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 Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 34  |  Issue : 4  |  Page : 152-160

Prevention of acute radiation-associated toxicity by traditional Chinese medicine Tianwang buxin mini-pills in patients with head and neck cancer


1 Department of Chinese Medicine, Tri-Service General Hospital, National Defense Medical Center; Graduate Institute of Chinese Medicine, China Medical University, Taichung, Taiwan, Republic of China
2 Department of Radiation Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China
3 Division of Hematology/Oncology, Department of Medicine, Shuang-Ho Hospital, Taipei Medical University, New Taipei City, Taiwan, Republic of China
4 Department of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China
5 Department of Chinese Medicine, Tri-Service General Hospital, National Defense Medical Center; Graduate Institute of Chinese Medicine, China Medical University, Taichung; ChanDer Clinic, Taipei, Taiwan, Republic of China
6 Department of Chinese Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China
7 Graduate Institute of Chinese Medicine; School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan, Republic of China
8 Department of Anesthesiology, Taipei Veterans General Hospital/National Yang-Ming University; Department of Anesthesiology, National Defense Medical Center, Taipei, Taiwan, Republic of China

Date of Submission06-Jan-2014
Date of Decision05-Mar-2014
Date of Acceptance24-Apr-2014
Date of Web Publication26-Aug-2014

Correspondence Address:
Dr. Shung-Tai Ho
Department of Anesthesiology, Taipei Veterans General Hospital, No. 201, Section 2, Shihpai Road, Taipei 112
Republic of China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1011-4564.139185

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  Abstract 

Background: Anemia and oral mucositis are main side effects of radiotherapy (RT) and are important factors affecting the quality of life (QOL) in head and neck cancer (HNC) patients treated with RT. This study aimed to explore the safety and therapeutic efficacy of Tianwang Buxin Mini-pills (TWBXM) for the prevention of acute RT toxicity in HNC patients by using a randomized, double-blind and placebo-controlled study design. Patients and Methods: Seventy-three HNC patients participated the study. They were randomized into a treatment group (n = 38) and a control group (n = 35). All patients received daily either TWBXM treatment or placebo starting from the initiation of RT until 1-month follow-up after RT completion. All patients were evaluated for QOL, acute RT toxicities and laboratory data (hemoglobin [Hgb], white blood cell and platelet) at 3 time points: Pre-RT, upon RT completion and at TWBXM completion. Results: The TWBXM group maintained normal levels of Hgb during the duration of the study while the placebo group showed a decrease in Hgb (P = 0.035). Conclusions: This study demonstrated the safety and efficacy of TWBXM applied in the HNC patients receiving RT. It prevented the decrease of Hgb in HNC patients undergoing RT treatment as well 1-month-post-RT treatment. Further studies are needed to assess the effects of TWBXM for the prevention of other RT toxicities.

Keywords: Head and neck cancer, traditional Chinese medicine, Tianwang Buxin Mini-pills, radiotherapy, toxicities


How to cite this article:
Lin KS, Jen YM, Chao TY, Lin YS, Wang LH, Lin CJ, Su YC, Ho ST. Prevention of acute radiation-associated toxicity by traditional Chinese medicine Tianwang buxin mini-pills in patients with head and neck cancer. J Med Sci 2014;34:152-60

How to cite this URL:
Lin KS, Jen YM, Chao TY, Lin YS, Wang LH, Lin CJ, Su YC, Ho ST. Prevention of acute radiation-associated toxicity by traditional Chinese medicine Tianwang buxin mini-pills in patients with head and neck cancer. J Med Sci [serial online] 2014 [cited 2019 Oct 22];34:152-60. Available from: http://www.jmedscindmc.com/text.asp?2014/34/4/152/139185


  Introduction Top


Head and neck cancer (HNC) is a broad term that encompasses epithelial malignancies that includes paranasal sinuses, nasal cavity, oral cavity, pharynx, and larynx. Radiotherapy (RT) is an effective treatment for HNC, but side-effects such as anemia and oral mucositis are common in patients undergoing RT. [1],[2]

Anemia may conduct to tumor hypoxia by decreasing the oxygen-carrying capacity of the blood, resulting in RT and in some instances, chemotherapy resistance. It may constitute an obstacle to achieving maximal loco-regional tumor control and survival with chemotherapy and RT for HNC. [3],[4] In addition, anemia negatively affects the quality of life (QOL) of cancer patients, as evidenced by worsening fatigue. [2] Correction of anemia has been associated with QOL improvements in anemic cancer patients. [5] Erythropoietin has been shown to correct anemia and improve QOL, [6] however, erythropoiesis-stimulating agents may increase the risk of thrombovascular events and result in decreased survival and poorer tumor control. [7],[8] Therefore, safer alternative strategies are needed to correct anemia in patients undergoing RT.

Radiation fields from RT for HNC cover not only salivary glands but also all or part of the oral mucosa, thereby increasing the risks of oral mucositis. [9] Xerostomia, pain, burning sensation, dysphagia, slurred speech, and related symptoms can cause discomfort, while accelerated dental caries may contribute to more serious complications such as osteoradionecrosis. [10],[11] During the last decade there has been increasing interest in the prevention of RT-induced severe mucositis. [12],[13],[14],[15] However, effective and safe intervention for the prevention of oral mucositis in RT has yet to be identified to date. [16],[17]

Tianwang Buxin Mini-pills (TWBXM) has been used for centuries for the treatment of anemia, oral mucositis, xerositis and oral ulcers in traditional Chinese medicine (TCM). Several studies have revealed the potential effectiveness of TCM on the treatment of RT-associated toxicity in HNC patients. [18],[19] However, all these studies had poor randomization techniques or lack of blind testing. In order to clarify the safety and efficacy of TWBXM in preventing RT-associated acute toxicity in HNC patients, we conducted a randomized, double-blind and placebo-controlled clinical trial to evaluate the effectiveness of TWBXM in preventing RT associated acute side-effects.


  Patients and Methods Top


Patient evaluation

From January 2003 to November 2004, 103 patients with histological evidence of carcinoma at the head and neck were identified by the otolaryngologist from Tri-Service General Hospital, Taipei, Taiwan. Every patient was classified according to the tumor node metastasis (TNM) (1997 AJCC TNM edition) classification system (T describes the size of the tumor and whether it has invaded nearby tissue, N describes any lymph nodes that are involved, and M describes distant metastasis). All the patients included for the study received treatment with RT, with life expectancy ≥3 months, showed no evidence of brain metastasis, and had Eastern Cooperative Oncology Group status of ≤2. The patients also had white blood cell (WBC) count ≥ 2500/uL, platelets (PLT) ≥75,000/uL, hemoglobin (Hgb) ≥8 g/dL, serum creatinine (Cr) ≤3.0 mg/dL, total bilirubin ≤ 3.0 mg/dL, and serum glutamic oxaloacetic transaminase (GOT), glutamate pyruvate transaminase (GPT) ≤ 3 times the upper limit of normal. Patients with prior RT, presence of oral lesions, and severe organ failure were excluded from the study.

Seventy-three patients who fulfilled the inclusion criteria and met none of the exclusion criteria signed the informed consent to join the study. All patients were required to sign an informed consent before study entry. The study was approved by the Institutional Review Board of Tri-Service General Hospital.

Study medication

The herbal formulation used in this study was modified from TWBXM first described in the Ming Dynasty, which is aimed at strengthening the qi, blood and yin functions to improve fatigue, anemia, oral mucositis, xerositis and oral ulcers. [20] Hence, we chose TWBXM to determine whether it can improve the side effects of RT in HNC patients.

The herbal preparation (TWBXM) used in this study contained 13 herbs, which were listed in [Table 1]. All herbs were obtained from Sun Ten pharmaceutical Co. Limited, (Taipei, Taiwan). After extraction of mixed herbs, decoction was separated, concentrated, and spray-dried into powder form. The powder was then packed in sealed opaque aluminum foil bags. The placebo was made of starch and designed to taste, smell, and look similar to the Chinese herbal formula and was packed in an identical package. All packages were stored reserved in a refrigerator at the hospital by the chief investigator.
Table 1: The Compositions of Tianwang Buxin Mini-pills (TWBXM)

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Study design

This study was a double-blind, randomized, and placebo-controlled trial. The enrolled patients were randomized to the study medication according to a computer-generated randomization schedule. Seventy-three patients who fulfilled the recruitment criteria were randomized to receive TWBXM (study group) or placebo (control group) [Figure 1].
Figure 1: Study flow chart

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All patients, the study nurse, and doctors were blinded to the group of the treatment group. All the patients took 3 g of TWBXM or placebo orally 3 times a day starting from the initiation of RT, and the treatment was not finished until 1-month after RT completion. All patients were monitored at pre-RT, upon RT completion, and at TWBXM/placebo completion for receiving a complete set of the QOL questionnaires, radiation and hematologic evaluation.

The QOL questionnaires included the cancer specific questionnaire "European Organization for Research and Treatment of Cancer into QOL-Cancer 30" (EORTC QLQ-C30) and the head and neck specific QLQ-H & N35 (Head & Neck 35). [21],[22],[23] The questionnaires were filled by a trained study nurse. Radiation toxicities were graded according to the Radiation Therapy Oncology Group (RTOG) acute radiation morbidity scoring criteria [24],[25] by the evaluating physician. The hematologic side effect included neutropenia, thrombocytopenia, and anemia. Liver and renal functions such as GOT, GPT, blood urea nitrogen (BUN), Cr, were evaluated at pre-RT and at TWBXM/placebo completion.

Statistical methods and analysis

All the analysis was performed using the SAS statistical software (version 9.1.3, SAS Institute, Cary, NC). First, the narrating statistics express with percentage the patient's basic analysis. Next, we analyzed with Fisher's exact that assays the baseline assessment, characteristics of tumor and RTOG Acute Morbidity Scoring Criteria. Finally, Independent t-test were used to detect the difference between the two different treatment groups in body mass index (BMI), age, EORTC QLQ-C30 scores, EORTC QLQ-H & N35 scores, the radiation dose, body weight loss and the laboratory blood test.

All tests were performed two-tailed and conducted at 5% significance level. To simplify the presentation, we chose only some items of the questionnaires listed in the text.


  Results Top


Patient demographics

Of the 73 patients with HNC and treated with RT, over 76% were male with an average age >50 years old. Thirty-eight patients were assigned to the TXBXM group and 35 to the placebo group. Age, BMI, lymph node metastasis, tumor localization, TNM classification, and tumor stage of the patients were similar between the two groups [Table 2].
Table 2: Baseline characteristics of patients

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Five patients withdrew from the study during RT completion (three patients in the TWBXM group and two in the placebo group). During the follow-up phase after RT completion, eight patients failed to return for follow-up and 16 patients refused to take TWBXM/placebo after completion of RT. There was no significant difference in patient pulling out between the two groups (12 patients in the TWBXM group and 12 in the placebo group).

There were also no differences in the mean radiation dose between the TWBXM group (6944.9 cGy) and the control group (7098.4 cGy, P = 0.476) [Table 3].
Table 3: Acute morbidity scoring criteria of radiation toxicities assessment of the two patient groups on the effects of TWBXM/placebo therapy

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Laboratory data (complete blood count/renal and liver function)

Hematological abnormalities were frequently observed in cancer patients with RT. In our study, complete blood counts were normal during the pre-RT in both groups [Table 4]. Hgb remained the level >12 g/dL from the pre-RT to the TWBXM completion in the TWBXM group, but the placebo group showed a significant drop (10.88 g/dL) at the placebo completion. At the completion of the study, A significant decrease (P = 0.035) in Hgb was found in the placebo group [Table 4]. The mean of WBC and PLT count were at normal range during the study period in both groups.
Table 4: Laboratory data assessment of the two patient groups on the effects of TWBXM/placebo therapy

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Renal and liver function tests (BUN, Cr, GOT, and GPT) obtained after TWBXM treatment showed no abnormal values [Table 4].

Results of the European Organization for Research and Treatment of Cancer QLQ-C30 and European Organization for Research and Treatment of Cancer QLQ-H and N35

For evaluating the QOL of HNC patients treated with RT, we used the EORTCQLQ-C30 and QLQ-H & N 35 to compare the QOL at all points and the changes in QOL from baseline for subgroups of patients with and without TWBXM treatment. Patients treated with RT showed a clinically significant deterioration in both functions and symptoms. The TWBXM group showed more pain score, while RT completion (P = 0.022), but less pain score at TWBXM completion (TWBXM group: 31.61; placebo group: 37.84) in QLQ-H & N 35, however, these improvements were not statistically significant. Other functions and symptoms analyzed in both QOL questionnaires also did not show any significant difference between the two groups [Table 5] and [Table 6].
Table 5: "EORTC-C30" assessment of the two patient groups on the effects of TWBXM/placebo therapy

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Table 6: "EORTC-H and N35" assessment of the two patient groups on the effects of TWBXM/placebo therapy

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Acute morbidity scoring criteria of radiation toxicities

At the pre-RT and RT completion, the patient's acute radiation toxicities were independently evaluated by radiation oncologists. At each evaluation, the patients were weighed, and the degrees of acute radiation toxicities for the following items were evaluated: Skin, oral mucosa, mucositis, nausea, vomiting, leukopenia, dry mouth, and loss of taste. In our study, the severity of skin, oral mucosa, mucositis, dry mouth and loss of taste increased from the pre-RT to RT completion both two groups. However, TWBXM treatment did not significantly improve the radiation toxicity [Table 3].


  Discussion Top


To our best knowledge, this is the first clinical trial using TCM in the prevention of radiation-induced toxicity of HNC patients with randomization, double-blinding, and a placebo-controlled group. TWBXM was aimed to improve acute side effects of RT in HNC patients such as anemia, oral mucositis, xerositis and fatigue. Liver and renal functions were monitored for all the study participants as a safety precaution, because liver and renal dysfunction has been reported to associate with the use of Chinese herbs. [26],[27],[28] In our study, liver and renal function were assessed at the end of TWBXM administration and the results showed that the use of TWBXM did not cause liver and renal dysfunction in all the patients [Table 4].

Birgegard et al. had noted that the correlation between a low Hgb level and poorer performance status revealed in European Cancer Anemia Survey is consistent with clinical evidence supporting a relationship between Hgb levels and relevant QOL parameters. [29] McCloskey et al. retrospectively reviewed outcomes among 78 patients at Roswell Park Cancer Institute, who were treated definitively with RT and concurrent chemotherapy for Stage III-IV squamous cell carcinoma of the head and neck. Patients with pretreatment Hgb levels <12 g/dL was found to have significantly inferior overall survival and local control. [30] The mean of pre-RT Hgb levels in our study were >12 g/dL in both groups (TWBXM group: 12.9; placebo group: 12.6). Hence, this study did not indicated that the loco-regional tumor control and patient survival of our patients. However, at the end of TWBXM/placebo treatment, the Hgb levels for patients in the placebo group dropped to 10.88 g/dL. Our study demonstrated that TWBXM could effectively prevent the decrease of Hgb in HNC patients have undergone RT. The result showed that the effects of TWBXM conformed to the theory of TCM on anemia-related hemogram parameters for "nourishing blood" and might provide HNC patients having undergone RT with better QOL.

Crawford's et al. has noted that a direct relationship exists between Hgb increases during epoetin alfa therapy and corresponding QOL improvements in cancer patients receiving chemotherapy across the clinically relevant Hgb range of 8-14 g/dL. [6] Our results revealed the TWBXM group showed more pain score while RT completion (P = 0.022), but less pain score at TWBXM completion. However, it failed to achieve statistical significance. This may be explained by the fact that two of RT's main toxicities, oral mucositis and dry mouth, which caused great discomfort to the patients showed no significant improvement in both groups [Table 3], and thus, this would significantly reduce the QOL scores examined on these patients.

One of the main reasons why TWBXM was chosen for this study because it has been used to treat oral mucositis. RT induced oral mucositis are initially thought to be damage to epithelial cells caused by radiation during RT. However, recent evidence suggests that RT induced oral mucositis is more biologically complex than originally suspected, involving a sequential interaction of all cell and tissue types that comprise the oral mucosa and various physiological elements (e.g., tissue factors, cytokines). [1] It can be speculated that the mechanism of action for mucositis in TWBXM does not target directly of the pathways of RT-induced oral mucositis, since our results did not support it. It is also likely that the dose used in this study was insufficient to treat RT induced mucositis.

The major limitation associated with this study was the high dropping rate. Most patients suffered from oral pain and mucositits after RT, so they refused to take oral medicine. In order to increase the compliance of patients, the next study we could use the liquid form of TWBXM. In addition, this study only monitored patients for 1-month after the completion of RT, and thus, it could not determine whether the use of TWBXM could improve mucositis of RT for more than 1-month. A study with longer follow-up is required to examine this.

It concluded that TWBXM may prevent the decrease of Hgb in HNC patients until TWBXM completion (1-month after the completion of RT). In this randomized, double-blinded and placebo-controlled trial, TWBXM was shown to be safe. Although not all radiation-associated toxicities responded to this therapy, our positive finding supports the consideration of further investigation of TWBXM. Additional research would be necessary to an extensive clinical trial with the liquid form of TWBXM and long-time follow-up study for understanding of the prevention of other acute RT toxicities, dose - response relationship.


  Acknowledgments Top


We would like to thank the Committee on Chinese Medicine and Pharmacy, Department of Health, Executive Yuan, Taiwan for the grants support (CCMP92-RD-011 and CCMP93-RD-008).


  Discloser Top


All authors declare that there are no conflicts of interest.

 
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