Randomized, Blinded Phase III Trial Comparing Calendula Officinalis Cream With Standard Aqueous Cream "Essex" for Treatment of Skin Reactions Caused by Postoperative Radiotherapy of Breast Cancer

Acute radiation skin reactions (ARSR) occur in the majority of patients undergoing postoperative radiotherapy (RT). Some patients experience more severe reactions such as dry and/or moist desquamation but most patients experience mild reactions e.g. erythema (Lopez et al., 2005). The radiation dose, volume, RT technique and previous treatment, such as type of surgery and previous chemotherapy, are factors that might impact on the risk for ARSR together with patient-related factors such as body mass index (BMI), smoking status and previous skin damage (Porock et al., 1998; Wells et al., 2004). In a pilot study (n=93) of the frequency of ARSR in patients with breast cancer who underwent adjuvant RT it was shown that 93% developed ARSR, mostly mild reactions. Patients reported low scores on pain and itching (Sharp et al., 2011). Over 80% of the patients reported adherence to the skin care recommendations which included application of a thin layer of Essex® cream, a non-perfumed aqueous cream, on the irradiated area at least two times a day (Sharp et al., 2011). The effects of skin care products containing Calendula Officinalis (marigold plant) on ARSR in patients with breast cancer were investigated in a randomized clinical trial (Pommier et al., 2004). Patients in the experimental group, treated with calendula cream had a statistically significant lower incidence of severe ARSR, pain and treatment interruptions in comparison with the patients in the control group, treated with trolamine.

The purpose of this blinded, randomized clinical trial is to compare two topical agents, Calendula Weleda® cream and Essex® cream, in terms of efficacy to reduce the risk of severe acute radiation skin reactions (ARSR) in relation to adjuvant radiotherapy (RT) for breast cancer.

Patients were instructed to apply a thin layer of the assigned cream twice a day, starting at the onset of RT and continue until two weeks after termination, or until the ARSR is healed. The application should include the whole treatment area including the armpit and shoulder/back area in patients treated with modified radical mastectomy. Patients are also advised to not apply the cream within two hours before the RT in order to avoid possible build-up effect. Daily wash with perfume free soap and tap water are recommended and patients are advised to refrain from use of other topical agents in the irradiated area.

The primary endpoint is the efficacy to reduce acute radiation skin reactions (ARSR), assessed with the Radiation Therapy Oncology Group/The Organization for Research and Treatment of Cancer Acute Radiation Morbidity Scoring Criteria (RTOG/EORTC scale) at follow-up.

Secondary endpoints include patient reported outcome measures; Quality of Life Questionnaire (QLQ-C30), Sleep disturbances (MOS-sleep questionnaire) and symptoms experienced from the irradiated area (visual analogue scale). Patients' experiences and adherence to the topical agents are also evaluated.

A total of 400 patients are required to detect a true absolute reduction in the proportion of patients with ARSR, from 35% with standard treatment (Essex® cream) to 20% with the experimental treatment (Calendula Weleda® cream), with a significance level of 5% a power of 90%. With this sample size, 95% confidence intervals for the difference in proportions are estimated to be in the order of ±10%. Assuming a rate of 5% of non-responders, the target size has been set to 420 patients.