Abstract

Objective

This prospective randomized Phase II study was designed to evaluate the preventive effect of an oral nutrition supplement composed of beta-hydroxy-beta-methylbutyrate, arginine and glutamine (beta-hydroxy-beta-methylbutyrate/arginine/glutamine) on radiation dermatitis in head and neck cancer patients.

Methods

Forty patients with histologically proven head and neck cancer, treated with concurrent chemoradiotherapy involving cisplatin were recruited. They were randomly assigned to the beta-hydroxy-beta-methylbutyrate/arginine/glutamine supplement treatment group (Group A) or the control group that received no supplement (Group B). The primary endpoint of this study was the percentage of patients developing ≥Grade 3 dermatitis. The secondary endpoints were the percentage of patients developing ≥Grade 2 dermatitis, and the duration of each grade of dermatitis relative to the observation period.

Results

The incidence of ≥Grade 3 dermatitis did not differ between the two groups. However, as secondary endpoints of this study, the incidence of ≥Grade 2 dermatitis was lower in Group A than B (62.6 vs. 94.4%; P < 0.05), and the duration of ≥Grade 1 dermatitis was shorter in Group A than B (44.8 vs. 56.7%; P < 0.01), as was the duration of ≥Grade 2 dermatitis (16.5 vs. 26.5%; P < 0.05).

Conclusions

Our study indicated that beta-hydroxy-beta-methylbutyrate/arginine/glutamine supplementation was potentially effective in the prevention of radiation dermatitis in head and neck cancer patients.

INTRODUCTION

Concurrent chemoradiotherapy (CCRT) involving the administration of cisplatin every 3 weeks has been shown in several studies to provide superior clinical results to those of radiotherapy alone in the following patient groups: patients with advanced laryngeal cancer requiring larynx preservation (1); patients with unresectable locally advanced head and neck cancer (2); and patients with head and neck cancer at high risk of postoperative recurrence (3,4). CCRT has played a major role in the treatment of advanced head and neck cancer in recent years; although this modality can improve the clinical results, it has negative effects that include an increased incidence of adverse events such as mucositis (5) and dermatitis (6). It is essential to establish supportive therapy to facilitate the completion of CCRT, since an increase in the incidence of adverse events can result in the deterioration of the quality of life of patients, and eventually reduce the treatment completion and survival rates (7).

The incidence of ≥Grade 3 radiation dermatitis has been reported to be 7% in a number of previous studies (1–3) and between 23 and 25% in an additional study (6). The incidence of Grade 3 dermatitis in patients who received radiation therapy in combination with cetuximab (an epidermal growth factor receptor antibody) has been reported to be 49% (8). Various interventions have been attempted as a means of preventing radiation dermatitis including vitamin C (9), Aloe vera (10), pantothenic acid cream (11), cortisone cream (12), chamomile cream, almond ointment (13) and trolamine emulsion (6). However, none of these treatments have been shown to be effective. Additionally, most of the studies regarding radiation dermatitis have focused on topical medication.

Over half of head and neck cancer patients are nutritionally compromised at the time of diagnosis, due to dysphagia or odynophagia related to the primary tumor (14,15). CCRT may additionally cause anorexia, nausea, vomiting and dysphagia; thus, nutritional compromise may be further exacerbated. In recent years, nutritional therapy has become recognized as an important supportive care method associated with CCRT (14,16).

It has been reported that nutrition therapy is associated with improved healing of skin wounds, such as pressure ulcers (17). However, to date there have been no studies regarding the prevention of radiation dermatitis, which is a type of inflammatory skin wound. We hypothesized that to prevent radiation dermatitis it may be important to provide appropriate nutritional therapy to patients undergoing radiotherapy.

An oral nutrition supplement composed of beta-hydroxy-beta-methylbutyrate (HMB), arginine (Arg) and glutamine (Gln) (HMB/Arg/Gln) has been reported to improve wound healing in diabetic foot ulcer patients (18), as well as in elderly volunteers (19). HMB, a metabolite of leucine, has been demonstrated to stimulate protein synthesis (20) and prevent proteolysis (21). Arg and Gln have been reported to increase collagen synthesis and protein synthesis (22–24). However, the effect of the HMB/Arg/Gln supplement on radiation dermatitis is unclear. The present Phase II clinical trial was designed to prospectively evaluate the preventative effect of HMB/Arg/Gln on radiation dermatitis in head and neck cancer patients.

PATIENTS AND METHODS

This prospective randomized, open-label, parallel design, Phase II study was conducted at our institution between April 2011 and June 2012. Patients with histologically proven head and neck cancer, treated with CCRT involving cisplatin were recruited. Prior to initiation of CCRT, 40 patients were randomly assigned to the following groups: the HMB/Arg/Gln treatment group, Group A; or the control group, Group B (no nutritional supplement). The primary endpoint of this study was the determination of the percentage of patients developing ≥Grade 3 dermatitis in these two groups. Based on our experience, we estimated that the incidence of ≥Grade 3 dermatitis would be 50% at the end of CCRT. We hypothesized that HMB/Arg/Gln supplementation could reduce this incidence to 10%; thus, the sample size estimated for this study, using α = 0.05 and β = 0.8 with a 10% inflation factor incorporated for anticipated ineligible or unassessable patients, was set at 40 patients with 20 patients per group. The secondary endpoints were the percentage of patients developing ≥Grade 2 dermatitis, and the duration of each grade of dermatitis relative to the observation period. Patients in Group A received 24 g of HMB/Arg/Gln (HMB 1.2 g, Arg 7 g and Gln 7 g) supplement (Abound®: Abott, Tokyo, Japan) dissolved in 240–300 ml of water twice daily, or received the supplement dissolved in 100 ml of water via a feeding tube. Patients who were not able to continue taking HMB/Arg/Gln were excluded. However, these patients were included in the statistical analysis if the radiotherapy had reached a dose level ≥60 Gy during the study period. HMB/Arg/Gln was administered from the first day of CCRT up until 1 week after the completion of CCRT. The inclusion criteria included the following: (i) age ≥20 years; (ii) a cisplatin plus radiation dose of ≥60 Gy; (iii) a planning target volume (PTV) that included the neck skin; (iv) performance status ≤1; (v) sufficient organ functions; (vii) life expectancy ≥3 months. Patients were excluded if they had skin diseases, and/or if they had undergone radiotherapy for head and neck cancer.

Ethics

The Institutional Review Board of Miyagi Cancer Center approved the study protocol and informed consent was obtained from each subject prior to entry into this study. Study procedures were followed in accordance with the Helsinki Declaration.

CCRT Treatment

All patients received computed tomography (CT) based three-dimensional conformal radiotherapy. X-rays of energy ≤6 MV were used. Patients undergoing the first radical therapy received a total dose of 70 Gy and patients with a high risk of postoperative recurrence, where the presence of residual tumor was unknown, received a total dose of 66 Gy. All patients received radiation doses of 40–46 Gy to the entire neck and supraclavicular regions, and an additional 20–30 Gy booster dose. Patients who received a dose of ≥60 Gy were included in the statistical analysis. Patients in whom radiotherapy was suspended for ≥3 days were excluded from the study. Chemotherapy involved the administration of cisplatin (100 or 80 mg/m2, every 3 weeks) based on renal function and the presence of systemic complications.

Observation Period and Evaluation

Dermatitis was evaluated daily by several oncologists in our division from the first day of CCRT up until 1 week after the completion of CCRT, using the Common Terminology Criteria for Adverse events version 4 (CTCAE ver.4) (25). The most severe dermatitis that presented in the whole irradiated area, including the boost area, was evaluated and scored. As a contribution, T.I., K.M., Y.A., S.S., K.K., E.I., D.S. and R.S. scored the dermatitis grades for the registered cases; T.I. and K.M. scored the dermatitis grades for all of the patients.

Supportive Care

To avoid malnutrition due to decreased oral intake arising from oral mucositis, we actively used prophylactic enteral tube feeding. Percutaneous endoscopic gastrostomy (PEG) or nasopharyngeal tube feeding was employed.

Throughout the radiotherapy period, the irradiated area was kept as clean as possible by means of frequent washing with mild soap. Local cleansing with mild soap has previously been shown to reduce the incidence of wet desquamation (26). When Grade 1 or 2 erythema manifested, topical treatment with dimethyl isopropyl-azulene ointment was initiated, with efforts made to keep the skin appropriately moist. Wound intervention with dimethyl isopropyl-azulene ointment and flocculent wound dressing was prescribed upon the onset of wet desquamation (27).

Statistical Analysis

Fisher's exact test was employed for the statistical analysis of the following parameters: incidence of ≥Grade 2, ≥Grade 3 and ≥Grade 1 dermatitis at each radiation dose; the percentage of patients requiring wound intervention; patient gender; radiation dose. The dermatitis grades during CCRT were analyzed using the t-test or the Welch test. The χ2test was used for the analysis of the primary site, stage and the number of courses of concurrent cisplatin. The level of significance was set at P < 0.05.

RESULTS

A total of 40 patients were recruited for this study; of these 6 dropped out. Three patients dropped out of treatment Group A after the first course of chemotherapy because of anorexia and nausea, and one patient dropped out after registration because of a refusal to ingest HMB/Arg/Gln. From the control group (Group B), one patient dropped out after ≥3 days of unscheduled suspension of therapy because of Grade 4 hematotoxicity and hematemesis, and another patient dropped out because of modification of the therapeutic strategy following the development of severe complications. One patient in Group A could not continue taking HMB/Arg/Gln until 1 week after the completion of CCRT. However, because the total dose level reached ≥60 Gy, the patient was considered to have completed the study protocol. As a result, 16 patients from Group A and 18 patients from Group B completed the treatment protocol. The demographic and clinical characteristics of the study population are detailed in Table 1. Three patients who had received prior chemotherapy with cisplatin, docetaxel and 5-fluorouracil were included in Group A.

Table 1.

Patient characteristics

 Group A (n = 16) Group B (n = 18) P value 
Gender 
 Male 12 15 0.43 
 Female  
Age 
 Mean 62 64 0.21 
 Range 42–74 41–76  
Primary site 
 Oral cavity 0.59 
 Epipharynx  
 Oropharynx  
 Hypopharynx  
 Larynx  
 Primary unknown  
Stage 
 Stage II 0.3 
 Stage III  
 Stage IV 10 15  
Radiation dose 
 66 Gy 0.21 
 70 Gy 12 10  
Concomitant CDDP 
 1 Course 0.43 
 2 Course  
 3 Course 11  
Prophylactic tube feeding 
 Percutaneous endoscopic gastrostomy 16 14 0.07 
 Nasopharyngeal tube  
 Group A (n = 16) Group B (n = 18) P value 
Gender 
 Male 12 15 0.43 
 Female  
Age 
 Mean 62 64 0.21 
 Range 42–74 41–76  
Primary site 
 Oral cavity 0.59 
 Epipharynx  
 Oropharynx  
 Hypopharynx  
 Larynx  
 Primary unknown  
Stage 
 Stage II 0.3 
 Stage III  
 Stage IV 10 15  
Radiation dose 
 66 Gy 0.21 
 70 Gy 12 10  
Concomitant CDDP 
 1 Course 0.43 
 2 Course  
 3 Course 11  
Prophylactic tube feeding 
 Percutaneous endoscopic gastrostomy 16 14 0.07 
 Nasopharyngeal tube  

Values expressed as number of patients, mean and range.

The maximum grade of dermatitis during the observation periods was evaluated using CTCAE version 4.0. The incidence of dermatitis in Groups A and B is shown in Table 2. In Group A, there were three patients with Grade 3, seven patients with Grade 2 and six patients with Grade 1 dermatitis. In Group B, there were two patients with Grade 3, 15 patients with Grade 2 and one patient with Grade 1 dermatitis. The primary endpoint of this study, namely the percentage of patients developing ≥Grade 3 dermatitis, did not differ significantly between the two groups (P = 0.44). However, the incidence of ≥Grade 2 dermatitis was significantly lower in Group A than in Group B (62.6 vs. 94.4%; P = 0.029). The duration of ≥Grade 1 dermatitis from the start of CCRT until 1 week after the end of CCRT, expressed as a percentage, was analyzed. Subjects in Group A had a significantly shorter duration of dermatitis as compared with those in Group B (44.8 vs. 56.7%; P = 0.009). A similar analysis was conducted regarding the duration of ≥Grade 2 dermatitis related to the observation period; this indicated that it was significantly shorter in Group A than in Group B (16.5 vs. 26.5%; P = 0.038).

Table 2.

Maximum grade of dermatitis

 Group A (n = 16) Group B (n = 18) P value 
Number of patients 
 Grade 1 0.03a 
 Grade 2 15 0.02a 
 Grade 3 0.44 
Percentage of patients 
 ≥Grade 2 62.6% 94.4% 0.03a 
 ≥Grade 3 18.8% 11.1% 0.44 
 Group A (n = 16) Group B (n = 18) P value 
Number of patients 
 Grade 1 0.03a 
 Grade 2 15 0.02a 
 Grade 3 0.44 
Percentage of patients 
 ≥Grade 2 62.6% 94.4% 0.03a 
 ≥Grade 3 18.8% 11.1% 0.44 

aStatistically significant.

The dermatitis grade was analyzed in relation to the radiation dose, and the incidence of dermatitis was examined at each radiation dose level. At a dose of 40 Gy, the incidence of ≥Grade 1 dermatitis was 43.75% in Group A and 77.78% in Group B (Fig. 1a). At a dose of 50 Gy, the incidence of ≥Grade 1 dermatitis was 68.75% in Group A and 100% in Group B (Fig. 1a). At both dose levels, the incidence of ≥Grade 1 dermatitis was significantly lower in Group A (40 Gy: P = 0.045; 50 Gy: P = 0.016). At a dose of ≥60 Gy, ≥Grade 1 dermatitis was observed in the majority of patients in both Groups A and B (60 Gy: 100 vs. 100%; 66–70 Gy: 93.75 vs. 100%). The incidence of ≥Grade 2 dermatitis was significantly lower in Group A than in Group B at a dose of 60 Gy (37.5 vs. 83.33%; P = 0.008) (Fig. 1b). At the end of CCRT (66–70 Gy) and at 1 week after the completion of CCRT, no significant difference in the incidence of ≥Grade 2 dermatitis was observed between Groups A and B (66–70 Gy: 56.2 vs. 66.67%; P = 0.39 and 1 week post radiotherapy: 37.5 vs. 55.56%; P = 0.24).

Figure 1.

(a) Incidence of ≥Grade 1 or greater dermatitis (%) relative to radiation dose. (b) Incidence of ≥Grade 2 or greater dermatitis (%) relative to radiation dose.

Figure 1.

(a) Incidence of ≥Grade 1 or greater dermatitis (%) relative to radiation dose. (b) Incidence of ≥Grade 2 or greater dermatitis (%) relative to radiation dose.

Wound intervention for wet desquamation (27) was prescribed for nine patients (56.3%) in Group A and 15 patients (83.3%) in Group B. The frequency of administration of medication tended to be lower in Group A relative to Group B, although no significant difference was observed between the two groups (P = 0.088).

DISCUSSION

In the present study, we evaluated the preventative role of the HMB/Arg/Gln supplement on radiation dermatitis in head and neck cancer patients undergoing CCRT. Although we could not demonstrate the effectiveness of the primary endpoint, the incidence of ≥Grade 3 dermatitis, several positive results were revealed in this study. We demonstrated that HMB/Arg/Gln reduced the incidence of ≥Grade 2 dermatitis, and shortened the duration of ≥Grade 1 and ≥Grade 2 dermatitis, as secondary endpoints. In addition, the incidence of ≥Grade 1 dermatitis at doses of 40 and 50 Gy was lower in Group A than in Group B, and the incidence of ≥Grade 2 dermatitis at a dose of 60 Gy was lower in Group A than Group B. These results can be interpreted as indicating that HMB/Arg/Gln supplementation can potentially delay the onset of dermatitis and reduce the severity of dermatitis.

Moist desquamation often appears in severe cases of dermatitis, which is one of the most painful of the adverse effects experienced by patients undergoing CCRT. Frequent wound intervention indicates the development of severe dermatitis. No significant difference was observed in the frequency of wound intervention in the current study; however, it tended to be lower in Group A than Group B (P = 0.088), suggesting that the incidence of severe dermatitis tended to be lower because of HMB/Arg/Gln treatment.

Gln represents the largest intracellular amino acid pool in the body, and is used as an energy source during the catabolic state. This amino acid is frequently used during the metabolic processes of rapidly dividing cells, such as lymphocytes, enterocytes and fibroblasts (23). In relation to radiation toxicity, Gln was reported to alleviate the severity of radiation induced oral mucositis and to shorten its duration in 17 patients during radiation therapy, suggesting a preventative role in relation to radiation toxicity (28). Furthermore, Gln was reported to enhance collagen synthesis in an in vitro study (24). These studies support our finding that Gln supplementation had a preventive effect with regard to radiation toxicity, and enhanced the synthesis of collagen in the wound healing of the dermatitis.

In several studies, Arg supplementation has also been reported to enhance collagen synthesis as well as T cell-mediated immune function (29,30). Therefore, Arg is recognized as a key nutrient in wound healing (22). HMB has been demonstrated to stimulate protein synthesis and attenuate proteolysis in studies that included a cancer cachexia model (20,21), as well as in athletes (31). It has also been reported that the expression of nuclear factor-kappaB was suppressed using HMB supplementation (32). These numerous reports on wound healing and anti-inflammatory effects support our results obtained using the HMB/Arg/Gln blend used as protective nutrients in relation to radiation dermatitis, an inflammatory skin wound; however, to date there have been no studies regarding the effects of either HMB or Arg on radiation toxicity.

The blend of these three nutrients has also been demonstrated to improve wound healing in diabetic foot ulcer patients (18), as well as in elderly volunteers (19). Furthermore, Yavas et al. (33) reported that the HMB/Arg/Gln supplement could ameliorate radiation induced acute inflammation and mucosal atrophy in an in vivo study. Radiation dermatitis can be recognized as an inflammatory skin wound induced by high-dose irradiation. We consider that the HMB/Arg/Gln supplement has a protective effect with regard to radiotherapy, and improves wound healing associated with radiation dermatitis.

Theoretical concerns regarding the use of the HMB/Arg/Gln supplement may exist. For example, because Gln is used by rapidly dividing cells, cancer cells are preferential consumers of Gln. Consequently, some oncologists may hesitate in administering Gln to cancer patients. However, in a review of in vivo experimental and clinical intervention studies, Kuhn et al. (23) concluded that appropriate Gln supplementation can beneficially contribute to improved host metabolism and clinical condition; this diminished the risks associated with chemotherapy and radiotherapy, without increasing tumor growth. Furthermore, in an in vivo experimental study, it was demonstrated that HMB supplementation exhibited an anti-tumor effect and participated in the cancer cell nuclear factor-kappaB pathway (32). Based on these previous reports, we speculate that HMB/Arg/Gln will similarly improve host metabolism, and supplementation of such nutrients will not decrease the therapeutic efficacy of cancer treatments.

The importance of nutritional therapy in head and neck cancer patients during CCRT has been reported on in several studies (14,16). However, the current study is the first prospective study to investigate the efficacy, safety and ease of use of HMB/Arg/Gln supplementation for the prevention of radiation dermatitis in head and neck cancer patients. Our study demonstrated that HMB/Arg/Gln was well tolerated and safe, as well as being easy to administer to patients undergoing CCRT. Our results did not show a significant difference in the incidence of Grade 3 dermatitis between the treatment and control groups. We consider that the estimation of the incidence of ≥Grade 3 dermatitis (50%) at our institution could be too high. Therefore, the sample size might be insufficient to demonstrate the difference in the incidence of ≥Grade 3 dermatitis. However, positive effects such as shortening the duration of dermatitis and decreasing its severity were significant.

In conclusion, our study indicated that supplementation with HMB/Arg/Gln is potentially effective in the prevention of radiation dermatitis. However, a limitation of the current study is that it was open-label. Larger multicenter double blind controlled trials involving nutritional intervention in patients undergoing CCRT are needed to confirm the preventative role of HMB/Arg/Gln.

Funding

This study was supported by a Health and Labour Sciences Research Grant for Clinical Cancer Research (H22-gann-rinnsyou-ippann-17) from the Ministry of Health, Labour and Welfare, Tokyo, Japan. The funders had no role regarding study design, data collection and analysis, the decision to publish or preparation of the manuscript.

Conflict of interest statement

The authors have no conflicts of interest to declare. They can also confirm that they had no financial relationship with the organization that sponsored the research. The authors also state that they have full control of all primary data and that they agree to allow the journal to review their data if requested.

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