Pommier, P., Gomez, F., Sunyach, M. P., D’Hombres, A., Carrie, C., & Montbarbon, X. (2004). Phase III randomized trial of Calendula officinalis compared with trolamine for the prevention of acute dermatitis during irradiation for breast cancer. Journal of Clinical Oncology, 22, 1447–1453.

To assess the effectiveness of Calendula for the prevention of acute radiation (RT)-induced dermatitis of grade 2 or higher during RT compared with trolamine (Biafine).

• Patients were randomly allocated to application of trolamine (n = 128) or Calendula (n = 126) on irradiated fields after each session.
• Patients started topical application of ointment on irradiated skin at onset of RT, twice a day or more, depending on the occurrence of dermatitis and pain, until completion of RT.
• Patients were instructed not to use agents two hours or less before an irradiation session or before treatment evaluation.
• No other prophylactic creams, lotions, or gels were allowed.
• Physicians were free to treat established dermatitis, grade 2 or higher, or allergy as considered appropriate.
• Clinicians were blinded to the treatment used.

• The sample was comprised of 254 women (Calendula, 128; trolamine, 126).
• Mean age was 56.5 years in the Calendula arm and 55.1 years in the trolamine arm (range 26.5–74.5). 
• Patients were post lumpectomy or mastectomy for nonmetastatic breast cancer.
• Patients were undergoing treatment with or without adjuvant postoperative chemotherapy or hormonal treatment.
• Standard irradiation fractionation (2 Gy per session, five sessions per week) was used.
• Patients who underwent lumpectomy received 52 Gy from two tangential fields to the whole breast with 10 Gy boost to the tumor bed.
• Patients who underwent mastectomy received 46 Gy to the chest wall.
• If relevant, internal mammary and supraclavicular nodes were irradiated.

• Single site
• Centre Leon Berard, Lyon, France

The study was a randomized, blinded, controlled trial.

• Once weekly acute dermal toxicity was evaluated according to the Radiaton Therapy Oncology Group (RTOG) scale.
• Pain was assessed weekly on a 10-cm visual analog scale (VAS). The occurrence, duration, and reasons for interruption of RT or of allocated cream application were registered, as were allergic reactions and quantity of agents used, until completion of RT.
• At study end, patients completed a questionnaire to assess satisfaction with respect to ease of application, pain, and dermatitis relief.
• Qualitative measures were compared to the chi-square test or Fisher exact test, as appropriate.
• For quantitative measures, Student’s t-test or Wilcoxon-Mann-Whitney test was used.

• The occurrence of acute dermatitis of grade 2 or higher was significantly lower (41% versus 63%; p < 0.001) with the use of Calendula versus trolamine.
• Twenty patients given trolamine presented with grade 3 toxicity (p = 0.034).
• Benefits were most marked at sites at risk of maceration (submammary fold, armpit, and tangential area) and sites with thin skin.
• Patients receiving Calendula had less frequent interruption of RT. Mean length of treatment interruption was 10 days (range 2–22 days). Fifteen treatment interruptions were observed in the trolamine group; 12 were due to skin toxicity.
• No allergic reactions were observed in the Calendula group, whereas four patients in the trolamine group developed the allergic-type reactions of pruritus and urticaria.
• Patients receiving Calendula had significantly reduced RT-induced pain.
• Mean maximal pain evaluated in the Calendula group was 1.54 and 2.10 in the trolamine group (p = 0.03).
• Self-assessed satisfaction was greater with Calendula.
• Prevention of erythema:  69% Calendula versus 39% trolamine.
• Prevention of pain:  65% with Calendula versus 46% trolamine.
• Calendula was considered more difficult to apply as noted by 30% of the calendula group versus 5% of the trolamine group.
• The risk of skin toxicity of grade 2 or higher was significantly increased for women whose body mass index was ≥25 kg/m² (p < 0.001) and for women who had received chemotherapy before RT after a lumpectomy (p = 0.01), and for those using trolamine (p < 0.001).

• A delivered dose of 61 Gy or less was not identical in the treatment groups, favoring the Calendula group over the trolamine group.
• Because of differences in texture, color, and smell, it was not possible to perform a double-blind, randomized study. Simple blinding of the clinician removed bias with respect to the main objective of the study.