Management of egfr tki –induced dermatologic adverse events

Review Article

Management of egfr tki –induced dermatologic adverse events


B. Melosky , MD * , N.B. Leighl , MD , J. Rothenstein , MD , R. Sangha , MD § , D. Stewart , MD , K. Papp , MD #

* BC Cancer Agency, Vancouver, BC.
Princess Margaret Cancer Centre, University Health Network, Toronto, ON.
R.S. McLaughlin Durham Regional Cancer Centre, Lakeridge Health, Oshawa, and Department of Oncology, Queen’s University, Kingston, ON.
§ Cross Cancer Institute, Edmonton, AB.
The Ottawa Hospital and University of Ottawa, Ottawa, ON.
# Probity Medical Research, Waterloo, ON.


doi: http://dx.doi.org/10.3747/co.22.2430


ABSTRACT

Targeting the epidermal growth factor receptor ( egfr ) pathway has become standard practice for the treatment of advanced non-small-cell lung cancer. Compared with chemotherapy, egfr tyrosine kinase inhibitors ( tki s) have been associated with improved efficacy in patients with an EGFR mutation. Together with the increase in efficacy comes an adverse event ( ae ) profile different from that of chemotherapy. That profile includes three of the most commonly occurring dermatologic ae s: acneiform rash, stomatitis, and paronychia. Currently, no randomized clinical trials have evaluated the treatments for the dermatologic ae s that patients experience when taking egfr tki s. Based on the expert opinion of the authors, some basic strategies have been developed to manage those key dermatologic ae s. Those strategies have the potential to improve patient quality of life and compliance and to prevent inappropriate dose reductions.

KEYWORDS: Non-small-cell lung cancer , adverse events , acneiform rash , paronychia , stomatitis , egfr tki s

1.  INTRODUCTION

Treatment of non-small-cell lung cancer ( nsclc ) with oral agents that target the epidermal growth factor receptor ( egfr ) pathway has become a standard therapy for patients whose tumours have an EGFR gene mutation1. The egfr tyrosine kinase inhibitors ( tki s) block the adenosine triphosphate binding site of the intracellular kinase domain of egfr and prevent phosphorylation, thereby inhibiting signal transduction and subsequent cell growth and proliferation24.

Two types of egfr tki s have been developed: reversible and irreversible egfr tki s. Two reversible egfr tki s are currently approved by Health Canada for the treatment of patients with advanced nsclc : gefitinib is approved in the first-line setting for patients whose tumours are EGFR –mutation positive, and erlotinib is approved in the second- and third-line settings in unselected patients after chemotherapy failure1. Gefitinib and erlotinib compete reversibly for the adenosine triphosphate binding site of the kinase domain of egfr . After treatment with a reversible egfr tki , patients frequently become resistant to those agents because of a secondary mutation in the receptor’s tyrosine kinase domain. In approximately half the cases of acquired resistance, the cause is a missense T790M mutation4.

To overcome resistance, the newer egfr tki s that have been developed bind irreversibly to the active site of the kinase domain. The newer agents include afatinib and dacomitinib. Afatinib is an ErbB family blocker that has been shown to be highly selective for egfr , her 2 (the human epidermal growth factor receptor, ErbB2), and her 4 (ErbB4)5,6. Afatinib is approved by Health Canada as monotherapy in egfr tki –naïve patients with metastatic lung adenocarcinoma who have an activating EGFR mutation. Like afatinib, dacomitinib is an irreversible pan-ErbB inhibitor that targets egfr , her 2, and her 47.

The primary dermatologic adverse event ( ae ) associated with reversible and irreversible egfr tki s is acneiform rash2, which is characterized by an eruption of papules and pustules that typically appear on the face, scalp, upper chest, and back8. Additional ae s that are more commonly associated with irreversible egfr tki s are paronychia and stomatitis or mucositis9. Paronychia is a disorder characterized by an inflammatory process involving the soft tissues around the nails8. Stomatitis and mucositis are terms that are frequently used interchangeably. However, mucositis refers to an inflammation of the entire gastrointestinal tract; stomatitis refers specifically to inflammation of the oral mucosa8,10.

Available evidence suggests that the severity of skin toxicity correlates positively with a response to therapy with egfr tki s1113. In the phase ii ideal study, which evaluated the safety and efficacy of gefitinib in pretreated patients with nsclc , skin toxicity was reported by 86% of patients who experienced symptom improvement and by 58% of patients who experienced no symptom improvement14. A retrospective analysis of patients treated under the gefitinib Expanded Access Program showed that median survival was 10.8 months in patients who experienced a skin rash compared with just 4.0 months in patients not experiencing a skin rash ( p < 0.0001)12,15.

Similar results were seen in a retrospective study of erlotinib: after controlling for baseline factors, overall survival and progression-free survival showed a strong, positive correlation with the presence of rash—a correlation that increased with rash severity12,16. The positive correlation between skin toxicity and clinical response suggests that rash could be a marker of egfr tki efficacy or adequate dosing.

2.  PHYSIOLOGIC EFFECTS OF EGFR TKI INHIBITION

The egfr is critical in the physiology and development of the epidermis, which is composed primarily of keratinocytes9. Undifferentiated proliferating keratinocytes, including those in the basal and suprabasal layers of the epidermis, express egfr , which stimulates epidermal growth, promotes differentiation, and accelerates wound healing. Use of an egfr tki affects epidermal-derived tissues; effects include impaired keratinocyte growth, migration, and chemokine expression, which leads to inflammatory cell recruitment and cutaneous injury, including symptoms of rash and periungual inflammation. Those effects result from inhibition of pathways downstream of egfr , such as the mapk pathway1,17.

2.1  Incidence of Dermatologic AEs

In phase iii clinical trials, the incidence of acneiform rash varied from 37% to 76% in patients treated with reversible egfr tki s and from 69% to 89% in patients treated with the irreversible egfr tki afatinib (Table i). In phase ii trials with dacomitinib, the incidence of acneiform rash was comparable to that in the phase iii afatinib trials. In the case of gefitinib, the incidence of rash appeared to be related to dose. The incidence of stomatitis or mucositis in patients participating in phase iii clinical trials of reversible egfr tki s varied from 6% to 19%. However, the incidence was higher in phase iii clinical trials of afatinib, ranging from 51% to 72%. Similarly, the incidence of paronychia or nail effects was lower with gefitinib (3%–14% of patients) than with afatinib (33%–57% of patients). The higher incidence of dermatologic ae s seen with irreversible egfr tki s might be attributable to the covalent bond formed between the tki and egfr , which prolongs the effect of the tki 6.

TABLE I  Incidence of three adverse events accompanying the administration of epidermal growth factor receptor ( egfr ) tyrosine kinase inhibitors ( tki s) in selected clinical trials in non-small-cell lung cancera

 

In the lux -Lung 3 trial of afatinib compared with pemetrexed–cisplatin chemotherapy, the all-grade incidences of acneiform rash, stomatitis or mucositis, and paronychia (89.1%, 72.1%, and 56.8% respectively) were higher than the all-grade incidences of the same ae s reported in the lux -Lung 6 trial (80.8%, 51.9%, and 32.6% respectively), which compared afatinib with gemcitabine–cisplatin chemotherapy50,51. The differences in the two trials were the ethnic origins of the patient populations and the types of chemotherapy given, which would not affect the ae profile for patients in the afatinib arm. A recent analysis analyzed the incidence of the ae s in the two trials by ethnicity: the patient population in lux -Lung 3 was approximately 72% East Asian, 26% white, and 2% other; the patient population in lux -Lung 6 was entirely Asian50,51. Overall rates of stomatitis or mucositis (65.3% vs. 39.1%) and paronychia (45.8% vs. 35.9%) were higher in Asian than in non-Asian patients. However, the rates of grade 3 events were low and comparable between those groups56.

2.2  Acneiform Rash

2.2.1  Assessment and Grading

Acneiform rash usually develops in stages. In week 1, the patient experiences sensory disturbance, erythema, and edema; a papulopustular eruption follows in week 2. In week 4, crusting occurs, and in weeks 4–6, if the rash has been treated successfully, a background of erythema and dry skin occurs where papulopustular eruptions had previously been seen1. Rash typically occurs on the face, shoulders, upper back, and upper chest. However, dry itchy skin can occur on the arms and legs of approximately 35% of patients and can become infected with the herpes simplex virus or Staphylococcus aureus 11. Acneiform rash seems to dissipate entirely once the egfr tki is discontinued11,12.

For the first 6 weeks, patients should be closely followed each week and should contact their health care provider if rash becomes problematic. Patient education about egfr tki –induced rash should ideally begin before treatment initiation and continue throughout treatment. It is important to tell patients that egfr tki –induced rash is a common ae and that it might indicate efficacy of treatment. To prevent dose reduction or discontinuation of the egfr tki , it is important that patients know to report and obtain early treatment for rash2. The impact of dose reduction on the clinical course of skin lesions has not been published and requires further investigation57.

The most common grading system for acneiform rash is the U.S. National Cancer Institute’s Common Terminology Criteria for Adverse Events 8 (Table ii, Figure 1). The grade is determined in part by the percentage of body surface area covered in papules or pustules. Other considerations are psychosocial impact, extent of superinfection, and interference with daily activities. Grade 4 is considered life-threatening, and grade 5 is death.

TABLE II Common Terminology Criteria for Adverse Events grading system for acneiform rash8

 

 


 

FIGURE 1 Acneiform rash induced by epidermal growth factor receptor tyrosine kinase inhibitors. (A) Grade 1, gefitinib. (B) Grade 2, erlotinib. (C) Grade 3, erlotinib. (D) Grade 4, erlotinib.

2.2.2  Management

Prophylactic Management Strategies:

Two randomized double-blind studies whose goal was to determine if prophylactic tetracycline diminished the severity of egfr tki –induced rash have been completed. The studies compared tetracycline (500 mg twice daily) given prophylactically (that is, before the egfr tki was started) with placebo58,59. The results of the studies showed that tetracycline did not prevent rash, reduce rash severity, or improve quality of life. Another study, the Pan-Canadian Rash Trial (http://clinicaltrials.gov/ct2/show/record/NCT00473083), investigated whether prophylactic minocycline has an effect on the overall incidence of rash. Patients starting erlotinib were randomized to receive prophylactic minocycline for 4 weeks, rash treatment according to grade, or no treatment unless rash was severe. Preliminary analysis suggested that prophylactic minocycline treatment does not affect efficacy outcomes and is associated with a decrease in severe rashes, making prophylactic minocycline an option for the management of egfr tki –induced rash.

Preventive Management Strategies:

A number of preventive measures can be taken to reduce the risk of egfr tki –induced acneiform rash. Patients should be instructed to apply an alcohol- and perfume-free emollient cream twice daily, preferably to the entire body. Creams and ointments are preferred over lotions, because lotions could contain alcohol. Sunscreen should be applied to sun-exposed areas twice daily to prevent sunburn or excess sun exposure, which can worsen symptoms of rash. Finally, hot showers and products that dry the skin should be avoided1,2.

Pharmacologic Management Strategies:

Treatment algorithms for egfr tki –induced acneiform rash vary widely between the expert centres using those agents. Hydrocortisone 1% cream is commonly found in treatment algorithms for rash. However, if it is insufficient, use of a higher-potency topical steroid—such as hydrocortisone valerate twice daily as needed for grades 1–3 rash—can be helpful (Table iii). In addition, for grades 2 and 3 acneiform rash, oral minocycline (100 mg twice daily for 4 weeks) should be added to the treatment regimen1.

TABLE III   Treatment algorithm for acneiform rash

 

The dose of egfr tki should be maintained through grade 2 acneiform rash. However, for prolonged grade 2 rash, the egfr tki can be temporarily discontinued until symptoms improve to grade 1 or less; it can then be reintroduced at a dose of the physician’s discretion. If rash progresses to grade 3, the egfr tki should be temporarily discontinued (2–4 weeks) and then reintroduced at a dose of the physician’s discretion. If no improvement occurs, the egfr tki should be discontinued1.

2.3  Stomatitis or Mucositis

2.3.1  Assessment and Grading

Before the start of treatment with an egfr tki , the patient’s oral cavity should be assessed to obtain a baseline for any changes that might occur with therapy10. Oral mucositis can occur as broad areas of erythema or aphthous-like stomatitis9. Stomatitis usually starts with asymptomatic redness and erythema; it can progress to the formation of white patches associated with minimal pain, eventually transitioning to acutely painful large continuous lesions10. Based on the clinical experience of the authors, abnormal tingling sensations in the mouth are often reported within the first week of treatment with an egfr tki .

The Common Terminology Criteria for Adverse Events grading system sets out five grades of oral mucositis (Table iv , Figure 2)8. Grade 1 is characterized as asymptomatic or mildly symptomatic, and grade 2 as moderate pain that does not interfere with eating and drinking. By grade 3, patients can experince severe pain that interferes with intake of food and drink, followed by grade 4, which is considered life-threatening. Grade 5 is death.

TABLE IV Common Terminology Criteria for Adverse Events grading system for oral mucositis8

 

 


 

FIGURE 2 Stomatitis or mucositis induced by epidermal growth factor receptor tyrosine kinase inhibitors. (A) Grade 1, afatinib. (B) Grade 2, afatinib. (C) Grade 3, afatinib.

2.3.2  Management

Oral Hygiene:

After an initial assessment of oral health before the start of therapy with an egfr tki , the oral cavity should be evaluated by a health care professional periodically throughout treatment and at treatment completion9.

A simple oral care regimen for patients includes brushing the teeth and tongue with a soft-bristle brush, flossing, rinsing (preferably with normal saline), and moisturizing. If unable to use a toothbrush, patients can use a foam swab [for example, Toothette (Sage Products, Cary, IL, U.S.A.)] or piece of gauze, which are softer and less abrasive. Commercial mouthwashes often contain alcohol, which can irritate and dry the mucosal tissue; they should be avoided10. For mild stomatitis, a patient should perform oral care every 2–3 hours; for patients with moderate-to-severe symptoms, oral care should be performed every 1–2 hours10.

Pharmacologic Management Strategies:

No randomized controlled trials have evaluated treatment for egfr tki –induced stomatitis or mucositis, which can range from painful lesions to general mouth sensitivity9. The recommendations in the treatment algorithm (Table v ) are based on the expert opinion of the authors.

TABLE V   Treatment algorithm for stomatitis or mucositis

 

For general mouth sensitivity, patients can gargle with Tantum [benzydamine rinse (Angelini, Ancona, Italy): 15 mL for 30 seconds and spit out] 3 times daily as needed. Treatment for grade 1 stomatitis or mucositis is triamcinolone in dental paste applied 2–3 times daily as necessary, a therapy that is also used to reduce pain and inflammation from aphthous ulcers60. Treatment for grade 2 stomatitis includes the same regimen of triamcinolone in dental paste, with the addition of either oral erythromycin (250–350 mg daily) or minocycline (50 mg daily). For grade 3, clobetasol ointment is used instead of triamcinolone in dental paste, and the erythromycin dose is increased to 500 mg daily or the minocycline dose to 100 mg.

As with acneiform rash, the dose of egfr tki is maintained for grades 1 and 2 stomatitis; the egfr tki is temporarily discontinued (2–4 weeks) for grade 3 events. Upon improvement to grade 2 or less, the egfr tki can be reintroduced at a dose of the physician’s discretion. However, if no improvement is seen, the egfr tki should be discontinued.

2.4  Paronychia

2.4.1  Assessment and Grading

Acneiform rash typically appears early in treatment, but paronychial inflammation occurs after a longer period (that is, after several weeks or months of egfr tki therapy)1,61. Nail changes are usually mild, but can also be symptomatic and severe1,62. Paronychia affects the nails of the fingers and toes, most commonly occurring on the first digits9.

The Common Terminology Criteria for Adverse Events grading system for paronychia ranges from grade 1 to grade 3, instead of grades 1–5 (Table vi , Figure 3)8. Grade 1 paronychia is associated with nailfold edema or erythema and cuticle disruption. By grade 2, the nailfold edema or erythema is associated with pain. In grade 2 paronychia, discharge or nail-plate separation can also occur, and instrumental activities of daily living are limited. Local or oral intervention is indicated. Grade 3 paronychia is characterized by limitations in self-care activities of daily living, and surgical intervention could be indicated.

TABLE VI Common Terminology Criteria for Adverse Events grading system for paronychia8

 

 


 

FIGURE 3 Paronychia or nail effects induced by epidermal growth factor receptor tyrosine kinase inhibitors. (A) Grade 1, erlotinib. (B) Grade 2, afatinib. (C) Grade 3, erlotinib.

2.4.2  Management

As for stomatitis, no randomized controlled trials have evaluated treatments for paronychia. The recommendations in the treatment algorithm (Table vii ) are based on the expert opinion of the authors.

TABLE VII   Treatment algorithm for paronychia

 

Local Care Strategies:

Local care strategies to manage paronychia include emolliation with petroleum jelly, cushioning of affected areas, nail trimming (no aggressive manicures), and the use of gloves when cleaning to avoid irritants. Antimicrobial soaks (for example, diluted white vinegar or diluted bleach in water) are recommended to help prevent superinfection9.

Pharmacologic Management Strategies:

In the general population, acute paronychia is typically associated with S. aureus infection, and chronic paronychia is usually associated with Candida albicans (or Monilia ) infection63, indicating a potential need for antibiotic or antifungal interventions8. However, egfr tki – associated paronychia is sterile and corresponds with an ungual-fold inflammation consisting primarily of plasma cells, lymphocytes, and neutrophils64,65. To treat this type of paronychial inflammation, beta-methasone valerate for grades 1 and 2 and clobetasol cream for grade 3 should be applied 2 or 3 times daily as needed. If paronychia reaches grade 3, the egfr tki should be temporarily discontinued (2–4 weeks) until symptoms improve to grade 1 or less, when the drug can be reintroduced at a dose of the physician’s discretion. If no improvement is seen during the temporary discontinuation period, the egfr tki should be stopped altogether. In cases of refractory paronychia, or if signs of a superinfection are present, topical antibiotics such as mupirocin ointment can be used.

3.  SUMMARY

Three of the most common dermatologic ae s associated with egfr tki therapy are acneiform rash, stomatitis, and paronychia. These dermatologic ae s can be significant and debilitating and can have a negative effect on the patient’s quality of life57,65. The potential for reduced treatment compliance resulting from egfr tki –induced ae s can complicate disease management, especially given that the severity of some of the ae s appears to correlate with treatment response65. Current ae management strategies have been developed based on physician experience. However, as treatment with targeted agents becomes more common for patients with nsclc , the most effective interventions for dermatologic ae s will need to be determined through rigorous, systematic evaluation, so as to ensure patient compliance and improve quality of life.

4. ACKNOWLEDGMENT

The authors acknowledge medical writing support from Cathie Bellingham p h d of New Evidence, which was funded by Boehringer Ingelheim (Canada).

5. CONFLICT OF INTEREST DISCLOSURES

We have read and understood Current Oncology ’s policy on disclosing conflicts of interest, and we declare the following interests: BM has received honoraria for advisory board participation from Eli Lilly, Hoffmann–La Roche, Pfizer, and Boehringer Ingelheim. JR has received honoraria from Eli Lilly, Boehringer Ingelheim, and AstraZeneca. KP has consulted for and received payment from 3M, Abbott, Akesis, Akros, Alza, Amgen, Astellas, Baxter, Boehringer Ingelheim, Celgene, Centocor, Cipher, Eli Lilly, Forward Pharma, Isotechnika, Janssen, Janssen Biotech (Centocor), Johnson and Johnson, Kataka, Kirin, Kyowa, Lypanosys, Meiji Seika Pharma, Medical Minds, Merck, Mitsubishi Pharma, Novartis, Pfizer, Takeda, UCB, Vertex, and Wyeth. DS has consulted for, or been on the advisory boards of, Easton Associates, SAIC, Trinity Partners, Coleman Research Group, Frankel Group, Align2Action, Amgen Canada, Hoffmann–La Roche Canada, Pfizer Canada, Boehringer Ingelheim Canada, Transport Canada, and Guidepoint Global/Warburg Pincus; has had grants paid to his institution from the U.S. National Institutes of Health, the U.S. Department of Defense, AstraZeneca, Hoffmann–La Roche Canada, and Pfizer Canada; has been a speaker for Pfizer Canada, AstraZeneca Taiwan, University of Michigan/ swog , Ventana, iaslc , University of Texas San Antonio, American Radium Society, and the 5th International Pulmonary Congress; and has received royalties from Springer. NBL and RS have no conflicts of interest to declare.

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Correspondence to: Barbara Melosky, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6. E-mail: bmelosky@bccancer.bc.ca

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Current Oncology , VOLUME 22 , NUMBER 2 , April 2015








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