Tan, E.H., & Chan, A. (2009). Evidence based treatment options for the management of skin toxicities associated with epidermal growth factor receptor inhibitors. Annals of Pharmacology, 43, 1658–1666.

To compile evidence from randomized controlled trials, case series, and case reports to identify the effectiveness of various therapeutic agents for prevention and treatment of skin toxicities associated with epidermal growth factor receptor (EGFR) inhibitor therapy

DATABASES: PubMed (January 2002–May 2009) and SCOPUS (January 2002–March 2009), manual searching for retrieval of additional references from articles reviewed

KEYWORDS: EGFR inhibitor, cetuximab, erlotinib, gefitinib, panitumumab, management, skin toxicity, and cutaneous effects

INCLUSION CRITERIA: Clinical trial, case series, case report, or clinical management guideline that studied treatment options of EGFR inhibitor-induced skin toxicities; EGFR inhibitor dosing regimen and treatment outcomes included in the publication

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Authors do not state the total volume of literature reviewed or decision-making regarding article exclusion processes. Authors report that randomized controlled trials, case series, and case reports were retrieved.

• FINAL NUMBER STUDIES INCLUDED = Final reports included in the analysis were two randomized controlled trials, three case series, and 10 case reports.
• TOTAL PATIENTS INCLUDED IN REVIEW = 156

Interventions were categorized as preventive intent or treatment intent. Interventions included in the review were topical antibiotics, systemic antibiotics, antiseptics, topical corticosteroids, retinoids, and other products. The majority of interventions were reported regarding effectiveness with EGFR inhibitor rash. Pruritus associated with the EGFR inhibitor-induced rash was documented in 47 patients in seven case reports; however, only three reports addressed pruritus treatment. Management of xerosis was mentioned in three case reports and one case series, for a total of 20 patients.

Preventive intent findings:

• Interventions found included topical erythromycin solution, systemic tetracyclines, and topical retinoid (tazarotene cream in combination with systemic antibiotics).
• Erythromycin solution was provided to two patients. These patients experienced only slight erythema without pustules, suggesting a protective effect.
• Two randomized controlled trials investigated the use of systemic tetracyclines to prevent EGFR inhibitor rash. In the total 51 patients across these trials, systemic antibiotic treatment did not prevent rash. Findings did suggest that the use of systemic antibiotic treatment along with EGFR inhibitor can decrease the severity of the rash during the first month of EGFR inhibitor treatment.
• Tazarotene cream, in combination with minocycline, demonstrated no effect on rash severity in 39 patients. The retinoid also was associated with significant skin irritation, causing one-third of the patients to discontinue its use.

Treatment intent findings:

• Interventions found for treatment of EGFR inhibitor skin toxicity included topical antibiotics, systemic antibiotics, antiseptics, topical corticosteroids, retinoids, colloidal sulfur galenic cream, and cream containing urea and vitamin K.
• Topical antibiotics were the most common treatments and were most often used in combination with other topical agents or systemic antibiotics. This intervention was reported in 49 patients.
  • Topical antibiotics used included clindamycin, erythromycin, fusidic acid, and metronidazole.
  • The majority of cases had either partial or complete responses with treatment.
• Systemic antibiotics were used to treat more severe EGFR inhibitor-induced rash in a total of 16 patients in several case reports and case series. Systemic tetracyclines were used in 12 patients in combination with topical medications for treatment of rash. In seven patients, non-tetracycline compounds (e.g., penicillin, clindamycin, fusidic acid) were used in combination with various topical agents.
  • Mixed results were seen. Some patients had complete or partial response, but in 58% of cases, results were confounded by concomitant delay or dose reduction in EGFR inhibitor treatment.
  • Results with non-tetracycline compounds also were confounded by withdrawal of EGFR inhibitor treatment.
• Antiseptics, including povidone iodine, hexamidine, benzoyl peroxide, and boric acid were reported in seven cases. In all cases, these were used in combination with other topical or systemic drugs. Response to these interventions was confounded by concomitant EGFR inhibitor dosage reduction in two patients who had a “complete response” to intervention with antiseptics.
• Retinoid interventions for rash treatment included oral isotretinoin in four patients and topical adapalene in three patients.
• Other intervention reports were retrieved that involved use of topical sulfur galenic cream and a cream containing urea and vitamin K. Improvement in these three patients was reported.

Strong evidence supports the use of topical antibiotics to manage EGFR inhibitor skin toxicities. Antibiotics are the most common treatment option. Use of anti-acne medications such as benzoyl peroxide and retinoids is controversial. Steroids are not recommended until well-designed clinical trials can demonstrate efficacy because steroid use can aggravate and induce acne.

This review did not identify strong evidence for any of the interventions reported for the management of skin toxicities associated with EGFR inhibitors. Antibiotics are most frequently used to manage EGFR inhibitor-induced skin toxicities, and more reports are available on the use of antibiotics than on the use of other approaches. The authors concluded that the evidence in support of the use of antibiotics is questionable. In this review, the total number of cases involved in the use of topical antibiotics was 49, and the total number of cases involved in the use of systemic antibiotics was 68. In many of the cases for systemic antibiotic use, reported findings were confounded by the additional intervention of dose modification (i.e., EGFR inhibitor dosages were reduced, delayed, or stopped).

• Reports reviewed involved a variety of mixed interventions, so identifying the combinations of interventions that appear to have the greatest promise for successful management of EGFR inhibitor-induced skin toxicities is difficult.
• This review only focused on skin toxicities associated with EGFR inhibitors. Little information on toxicities other than skin rash was found.
• This review, as well as the current literature evaluating the interventions, had a number of limitations. The review was limited by a lack of information found on pruritus and xerosis, as well as a lack of substantive, well-controlled research in this area. Most reports gave information about the resolution of rash in terms of lesion count but did not evaluate patient symptoms or specific patient-centered outcomes.
• Most reports did not provide a determination or measurement of the severity of skin problems. Most studies did not conduct a follow-up to determine long-term resolution. Reports of complete resolution of skin rash often involved discontinuation or dose reduction of the EGFR inhibitor, so efficacy of the intervention is likely to have been overestimated.

This review emphasized the need for well-designed research in this area that includes appropriate follow-up strategies. This review also discusses the widespread use of antibiotics to treat EGFR-induced skin toxicities. It notes that topical antibiotics are recommended for treatment of milder skin reactions, and systemic antibiotics (e.g., minocycline or doxycycline) are recommended for treatment of more severe rash. The authors state that their recommendations are aligned with several proposed treatment algorithms that have been obtained from international and interdisciplinary EGFR inhibitor dermatologic toxicity forums. As evident in this review, these recommendations are not based on strong evidence.