Acute Radiation Therapy-related Dermatitis

Radiation therapy (RT) following breast-conserving surgical excision of cancer reduces cancer-related mortality and recurrence.¹ However, most patients experience acute radiation dermatitis (ARD) within weeks after beginning RT²; symptoms of ARD, including severe skin erythema, dryness, moist or dry desquamation, and/or ulceration, may interrupt radiotherapy. This can negatively affect patient quality of life (QoL) and cancer outcomes. Acute radiation dermatitis is not to be confused with chronic radiation dermatitis, which can lead to fibrosis, skin atrophy, pigmentation, and telangiectasia months to years after RT.³ Evidence-based guidelines⁴ to both prevent and treat ARD recommend the application of 1 of 2 topical interventions during and/or after RT: (1) corticosteroids to improve ARD-related discomfort and itching⁵ or (2) 1% silver sulfadiazine (SSD) cream to reduce ARD-related dermatitis scores.⁶ This Evidence Corner reviews evidence supporting the 2 aforementioned topical interventions for patients undergoing RT for breast cancer.

Reference: Haruna F, Lipsett A, Marignol L. Topical management of acute radiation dermatitis in breast cancer patients: a systematic review and meta-analysis. Anticancer Res. 2017;37(10):5343–5353.

Rationale: Moisturizing agents can prevent cutaneous dehydration of ARD but not RT-induced desquamation or ulceration. Topical corticosteroid anti-inflammatory properties and cytokine gene expression suggest their potential to improve the full course of ARD.

Objective: The authors conducted a systematic review and meta-analysis of studies applying topical corticosteroids to manage ARD, pain, and QoL in women undergoing RT following breast cancer surgery.

Methods: EMBASE, MEDLINE, CINAHL, Science Direct, Google Scholar, and ClinicalTrials.gov reference databases were searched through March 2017, for randomized controlled trials (RCTs) using the terms “corticosteroid,” “radiation dermatitis,” “breast cancer,” “prevention,” and “management.” Randomized controlled trials enrolling women with breast cancer of any stage who underwent either mastectomy or conservative breast surgery, and subsequently received at least 40 Gy adjuvant RT to the breast or chest wall and optionally to lymph nodes, qualified for analysis. However, the RCTs also needed to include a measured effect on ARD or QoL that was statistically analyzed for those treated with a topical corticosteroid as compared with that of a placebo, no treatment, or a non-steroidal topical agent solely used to prevent or treat ARD. Wet desquamation, the criterion for ARD onset, typically was measured as Grade 3 on the standardized Radiation Therapy Oncology Group (RTOG) scale or similar clinical scales for ARD. Studies comparing only topical corticosteroids or only non-steroidal agents were excluded. In total, 2 independent reviewers extracted and summarized data on participants, beam energy, overall RT dose, surgery type, and corticosteroid application. Statistical power was reported when available, with statistical significance set at P < .05. 

Results: In total, 10 RCTs with 919 patients qualified for inclusion. Of the 10 RCTs, 9 compared corticosteroid treatment with a non-steroidal treatment; 1 had a “no treatment” control group. Steroids studied consisted of 0.1% mometasone furoate, beclomethasone, methylprednisolone, betamethasone, and 1.0 % hydrocortisone, which typically were all administered in a cream formulation, with the exception of 2 betamethasone ointment RCTs. Type of surgery and dosing frequency (ie, once or twice daily) were comparable within each RCT. Treatment began on the first day of RT and was continued for up to 9 weeks (3 weeks after the last RT). Among 845 patients evaluated for ARD, 36 were treated with corticosteroids and 92 control patients reported wet desquamation, resulting in lower likelihood of developing ARD in those treated with corticosteroids (odds ratio, 0.29; P < .00001). Mean ARD scores of 806 patients were about half (0.47%) as intense for those treated with corticosteroids compared with control patients (P < .00001). Among 6 RCTs explaining and measuring burning and itching, 4 reported pain, itching, and burning, but no significant differences in pain were reported. However, those treated with corticosteroids in all 6 RCTs reported less itching and burning, with P < .05 in 4 of the 6. Among the studies reviewed, smaller bra size was reportedly associated with less wet desquamation. 

Authors’ Conclusions: Topical corticosteroids can reduce the likelihood of wet desquamation associated with RT and reduce mean ARD scores, while improving subjective symptoms. However, more research is needed to validate ARD measurements, test comparative effectiveness of different corticosteroids, and evaluate their potential adverse effects.

Reference: Hemati S, Asnaashari O, Sarvizadeh M, Motlagh BN, Akbari M, Tajvidi M, Gookizadeh A. Topical silver sulfadiazine for the prevention of acute dermatitis during irradiation for breast cancer [published online October 19, 2011]. Support Care Cancer. 2012;20(8):1613–1618.

Rationale: Up to 90% of those undergoing RT for breast cancer develop ARD, sometimes so severe it reduces QoL and interrupts RT. The pathophysiology can include impaired skin barrier function, bacterial colonization, superinfection, and superantigen production. Silver sulfadiazine 1% cream has documented anti-inflammatory and antimicrobial properties in treating cutaneous burns and may be expected to moderate ARD similarly.

Objective: This RCT explored the efficacy of topical SSD 1% cream in preventing ARD in women undergoing RT for breast cancer.

Methods: Following Institutional Ethics Committee approval, women who had pathologist-confirmed breast cancer and gave informed consent were referred to a central Iran RT center following modified radical mastectomy and 6 to 8 courses of chemotherapy. At least 3 weeks after the last course of chemotherapy, participants receiving RT were matched for flat or not flat chest wall anatomy and randomly assigned to receive either SSD 1% cream plus standardized skin care (n = 51) or standardized skin care alone (n = 51). Chest wall RT was delivered for 5 weeks, by 9-10 MeV electron beam linear accelerator in fractions of 200 cGy 5 days per week Saturday through Wednesday, with an axillary boost field added for 60 patients. Beginning after the fifth day of RT in week 1, patients applied the SSD 1% cream at least 2 hours after the Wednesday dose of RT. The SSD 1% cream treatment continued every 8 hours on the non-RT days. Patients used baby soap and water to gently remove the cream from the radiated skin and pat it dry before restarting RT each Saturday. All patients were provided leaflets and instructions on skin care and used the same skin cleansing procedure, while avoiding non-study lotions, creams, or gels on the affected area, as well as perfumes, cosmetics, deodorants, or adult soap. The application of SSD 1% cream continued for 1 week after the last dose of RT. A radiation oncologist, who was unaware of the patient treatment group, rated ARD scores weekly during RT and at 1 week after the last RT dose, according to RTOG criteria (0 = no change from baseline; 1 = dull, faint, or follicular erythema, decreased sweating, epilation, dry desquamation; 2 = bright erythema, tenderness, patchy moist desquamation with moderate edema; 3 = confluent, moist desquamation, pitting edema, other skin folds; and 4 = ulceration, hemorrhage, necrosis). Baseline comparability of the 2 groups’ characteristics was tested using independent sample t test and a chi-square test. Differences between groups on frequency or severity of ARD injuries were tested using appropriate chi-square or Mann-Whitney tests. Factors associated with more severe ARD were tested using multivariate analysis. A statistically significant effect was determined to be P < .05. 

Results: The 2 groups were comparable on age, chest wall anatomy, and RT dosage. The SSD 1% cream group (n = 51) experienced significantly less severe ARD scores compared with the usual skin care control group (n = 51) at all measurements on study weeks 2 through 6 (P < .003). Though ARD severity scores increased throughout the 6-week study, with the progressively increasing RT dose, no patient’s ARD score ever exceeded an RTOG score of 3 in either group. Only 2 patients, who were in the control group, discontinued RT because of severe ARD (RTOG grade 3). The incidence of moist desquamation (RTOG grade 3) in the SSD 1% cream group (3.9% at week 5 or 21.5% 1 week after the last therapy) was higher than that reported in studies of other topical agents (0%–2%). These differences may be attributed to study differences in quantity or anatomical target of the RT dosage or frequency, composition, or timing of the topical formulations applied.

Authors’ Conclusions: Though the SSD 1% cream color and odor prevented a true double-blind assessment of ARD, results of this RCT consistently supported efficacy and safety of SSD 1% cream in preventing and treating ARD. 

Evidence supports topical application of corticosteroids⁵ or SSD 1% cream⁶ to reduce ARD scores and improve related pain or itching sufficiently to positively impact QoL of those undergoing RT to treat breast cancer following surgery. This evidence is strong enough to counter prior guidelines that found limited evidence to support topical ARD prevention or treatment interventions⁷ and poorly validated opinion-based RT-related skin care practices that varied across institutions.⁸ This conclusive evidence offers global opportunities to standardize ARD management practices to improve patients’ QoL and reduce their risk of interrupted RT. Further research is needed to examine the recognized cutaneous atrophy or immunosuppressive effects of corticosteroids not examined in the review, which reported their capacity to limit ARD during short-term use.⁵ Mechanisms of action, ideal temperatures, and properties of topical interventions to manage ARD, or their delivery systems and schedules, remain to be explored. Important gaps remain in understanding the mechanisms of action in topical corticosteroids, SSD 1% cream, and moisturizing vehicles. For example, a double-blind, vehicle-controlled SSD study would clarify what portion of the reported⁶ SSD-cream-reduced ARD severity was due to the SSD moisturizing cream vehicle compared with its active ingredient (SSD 1%). These results^5,6 raise the question — what synergistic effects of vehicles, combined with optimal corticosteroid doses and/or SSD 1%, may further enhance patient ARD outcomes? Further research is needed to determine why a flat-chested anatomy⁶ or smaller bra size⁵ is associated with decreased ARD injury, as well as if and how these results may generalize to other sites receiving more variable doses of RT. These studies are important early steps toward improving comfort and QoL for those with breast cancer undergoing RT.^5,6 More importantly, they highlight exciting research opportunities to further improve ARD outcomes for those undergoing RT.