (n = 435) in these 7 studies was 67% (195/435) and in the control groups (n = 319) was 62% (198/319), showing that THM therapy significantly affected the 3-year survival rate, in favor of the treatment group (OR = 1.49, 95% CI = 1.09-2.05) (Figure 2B). The survival rate for more than 5 years in the treatment groups (n = 391) of the 6 studies was 53% (208/391) and in the control groups (n = 345) was 42% (145/345), showing THM therapy significantly affected the 5-year survival rate, in favor of the treatment group (OR = 1.58, 95% CI = 01.18-2.13) (Figure 2C).

Figure 2.

Meta-analysis of combination cancer therapy versus conventional cancer therapy; the effect of THM with standard therapy on overall survival. (A) The number of patients with a survival period of >1 year. (B) The number of patients with a survival period of >3 years. (C) The number of patients with a survival period of >5 years. CI, confidence interval; NPC, nasopharyngeal carcinoma; OR, odds ratio; THM, traditional herbal medicine.

The advantage of THM treatment on overall survival was evident in all studies included, with the exception of the one study by Yuan et al, ²³ in which the survival rate at 3 years had an OR of 0.78 and a 95% CI of 0.35-1.73.

Immediate Tumor Response

An investigation of immediate tumor response, as defined by WHO, was conducted using 4 of the 22 controlled trials. In these studies, 90% of patients reported complete or partial response in the treatment groups (n = 310), whereas 68% of patients did so in the control groups (n = 285). These results showed that concomitant THM therapy was significantly and positively correlated with immediate tumor response (OR = 5.21, 95% CI = 3.26-8.34) (Figure 3A).

Figure 3.

Meta-analysis of combination cancer therapy versus conventional cancer therapy; the effect of THM with standard therapy on immediate efficacy. (A) The number of patients who achieved complete or partial tumor responses as determined using the World Health Organization (WHO) scale. (B) The number of patients with grade 2 to 4 oral mucositis evaluated using the WHO scale. (C) The number of patients with distant metastasis. CI, confidence interval; NPC, nasopharyngeal carcinoma; OR, odds ratio; THM, traditional herbal medicine.

Reduction in Therapy Toxicity

The efficacy outcomes of concomitant THM treatment to alleviate acute AEs induced by cancer therapy in NPC patients were also examined. In 7 of the 22 controlled trials, 58% of patients suffered from grade 2 to 4 oral mucositis in the treatment groups (n = 424) whereas 79% did in the control groups (n = 383), which indicated a significantly lower risk in the treatment group (OR = 0.26, 95% CI = 0.13-0.54).

In addition, 3 studies presented grade 2 to 4 nausea and vomiting results. Ten percent of patients reported nausea and vomiting in the treatment groups (n = 158) and 22% in the control groups (n = 135), which represented a significantly lower risk in the treatment groups (OR = 0.35, 95% CI = 0.17-0.73) (Figure 3B).

Distant Metastasis

The effect of THM on distant metastasis was investigated in three of the 22 controlled trials. A total of 18% of patients developed distant metastasis in the treatment groups (n = 266) and 26% did so in the control group (n = 239), indicating a significantly lower risk in the treatment groups (OR = 0.64, 95% CI = 0.42-0.98) (Figure 3C).

Response Rate

In 2 studies,^18,24 the response rate in nasopharyngeal patents with symptoms were analyzed. In the treatment groups, 94% of patients (n = 73) responded, whereas in the control group 52% (n = 73) responded, indicating that THM significantly affected symptomatic improvements (OR = 16.83, 95% CI = 5.45-51.92).

T Lymphocytes and Post–Visual Pathway Injury

In 1 study, ²¹ a search was conducted on reductions in the percentages and absolute counts of T lymphocytes after radiotherapy. In this study, the absolute mean count percentages in the treatment and control groups were −62.7% and −75.1%, respectively, showing that THM significantly affected the number of T lymphocytes after conventional treatment. In addition, in another study, ²⁵ a search was conducted to investigate the damage caused to the post–visual pathway by radiotherapy. Pre to post differences in the latency and amplitude of evoked potentials in the upper visual field were not significantly different in the treatment group, whereas in the control group they were significantly shorter (P < .01). In the lower visual field, results were also significantly different in the control group (P < .01), and no difference was observed in the treatment group. These results showed that THM significantly shortened the latencies and amplitudes of evoked potentials.

Herbs Most Often Used in Nasopharyngeal Carcinoma

All 22 studies reported herbs and decoctions, and Radix ophiopogonis, Salvia miltiorrhiza, Scrophularia buergeriana, and Radix rehmanniae were the herbs most frequently used to treat NPC (Table 2).

Table 2.

Herbs Most Often Used in Nasopharyngeal Carcinoma.

Traditional Herbal Medicine	Frequency (%)
Radix ophiopogonis	16 (63.6)
Salvia miltiorrhiza	12 (54.5)
Scrophularia buergeriana	12 (54.5)
Radix rehmanniae	12 (54.5)
Oldenlandia diffusa	9 (40.9)
Radix adenophorae	8 (36.3)
Radix trichosanthes kirilowii	8 (36.3)
Radix pseudostellaria angustifolia	7 (31.8)
Radix paeonia lactiflora	7 (31.8)
Flos Lonicera japonica	7 (31.8)
Radix Glycyrrhizae	7 (31.8)

Discussion

This systematic review of 22 RCTs, investigated the efficacy of THM when coadministered with conventional therapy in patients with NPC. To our knowledge, this is the first systematic review to include only RCTs that investigated the effects of THM as an adjunctive therapy on nasopharyngeal cancer.

In this study, we investigated the effect of adjunctive THM therapy in a variety cancers and on a variety variables, such as, AEs, survival rates, and treatment responses. A significant amount of evidence has been presented supported the beneficial effects of THMs. In terms of survival period, treatment groups showed significantly longer survival than control groups over 1, 3, and 5 years. It had a significant difference in the 5-year survival period which is a meaningful result for cancer treatment as 5-year survival is viewed as the criterion of improvement. ²⁶

The high prevalence of distant metastasis, despite the recent advances in NPC management, has been observed in many studies on NPC patients.^27,28 We conducted research on 3 articles that investigated the effect of THM on distant metastasis. However, although results were positive, the numbers of trials involved were too small to draw firm conclusions, and thus, these results should be interpreted with caution. Further investigation of this issue is required.

This study had several limitations. First, the quality of included studies was not rigorously assessed. To assess the quality of the studies included, we used the “risk of bias” assessment tool by the Cochrane collaboration. ²² As with the method of the quality rating scale, it is difficult to justify the subtle difference of each of the items in the scale, ²⁹ we assessed each study using 7 critical domains, that is, randomization, allocation concealment, blinding of participants and personnel, blinding of outcome assessments, incomplete outcome data reporting, selective outcome reporting, and other biases. However, the “risk of bias” assessment tool may not be entirely free of subjectivity. ³⁰ Allocation sequence generation and concealment were noted to be unclear all but one study. ²⁰ The blinding of participants, personnel, and outcome assessments were not mentioned or were not performed properly in all studies with the exception of one by Bao et al. ²¹

Second, of the 22 articles only 2 articles^21,31 were written in English. The remaining 20 articles were written in Chinese, which makes it difficult for other researchers to continue further research based on the result of these studies. Third, in most of the articles included, a combination of several herbs were used, and thus, the actions of multiple active ingredients on cancer have not been established yet.

However, Eisenberg et al ³² reported research on a single active compound does not reflect the diverse and complex effects of traditional herbal medicine, where patients are mostly prescribed with multiple compound than single herb. Also, some evidence suggests that single components extracted from plants are less potent than complete extracts ³³ and that the multitargeted approach can be more effective than the single target approach.

Regarding recommendations for future research, as conventional treatments develop further due, for example to the introductions of more specific radiotherapy devices, such as IMRT, more studies are need to assess the effects and relationships between THM and IMRT. Also, because the quality of trials included in the present study were generally weak, further high-quality trials are required to assess the effectiveness of THM in patients with NPC.

In conclusion, this systematic review demonstrates the significant efficacy of THM treatment with standard therapy versus standard therapy in terms of prolonging survival period, enhancing immediate tumor response, and alleviating acute AEs. Additional controlled trials are needed to investigate other efficacy measures of potential interest, such as, distant metastasis. In addition, more randomized controlled trials should be investigated to determine the role of THM in combination with different cancer therapies.