Effects of topical timolol for the prevention of radiation-induced dermatitis in breast cancer: a pilot triple-blind, placebo-controlled trial

Abstract

Introduction Radiation therapy is one of the standard methods in the treatment of breast cancer. Radiotherapy-induced dermatitis (RID) is a common complication of radiotherapy (RT) resulting in less tolerance in RT and even discontinuation of treatment. Timolol is a β-adrenergic receptor antagonist that presents the best wound healing effects on both chronic and incurable wound healing. Topical forms of timolol could be effective in the prevention of RID due to the role of β-adrenergic receptors in skin cells and keratinocyte migration, as well as the anti-inflammatory effect of timolol. However, no placebo-controlled randomized trial is available to confirm its role. The current trial aimed to evaluate the efficacy of topical timolol 0.5% (w/w) on the RID severity and patients' quality of life (QOL). Method Patients aged older than 18 years with positive histology confirmed the diagnosis of invasive and localized breast cancer were included. Patients were randomized based on the random number table to receive each of the interventions of timolol 0.5% (w/w) or placebo topical gels from the first day of initiation of RT and for 6 weeks, a thin layer of gel twice daily. Patients were asked to use a thin layer of gel for at least two hours before and after radiation therapy. Primary outcomes were acute radiation dermatitis (ARD) grade using Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer (RTOG/EORTC) scale and severity of desquamation based on Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Secondary outcomes were QOL based on Skindex16 (SD-16), maximum grade of ARD, and time of initial RD occurrence. Results A total of 64 female patients with an age range of 33 to 79 years were included. The means (SD) of age were 53.88 (11.02) and 54.88 (12.48) in the control and timolol groups, respectively. Considering the RTOG/EORTC and CTCAE scores the difference between groups was insignificant (P-Value = 0.182 and P-Value = 0.182, respectively). In addition, the mean (SD) of time of initial RID occurrence in placebo and timolol groups were 4.09 (0.588) and 4.53 (0.983) weeks, respectively (P-Value = 0.035). The maximum grade of RID over time was significantly lower in the timolol group. During the study period, 75.0% of patients in placebo groups had grade 2 of ARD while in the timolol group it was 31.3% (P-Value = 0.002). QoL was not significantly different between groups (P-Value = 0.148). Conclusion Although the topical formulation of timolol, 0.5% (w/w), was found to reduce the average maximum grade of ARD and increase the mean (SD) time of initial RID occurrence, it showed no effect on ARD, severity, and QOL. However, future clinical trials should be performed to assess timolol gel formulation in larger study populations. Trial registration https://irct.ir/ IRCT20190810044500N11 (17/03/2021).

Mechanism and application of β‐adrenoceptor blockers in soft tissue wound healing

“…In addition, there was a significant reduction in pain suggesting that the application of timolol in the donor area of the skin graft has a positive effect on wound healing 4 . In addition, in a triple‐blind controlled trial, patients who were asked to apply timolol gel 2 h before and after radiotherapy had a delay in the initial time to radiotherapy‐induced dermatitis and a weakening of the severity of dermatitis 150 …”

The efficacy of medicinal plant preparations in the alleviation of radiodermatitis in patients with breast cancer: A systematic review of clinical trials

“…This common, unpleasant, and debilitating complication of radiotherapy is called radiodermatitis (Singh et al, 2016). The severity of radiodermatitis is influenced by the dosage per fraction, total dose, radiation quality, radiation modality, prior chemotherapy, and skin type (Nabi‐Meybodi et al, 2022). However, acute skin problems (i.e., radiation dermatitis or radiodermatitis) may develop during, or shortly after the completion of, the recommended radiotherapy course (Ansari et al, 2013).…”

“…Radiotherapy may be administered before or after surgery. Protocols combining radiotherapy with surgical resection greatly reduce the risk of recurrence of breast cancer and mortality (Nabi-Meybodi et al, 2022). However, the "normal" skin in close proximity to tumor cells also receives large doses of radiation.…”

“…However, the "normal" skin in close proximity to tumor cells also receives large doses of radiation. This collateral damage can induce dermal erythema (redness), dry and moist desquamation, and tissue necrosis (Nabi-Meybodi et al, 2022). This common, unpleasant, and debilitating complication of radiotherapy is called radiodermatitis (Singh et al, 2016).…”

“…This common, unpleasant, and debilitating complication of radiotherapy is called radiodermatitis (Singh et al, 2016). The severity of radiodermatitis is influenced by the dosage per fraction, total dose, radiation quality, radiation modality, prior chemotherapy, and skin type (Nabi-Meybodi et al, 2022).…”