Clinical Investigation
Topical Betamethasone Valerate As a Prophylactic Agent to Prevent Acute Radiation Dermatitis in Head and Neck Malignancies: A Randomized, Open-Label, Phase 3 Trial

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Purpose

We assessed the role of topical betamethasone as a prophylactic agent in patients receiving radiation for head and neck malignancies.

Methods and Materials

This randomized, open-label, phase 3 trial was completed at a single research institute. Patients receiving curative radiation for head and neck cancer were randomized into 2 groups of 75 patients each by computer-generated permuted block random assignment. Patients in the test arm applied 0.1% topical betamethasone valerate cream once a day, after radiation. Patients in the control arm received best supportive care. The Radiation Therapy Oncology Group acute toxicity grading scale was used to assess radiation dermatitis after every fifth fraction until completion and at 2 weeks after treatment. Primary outcome in both arms was the proportion of patients who developed grade 2 and 3 acute skin reaction. The trial is registered at the Central Trial Registry of India (CTRI/2017/04/008298).

Results

Between April 15, 2017, and October 30, 2018,150 patients were randomized into the study, with 75 patients in each arm. Fourteen patients in the test arm and 15 patients in the control arm did not complete the intended treatment. Per the intention-to-treat analysis, 25 of 75 patients (33.3%) and 38 of 75 patients (50.7%) developed grade 2 or greater radiation dermatitis in the test and control arms, respectively (absolute difference, 17.4%; 95% confidence interval, 4%-30%; P = .032). Fifteen of 75 patients (20%) developed grade 3 reactions in the test arm compared with 18 of 75 patients (24%) in the control arm (absolute difference, 4%; 95% confidence interval, 7%-15%; P = .554).

Conclusion

Although prophylactic use of betamethasone significantly reduced the composite outcome of the proportion of patients developing grade 2 and grade 3 radiation dermatitis, it did not reduce the proportion of patients developing the clinically significant outcome of grade 3 radiation dermatitis.

Introduction

According to the Globocan statistics for 2018, head and neck cancer accounts for more than 650,000 cases and 330,000 worldwide deaths annually.1 More than 70% of patients with head and neck cancer need radiation in the definitive, adjuvant, or palliative settings.2 Radiation has to pass through the skin to reach the target; therefore, radiation-induced dermatitis is inevitable. Approximately 85% of patients will experience a moderate skin reaction, and if radiation is allowed to continue, 25% will progress to confluent moist desquamation.3 Once confluent moist desquamation develops, treatment has to be stopped until healing has occurred. Any interruption of treatment is detrimental to outcome because delays will result in tumor repopulation and recurrence.4 Therefore, any intervention that can delay the development and progression of radiation dermatitis can prevent delays in treatment. Currently, there are no approved medications for the prevention or treatment of radiation dermatitis.5, 6, 7 Agents used include gentian violet, silver sulfadiazine, sucralfate, aloe vera, and biafine.6 Randomized trials in this area, especially in head and neck cancers, have been few, and the information currently available is not sufficient to recommend any particular medication as a gold standard. Meta-analyses and systematic reviews into this topic have reached similar conclusions.5,6

GORTEC 2009-01 evaluated the effect of a regenerating agent on radiodermatitis in head and neck patients receiving cetuximab and radiation. Despite the good preclinical rationale, the agent did not reduce the incidence and severity of radiodermatitis.8 Chan et al9 studied a silicone-based film forming gel dressing versus 10% glycerol in head and neck cancers. Although the dressing proved to be effective in preventing and delaying the development of grade 2 and 3 skin toxicity, concerns remain regarding its cost and wide availability.9

One of the pathognomonic mechanisms of radiation induced skin reaction is inflammation. Corticosteroids are potent anti-inflammatory agents and can delay the development of radiation dermatitis.10 Betamethasone is a medium-potency topical anti-inflammatory agent. It has a long half-life and therefore can last for a longer time. We expect that the long-term adverse effects of prolonged steroid cream use will be less for a medium-potency steroid compared with highly potent creams.

Betamethasone valerate is a widely available and cheap drug; therefore, it is more likely to be used by patients in view of the affordability and easy availability.

Most studies on corticosteroids in this setting were done in patients with breast cancer.10,11 We decided to study their role in patients with head and neck cancer for several reasons. The dose delivered in the radical–adjuvant treatment for head and neck cancers is much higher (60-66 Gy). The dose to the skin is also higher because the skin is usually infiltrated either by the tumor or the involved nodes. Therefore, we expect the proportion of patients who experience grade 2 and 3 reactions to be higher. Second, if the patient develops a grade 3 reaction, treatment has to be stopped temporarily, and any prolongation of treatment is particularly deleterious to outcomes in head and neck cancers.4 Therefore, identifying an agent that can prevent or delay radiation dermatitis can be a valuable aid in preventing treatment delays, thereby improving oncologic outcome. Preventing these acute toxicities can also positively affect the patient’s quality of life.

We aimed to test the efficacy of 0.1% betamethasone valerate versus best supportive care in the prevention and treatment of acute radiation dermatitis in patients undergoing radiation for head and neck malignancies.

Section snippets

Study design and participants

We conducted this open-labeled randomized control trial in a tertiary cancer care center. Eligible patients had biopsy-proven nonmetastatic carcinoma of the head and neck, referred for either upfront radical radiation or for postoperative treatment after primary surgical resection. Other eligibility criteria included age >18 years and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Patients with rash, ulceration, or open wounds in the treatment field, allergy to

Results

Between April 15, 2017, and October 30, 2018, we recruited 150 patients, with 75 patients in each arm. Details of patient enrollment, allocation, therapy, and assessment are presented in a CONSORT diagram (Fig. 1). Thirteen patients in the betamethasone arm and 15 patients in the control arm defaulted treatment after a varying number of fractions. The median fraction at which they defaulted was 15 (range, 0-25). One patient in the betamethasone arm died of myocardial infarction. The primary

Discussion

In our study, although the prophylactic use of corticosteroid significantly reduced the composite outcome of the proportion of patients developing grade 2 and 3 radiation dermatitis, it did not reduce the clinically significant outcome of grade 3 radiation dermatitis. Our study observed a difference of only 4% in grade 3 radiation dermatitis between the 2 arms (it was powered to detect a 15% difference).

Steroids are sometimes prescribed indiscriminately by physicians worldwide for the treatment

Conclusion

Our results do not support the use of topical 0.1% betamethasone valerate as a prophylactic agent for preventing grade 2 or 3 radiation dermatitis in patients receiving radiation for head and neck cancer. At best, topical betamethasone had a beneficial effect in ameliorating the burning sensation produced by radiation. Future studies in this area may focus on identifying agents that can repair the proliferative capacity of stem cells damaged by radiation, as a more effective means to prevent

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    Citation Excerpt :

    In a RCT by Menon et al. topical betamethasone was compared with the institutional standard skincare in 121 HNC patients. 33% versus 51% of the patients developed grade 2 ARD and 20% versus 24% grade 3 ARD in the experimental and control arm, respectively [30]. These contrasting numbers on severe ARD are due to differences in the treatment protocol (e.g., total RT dose, use of concomitant therapies, the volume of the treated area) and the standard skincare used [6].

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Research data are stored in an institutional repository and will be shared upon request to the corresponding author.

This work has received financial support from the Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry. We acknowledge the Department of Biostatistics and Department of Preventive Medicine for the statistical analysis.

Disclosures: none.

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