Evidence-based Treatment Options for the Management of Skin Toxicities Associated with EGFR Inhibitors Department of Pharmacy, Faculty of Science, National University of Singapore Block S4, 18 Science Drive 4, Singapore 117543 ABSTRACT Epidermal Growth Factor Receptor Inhibitors (EGFRI) are novel agents used in anticancer therapy. However, their usage is associated with dermatological toxicities of varying severities. The management of these cutaneous adverse effects is essential for the optimisation of anticancer therapy. Currently, there is little evidence-based data available on the effective management strategies of EGFRI-induced toxicities. This review aims to compile evidence from randomised controlled trials, case series and case reports and discuss the effectiveness of various therapeutic agents for the treatment and prevention of dermatological effects secondary to EGFRI administration. INTRODUCTION
The epidermal growth factor receptor (EGFR) has emerged as an important target for cancer therapy, namely in head and neck, colorectal, lung and pancreatic cancers. (AstraZeneca 2005; Genentech, 2008; Imclone, 2006) However these drugs are found to be associated with dermatologic toxicities including rash (75-89%), pruritus, (42% in cetuximab, 13% in erlotinib) xerosis (49% in cetuximab, 12% in erlotinib) and paronychia. (Genentech, 2008; Imclone, 2006) These side effects can cause great discomfort and may compromise willingness to continue anti- EGFR therapy if left untreated. Therefore, it is imperative for clinicians to use the most effective treatment option in order to minimise any effects on patients’ quality of life, and also to allow the uninterrupted progress of anti-EGFR therapy. The concept of evidence-based medicine stresses the application of external clinical evidence which supports more accurate, efficacious and safer treatment options. (Sackett, 1996) Therefore, the objective of this study is to compile available evidence-based data that is published on the management of dermatological toxicities, rather than opinion-based treatment options, and to review the effectiveness of these options in terms of resolution and prevention. METHODS This is a literature evaluation of treatment options for EGFR-induced skin toxicities. Literature search was carried out using Pubmed and Scopus with the keywords “Epidermal Growth Factor Receptor Inhibitor”, “cetuximab”, “erlotinib”, “gefitinib”, “management”, “skin
toxicity” and “cutaneous effects”. Clinical trials, case reports, case series and clinical management guidelines published from 2002 to 2008 were included in this literature review. For the purpose of this review, cutaneous toxicities shall be limited to rash, pruritus and xerosis. The exclusion criteria for the summary table are the lack of: (1) dosing regimen information for treatment option, (2) follow-up and (3) rate and status of resolution The grading of skin rash is adapted from the National Cancer Institute Common Toxicity Criteria (NCICTC) (Version 3.0) for rash/desquamation. Complete response denotes resolution of all pustules, near complete resolution after treatment and no incidence of rash or only slight erythema after prophylaxis. Partial response denotes improvement of lesions, reduction in lesion count after treatment and incidence of rash after prophylaxis RESULTS
A total of 18 articles were reviewed, including 2 randomized controlled trials, 3 case series and 10 case reports. 3 articles were excluded due to lack of comprehensive outcome information. A total of 156 patients were reviewed. Rash
Table 1 Compilation of evidence-based treatment options for rash associated with EGFR inhibitors.
CR: Complete response, PR: Partial response, NR/WR: No response/Worsen, NA: Not available, L: Topical, S: Systemic, P: Prevention, T: Treatment, d: days, w: weeks, RCT: Randomized controlled trial, ┼EGFRI dose reduction, #EGFRI dose discontinuation Pruritus Pruritus was recorded in seven reports in a total of 47 patients. (30.1%) (DeWitt, 2007; Lacouture, 2006; Micantonio, 2005; Morse, 2006; Ocvirk, 2008; Racca, 2007, Vezzoli, 2007). Racca and colleagues (2007) recorded that cetirizine provided symptomatic relief for 24 patients with Grade 2/3 rashes. Morse and Calarese (2006) advised the use of oral antihistamines to decrease the itch. In two cases, topical immunomodulator cream, namely pimecrolimus (Elidel) (Lacouture, 2006; Morse, 2006) were used. Xerosis Xerosis was mentioned in four case reports (Adams, 2005; Gutzmer, 2005; Morse, 2006) and one case series, with a total of 20 patients. (12.8%) (Racca, 2007) All case reports stated the use of moisturisers or emollients provided good control of dry skin. Racca et al (2007) used topical antibiotic ointment, soap substitutes, bath oil and moisturizing emollient in 16 patients and reported the recommended treatment provided good control of symptoms. DISCUSSION
It is important to note that, rarely a single therapeutic agent is used to treat EGFRI-induced rash. Agents that are commonly used together include systemic antibiotics with topical antibiotics or retinoid creams. Topical antibiotics appear to be the most commonly used and seemed to be more effective. Tetracyclines appear to be the drug of choice for oral antibiotics due to their additional anti-inflammatory effect. (Scope, 2007) There is evidence that tetracyclines reduce the severity of rash when administered at the start of anti-EGFR therapy, hence it minimizes the chance of discontinuing anti-EGFR therapy.
The usage of corticosteroids, retinoids or benzoyl peroxide is debatable. As a limited number of case reports are available, it is not recommended until more evidence on the efficacy of these agents can be compiled. An alternative agent like Reconval K1® was reported to be useful as monotherapy for Grade 1 rash, but likewise more evidence on its efficacy is required. There are a few limitations in this study, one of which is the lack of information on pruritus and xerosis in the form of follow up and treatment outcome. In addition, for most reports with partial response, there is insufficient subsequent follow up on the patient to determine whether the long term use of selected medication has led to complete resolution of the rash. This could lead to an underestimation of the drug efficacy if follow up was done early and no subsequent follow up scheduled after initial assessment. Thus it is advisable to follow-up of at least four weeks, although more severe unresolved symptoms may call for longer follow up. On the other hand, complete resolution achieved with the discontinuation or dose reduction in some case reports may lead to an overestimation of the efficacy of a therapeutic agent due to the confounding effect of interrupting anticancer therapy. As the usage of EGFRI is a relatively new advancement in anticancer therapy, the evidence- based information available on the effective management of EGFRI-induced skin toxicities is not abundant. Therefore, it is strongly encouraged for clinicians to file reports on successful outcomes with therapeutic agents for managing these skin toxicities. The availability of such data would strongly facilitate the decision-making process for a clinician to initiate therapy for cutaneous toxicities associated with EGFRI. CONCLUSION
This review has emphasized the need for evidence-based treatment options to facilitate the clinician’s decision making process. The use of antibiotics to manage EGFRI adverse effects is supported by the strongest evidence due to its widespread use by clinicians. The same cannot be said for retinoids, corticosteroids and newer agents. Therefore, it is essential for more clinical studies with comprehensive recording of relevant data on the management of EGFRI-induced dermatological effects to evaluate the usage of these therapeutic agents. REFERENCES
ImClone. (2006). Erbitux® (cetuximab) [Package insert]. Retrieved March 5, 2009 from http://packageinserts.bms.com/pi/pi_erbitux.pdf Jacot W, Bessis D, Jorda E, Ychou M, Fabbro M, Pujol JL, Guillot B. (2004). Acneiform eruption induced by epidermal growth factor receptor inhibitors in patients with solid tumours. Br J Dermatol., 151 (1): 238–241 Jatoi A, Rowland K, Sloan JA, Gross HM, Fishkin PA, et al. (2008). Tetracycline to prevent epidermal growth factor receptor inhibitor-induced skin rashes: results of a placebo- controlled trial from the North Central Cancer Treatment Group (N03CB). Cancer, 113(4):847-53. Scope A, Agero AL, Dusza SW, Myskowski PL, Lieb JA, Saltz L, Kemeny NE, Halpern AC. (2007). Randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab-associated acne-like eruption. J Clin Oncol., 25(34):5390-6.
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