Overview of the Active Ingredients in Cosmetic Products for the Care of Skin That Has Been Exposed to Ionizing Radiation – Analysis of Their Effectiveness in Breast Cancer Radiotherapy

Figures & data

Table 1 Comparison of the Scoring of Acute Toxicity in RTOG and CTCAE

	RTOG	NCI CTCAE v.5.0
Grade 0	Normal skin, no visible symptoms	Normal skin, no visible symptoms
Grade I	Follicular, faint or dull erythema, Epilation, dry desquamation decreased sweating	Faint erythema, dry desquamation
Grade II	Tender or bright erythema, patchy moist desquamation confined to skin folds, moderate edema	Moderate to brisk erythema, patchy moist desquamation confined to the skin folds and creases, moderate edema
Grade III	Confluent, moist desquamation in areas other than in the skin folds, pitting edema - bleeding may occur	Moist desquamation in areas other than in the skin folds and creases, bleeding induced by minor trauma or abrasion
Grade IV	Ulceration, hemorrhage and necrosis	Skin necrosis or ulceration of full thickness in the dermis, spontaneous bleeding from involved site
Grade V	The intensity of the reaction was not determined	Death

Note: Data from these studies.^4,11,12

Table 2 Summary of the Research on the Active Ingredients

Active Ingredient	Study/Year	Type of Study/Sample Size and Patient Characteristics	Radiotherapy Schedule	Subject of the Study	Outcome Measurements	Result	Clinical Efficacy
Hyaluronic Acid	Liguori et al 1997^Citation15	2-arm, randomized, double-blind, placebo-controlled clinical trial (n = 152 patients with head, neck, breast and pelvic cancer)	Head and neck tumor: 66–80.5Gy Breast cancer: 60–66Gy Pelvic cancer: 60–66Gy	Hyaluronic acid cream vs placebo cream	Global judgement on the therapeutic efficacy and the tolerability of both treatments (in house scale)	Skin reaction week 3–7 p ≤0.01 (in favor of hyaluronic acid) week 8–10 p < 0.05 (in favor of hyaluronic acid) tolerance of treatment: p=0.18 according to physician and p = 0.42 according to patients global efficacy judgment p < 0.01 by physician and p < 0.05 by patients (in favor of hyaluronic acid)	Hyaluronic acid cream reduced the severity of the skin reaction and shortened the recovery time
	Pinnix et al 2011^Citation17	2-arm, single-blind randomized, phase III clinical Trial (n=65 patients with breast cancer)	50Gy in 25 daily fractions with or without 10 to 16- Gy surgical bed boost	Hyaluronic acid-based gel vs petrolatum gel	Grade of skin toxicity (CTCAE v.3)	Grade ≥ 2 hyaluronic acid = 61.5%, petrolatum gel = 47.7%; p = 0.027	No benefit from using the hyaluronic acid- based gel
	Kirova et al 2011^Citation16	2-arm, phase III randomized trial (n = 200 patients with breast cancer)	50Gy	Hyaluronic acid cream vs placebo (emollient)	Erythema success -disappearance of the erythema 30 days after occurrence Failures - interruption of radiotherapy due to worsening of the erythema Pain, colorimetry and quality of life (EORTC)	Failures: Hyaluronic acid: 24% Emollient: 34% p = 0.15 Level of pain hyaluronic acid +7.0 emollient +13,7 p = 0.053 the relative reduction of colorimetric value: hyaluronic acid = 20.4%, emollient = 13.0%; p = 0.46	No significant difference between the creams
Calendula Officinalis	Pommier et al 2004^Citation24	2-arm, single-blind, randomized controlled clinical trial (n=254 patients with breast cancer)	46–52Gy or 46–60Gy in case of patients after mastectomy 60–64Gy or 59–64Gy in case of patients after lumpectomy	Calendula officinalis vs trolamine	Acute dermatitis grade ≥2 (RTOG) Pain	Grade 2 or 3 Calendula 41% Trolamine 63% p = 0.001 Max pain score (VAS) Calendula 1.54 Trolamine 2.10 p= 0.03	Calendula was more effective than trolamine in reducing the RD grade and the radiation-induced pain
	Sharp et al 2013^Citation26	2-arm, blinded, randomized Phase III trial (n = 420 patients with breast cancer)	50Gy or 42, 56Gy (patients under 40 years – additional boost of 16Gy, 2Gy per fraction)	Calendula cream (10%) vs aqueous cream	Grade of acute radiodermatitis (RTOG/EORTC) at first and final radiotherapy Pain, burning, itching, pulling, tenderness	Grade ≥2: Calendula: 23% Aqueous cream: 19% No grade 4 toxicity was reported Pain, burning, itching, pulling, tenderness - no difference between both groups	No difference between the creams
	Schneider et al 2015^Citation27	2-arm, randomized, double-blind controlled clinical trial (n = 51 patients with head and neck cancer)	Calendula: 68.1 ± 4.6 Gy essential fatty acid: 69.7 ± 4.4 Gy	Calendula cream (4% of calendula oil) vs essential fatty cream (EFA)	Development of radiodermatitis (RTOG)	Grade 0, week 7 calendula = 22.22%, EFA = 0% Grade ≥ 2 week 7 calendula = 22.22%, EFA = 42.86%	Calendula cream was significantly better in the prevention and treatment of radiodermatitis
Aloe Vera Gel	Hoopfer et al 2015^Citation33	3-arm, randomized Phase III trial (n=248 patients with breast cancer)	45 Gy in 20 fractions or 50 Gy in 25 fractions	Aloe and placebo cream vs powder	Acute skin reactions (CSSP scale) Dryness, itching, burning, pain, desquamation	Maximum CSSP scores: Powder = 6.27 Aloe cream = 6.96 (p = 0.0227) Placebo cream = 6.99 (p=0.0127) CSSP scores at 1 week after radiation Powder = 5.68 Aloe cream = 6.47 (p = 0.0283) Placebo cream = 6.29 (p=0.0845)	Aloe vera cream did not reduce the skin’s reaction during radiotherapy
	Heggie et al 2002^Citation32	2-arm, Phase III, double-blind, randomized, controlled clinical trial (n=225 patients with breast cancer)	60Gy	Aloe vera vs aqueous cream	Itching, pain, erythema, dry and moist desquamation	Dry desquamation: p <0.001 (in favor of aqueous cream)	The aqueous cream was significantly better in reducing dry desquamation and pain
	Williams et al 1996^Citation11,Citation39	2-arm, randomized, double-blind, controlled clinical trial (n = 194 patients with breast cancer)		Aloe vera gel vs placebo gel	Severity of radiodermatitis Time and duration of reaction	Max severity of skin p = 0.36	No benefits of using the aloe vera gel
	Ahmadloo et al 2017^Citation31	2-arm, prospective randomized controlled clinical trial (n = 100 patients with breast cancer)	50Gy	Aloe vera gel vs no treatment	Grade of dermatitis (Acute Radiation Morbidity Scoring Criteria)	Grade 1 after 2 weeks p=0.0240 (in favor of aloe vera) Grade 1 after 3 weeks p = 0.317 Grade ≥1 after 5 weeks p = 0.488	No difference between the groups of patients
D-panthenol	Løkkevik et al 1996^Citation19	2-arm, randomized controlled trial (n = 86 patients with laryngeal and breast cancer)	50Gy – breast cancer 70Gy – laryngeal cancer	Bepanthen cream vs no treatment	Erythema and itching (EORTC/RTOG)	Erythema grade p = 1.00 Pain p = 0.56 Itching p = 0.43 Desquamation p = 0.027 in favor of d-panthenol (week 6)	No difference between the groups of patients
Allantoin	Chan et al 2014^Citation22	2-arm, double-blind, randomized, controlled trial (n=174 patients with lung, breast or head and neck cancer)	>50 Gy	Allantoin (oil-based emulsion) vs aqueous cream	Severity of radiation-induced skin reaction (CTCAE v.4) Pain, itching	Skin toxicity: Week 3 p<0.05 (in favor of allantoin) Week 7–9 p <0.001 (in favor of aqueous cream) Worst pain (p < 0.05) and worst itching (p =0.046) at week 3 in case of aqueous cream (difference not observed in other weeks)	No significant difference between allantoin and the aqueous cream
Chamomile Recutita	Maiche et al 1991^Citation35	2-arm, randomized, single-blind, controlled clinical trial (n = 48 patients with breast cancer)	50Gy	Chamomile cream vs almond ointment	Extent of acute reaction Subject evaluation of tested products	Less and later appearance of grade 2 (in house scale) in case of chamomile cream, but difference was not statistically significant	No significant difference between chamomile cream and almond ointment, no benefit in managing radiodermatitis
	Ferreira et al 2020^Citation36	2-arm, randomized, preliminary clinical trial (Study 2) (n = 48 patients with head and neck cancer)	70Gy	Chamomile gel vs urea cream	Time from beginning of radiation to the first occurrence (in weeks) of grade 1 or 2 (RTOG) Participants self-report of presence of tenderness, pain, itching, burning and interference in daily activities Nurse evaluation of hyperpigmentation	Occurrence of Grade 1 p = 0.67 Occurrence of Grade 2 p = 0.17 Time of occurrence of Grade 1: 2.08 weeks in chamomile group 2.22 weeks in urea group Time of occurrence of Grade 2: 5.08 weeks in chamomile group 4.48 weeks in urea group Visual observation: chamomile gel might delay or reduce itching and burning sensations, and the development of hyperpigmentation	No significant difference between chamomile gel and urea cream in the delay of the development of grades 1 and 2 radiodermatitis, but overall result indicated potential efficacy of the chamomile gel
SILYMARIN (Silybum marianum L.)	Karbasforoo shan et al 2018^Citation37	2-arm, randomized, double-blind, placebo-controlled clinical trial (n = 40 patients with breast cancer)	50Gy	Silymarin gel vs placebo	Radiodermatitis occurrence Compliance and adverse drug reaction	Radiodermatitis grade lower in silymarin group p < 0.05 Both products were well tolerated and no adverse effect was noticed	Potentially useful for reducing the severity of acute radiodermatitis and to slow down its progression
Nigella sativa L.	Rafati et al 2019^Citation38	2-arm, randomized, double-blind, placebo-controlled clinical trial (n = 62 patients with breast cancer)	> 50Gy	Nigella sativa gel vs placebo	Reducing the incidence and delaying onset of acute radiodermatitis Pain, moist desquamation, skin-related quality of life	Skin toxicity by RTOG/EORTC, p < 0.05 (in favor of N.sativa gel) for all weeks of study, except second week, where p = 0.36 Occurrence of moist desquamation: N.sativa = 37 days, placebo = 33 days, p = 0.01; Time of the incidents of skin toxicity RTOG/EORTC grade 2: N.sativa = 35 days, placebo = 29 days, p = 0.00 Pain: p < 0.05 (in favor of N.sativa gel at week 3) Skin-related quality of life: p > 0.05	Potentially useful for reducing the severity of acute radiodermatitis and delaying related symptoms

White J, Joiner MC. Toxicity from radiation in breast cancer. In: Small W, Woloschak GE, editors. Radiation Toxicity: A Practical Guide. (Cancer Treatment and Research V.128). New York: Springer Science + Media Business; 2006:65–110.

 Google Scholar

Rosenthal A, Israilevich R, Moy R. Managment of acute radiation dermatitis: a review of the literature and proposalfor treatment algorithm. J Am Acad Dermatol. 2019;81:558–567. doi:10.1016/j.jaad.2019.02.047

 Web of Science ®Google Scholar

Kitajma M, Noto K, Itaki C, et al. Quantitative assessment of radiodermatitis through a non-invasive objective procedure in patients with breast cancer. Mol Clin Oncol. 2019. doi:10.3892/mco.2019.1948

 Web of Science ®Google Scholar

Liguori V, Guillemin C, Pesce GF, Mirimanoff RO, Bernier J. Double-blind, randomized clinical study comparing hyaluronic acid cream to placebo in patients treated with radiotherapy. Radiother Oncol. 1997;42(2):155–161. doi:10.1016/S0167-8140(96)01882-8

 Web of Science ®Google Scholar

Pinnix C, Perkins GH, Strom EA, et al. Topical hyaluronic acid vs. standard of care for the prevention of radiation dermatitis after adjuvant radiotherapy for breast cancer: single-blind randomized phase III clinical trial. Int J Radiat Oncol Biol Phys. 2011;83(4):1089–1094.

 Web of Science ®Google Scholar

Kirova YM, Fromantin I, De Rycke Y, et al. Can we decrease the skin reaction in breast cancer patients using hyaluronic acid during radiation therapy? Results of phase III randomised trial. Radiother Oncol. 2011;100:205–209. doi:10.1016/j.radonc.2011.05.014

 PubMed Web of Science ®Google Scholar

Pommier P, Gomez F, Sunyach MP, D’Hombres A, Carrie C, Montbarbon X. Phase III randomized trial of Calendula officinalis compared with Trolamine for the prevention of acute dermatitis during irradiation of breast cancer. J Clin Oncol. 2004;22(8):1447–1453. doi:10.1200/JCO.2004.07.063

 PubMed Web of Science ®Google Scholar

Sharp L, Finnilä K, Johansson H, Abrahamsson M, Hatschek T, Bergenmar M. No differences between Calendula cream and aqueous cream in the prevention of acute radiation skin reactions—results from a randomised blinded trial. Eur J Oncol Nurs. 2012;17(4):429–435.

 Web of Science ®Google Scholar

Schneider F, Danski MT, Vayego SA. Usage of Calendula officinalis in the prevention and treatment of radiodermatitis: a randomized double-blind controlled clinical trial. Rev Esc Enferm USP. 2015;49(2):221–228. doi:10.1590/S0080-623420150000200006

 PubMed Web of Science ®Google Scholar

Hoopfer D, Holloway C, Gabos Z, et al. Three-arm randomized phase III trial: quality aloe and placebo cream versus powder as skin treatment during breast cancer radiation therapy. Clin Breast Cancer. 2014;15(3):181–190.

 Web of Science ®Google Scholar

Heggie S, Bryant GP, Tripcony L, et al. A phase III study on the efficacy of topica aloe vera gel on irradiated breast tissue. Cancer Nurs. 2002;25(6):442–451. doi:10.1097/00002820-200212000-00007

 PubMed Web of Science ®Google Scholar

Kumar S, Juresic E, Barton M, Shafiq J. Management of skin toxicity during radiation therapy: a review of the evidence. J Med Imaging Radiat Oncol. 2010;54:264–279. doi:10.1111/j.1754-9485.2010.02170.x

 PubMed Web of Science ®Google Scholar

Ahmadloo N, Kadkhodaei B, Omidvari S, et al. Lack of prophylactic effects of aloe vera gel on radiation induced dermatitis in breast cancer patients. Asian Pac J Cancer Prev. 2017;18(4):1139–1143.

 Google Scholar

Løkkevik E, Skovlund E, Reitan JB, Hannisdal E, Tanum G. Skin treatment with Bepanthen Cream versus no cream during radiotherapy: a randomized controlled trial. Acta Oncol. 1996;35(8):1021–1026. doi:10.3109/02841869609100721

 PubMed Web of Science ®Google Scholar

Chan RJ, Mann J, Tripcony L, et al. Natural oil-based emulsion containing allantoin versus aqueous cream for managing radiation-induced skin reactions in patients with cancer: a Phase 3, double-blind, randomized, controlled trial. Int J Radiat Oncol Biol Phys. 2014;90(4):756–764.

 Web of Science ®Google Scholar

Maiche AG, Grӧhn P, Mӓki-Hokkonen H. Effect of chamomile cream and almond ointment on acute radiation skin reaction (1991) correspondence and short communications. Acta Oncol. 1991;30(3):395–397.

 Web of Science ®Google Scholar

Ferreira EB, Ciol MA, de Meneses AG, Bontempo PSM, Hoffman JM, Reis PEDD. Chamomile gel versus urea cream to prevent acute radiation dermatitis in head and neck cancer patients: results from a preliminary clinical trial. Integr Cancer Ther. 2020;19:1534735420962174. doi:10.1177/1534735420962174

 Web of Science ®Google Scholar

Karbasforooshan H, Hosseini S, Elyasi S, et al. Topical silymarin administration for prevention of acute radiodermatitis in breast cancer patients: a randomize double-blind, placebo-controlled clinical trial. Phytother Res. 2018;33(2):379–386.

 Web of Science ®Google Scholar

Rafati M, Ghasemi A, Saeedi M, et al. Nigella sativa L. for prevention of acute radiation dermatitis in breast cancer: a randomized, double-blind, placebo-controlled, clinical trial. Complement Ther Med. 2019;47:102205. doi:10.1016/j.ctim.2019.102205

 Web of Science ®Google Scholar