Recommendations on management of EGFR inhibitor-induced skin toxicity: A systematic review

doi:10.1016/j.ctrv.2011.09.004

Cancer Treatment Reviews

Volume 38, Issue 5, August 2012, Pages 505-514

https://doi.org/10.1016/j.ctrv.2011.09.004 Get rights and content

Summary

Epidermal growth factor receptor (EGFR) inhibitors, such as the monoclonal antibodies cetuximab and panitumumab, have proven efficacy in various types of cancer. However, these agents frequently result in skin toxicity, due to the expression of the EGFR in the skin. A correlation between the occurrence of skin toxicity and anti-tumor activity has been suggested in several phase III studies. However, since skin toxicity may impair the quality of life, and severe skin toxicity requires dose reduction or interruption, adequate and timely management of skin toxicity is important to maximize the anti-tumor efficacy of the EGFR inhibitor, as well as maintaining the patient’s quality of life. Due to the small number of randomized controlled trials conducted in the field of EGFR inhibitor-induced skin toxicity so far, it is not possible yet to generate evidence based guidelines on its management. Here, we review and discuss available trials and case studies reporting on the management of EGFR inhibitor-induced skin toxicity.

Introduction

Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR), such as cetuximab and panitumumab, either alone or in combination with chemo- and/or radiotherapy,1, 2, 3, 4, 5, 6, 7 have proven to be active anti-tumor agents in various types of cancer, including: colorectal cancer (CRC); squamous cell carcinoma of the head and neck (SCCHN); and non small cell lung cancer (NSCLC). Additionally, both agents have fewer nonspecific and hematopoetic side effects compared with conventional chemotherapy. However, since the EGFR is not only expressed in various tumors but also present in healthy skin tissue, skin-specific toxicity is common, mainly acneiform rash (Fig. 1), but also folliculitis, xerosis cutis, pruritis, erythema, and paronychia.8, 9 Small molecule tyrosine kinase inhibitors (TKIs) targeting the EGFR, such as gefitinib, erlotinib, and also the dual inhibitor lapatinib, have similar reported side effects to the monoclonal antibodies, although skin toxicity of TKIs appears to be less severe.9, 10, 11, 12

Toxicity induced by EGFR targeting agents can negatively affect quality of life, partly due to skin toxicity.¹³ In severe cases (i.e., ⩾grade 3, according to NCI Common Terminology Criteria for Adverse Events (NCI CTCAE)) skin toxicity may impact on efficacy due to the requirement for dose delays, dose reductions, and even permanent discontinuation of EFGR targeting therapy altogether. Knowledge regarding the appropriate management of skin toxicity is therefore crucial. However, currently, evidence-based guidelines on how to prevent or treat EGFR inhibitor-induced skin toxicity are lacking. This paper systematically reviews the literature available on management of skin toxicity in order to compose recommendations on management of EGFR inhibitor-induced skin toxicity based on the currently available literature. We also elaborate on the relevance and impact of adequate management of skin toxicity on tumor-related outcome.

Note to editors: the appropriate location for illustration 1 is considered to be near the introduction section.

Section snippets

Objectives

The primary objective of this systematic review is to formulate evidence based recommendations on the management, either treatment or prevention, of EGFR inhibitor induced skin toxicity. Secondary objectives are to evaluate current knowledge on: (1) the pathophysiology of this type of skin toxicity, (2) the prediction of the occurrence of (severe) skin toxicity in the individual patient, (3) the need for adequate management of skin toxicity, and (4) the possibility of any interference between

Search methods

A literature search within the Pubmed (MEDLINE) database was conducted (on the 9th of February 2011), searching for relevant English literature, published since the 1st of January 2004. The following keywords were used, alone or in combination, both as MESH terms as well as free text words: skin toxicity, rash, acneiform rash, acne, exanthema, cetuximab, panitumumab, erlotinib, gefitinib, lapatinib, monoclonal antibodies, EGFR, antibiotics, antibody dependent cell mediated cytotoxicity, NK

Results

The initial search resulted in 283 hits, which was reduced to 172 possibly relevant papers after screening all of the abstracts. Of the excluded papers, 34 were excluded because they reported on agents not directed at the EGFR (i.e., classic chemotherapeutic agents or other types of targeted therapy). Twenty-six were excluded since these were reviews of the general treatment of a specific type of tumor. Eight were excluded since these elaborated on biomarkers in colorectal cancer in general,

Is the management of EGFR inhibitor-induced skin toxicity necessary?

In a word: yes. Some argue that when we implement prophylactic skin toxicity management, skin toxicity will no longer act as a potential biomarker. Although attempts have been made to implement skin toxicity in clinical decision making,⁷⁶ it is not a validated tool with sufficient positive or negative predictive power on an individual patient level to justify decisions with high clinical impact on continuation, discontinuation, or dose-adjustments of EGFR inhibitor therapy. Perhaps more

Conflict of interest

H.-J. Guchelaar: research grants. Amgen Inc, Merck BV; F.A. de Jong: Employee: Amgen BV; Stock holder: Amgen BV; H. Gelderblom: research grants: Amgen Inc, Merck BV

Acknowledgement

The authors thank J. Pander, PharmD (Leiden University Medical Center, The Netherlands), for his assistance on the paragraph discussing antibody-dependent cell-mediated cytotoxicity.

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Citation Excerpt :
However, the combination of cicatricial ectropion and madarosis associated with panitumumab has not been previously described to our knowledge, although is not unexpected given that this has been previously reported with cetuximab.2,3,6 The use of oral doxycycline and topical ophthalmic steroid/antibiotic ointment have been tried to treat EGFR-inhibitor induced cicatricial ectropion 5; however, results from randomized clinical trials on the effects of various interventions (i.e. sunscreen, skin moisturizer, topical steroid, oral tetracycline) in the management of EGFR inhibitor-induced skin and periocular toxicity have been equivocal.8 In our case, the patient had been previously treated with FOLFIRI without experiencing periocular side effects.
To report a case of cicatricial ectropion and madarosis with the use of anti-epidermal growth factor receptor medication panitumumab.
An 82-year-old man with metastatic colorectal cancer presented with cicatricial ectropion and madarosis after starting panitumumab, an anti-epidermal growth factor receptor medication used to treat metastatic colorectal cancer. His findings resolved several weeks after discontinuation of panitumumab and treatment with lubrication and antibiotic/steroid ointment.
This case demonstrates the importance to consider potential medication side effects when treating periocular conditions in patients taking anti-epidermal growth factor receptor (anti-EGFR) agents.
Monoclonal antibody-induced papulopustular rash: Clinical course, communication to health-care professionals and reactive measures as reported by patients
2016, European Journal of Oncology Nursing
Citation Excerpt :
Therefore, patients should be recommended to contact health-care professionals as soon as they develop any symptom of skin toxicity aiming at avoiding dose modifications that may reduce treatment efficacy (Eaby et al., 2008). To date, few management guidelines for EGFRI-induced rash have been published (Baas et al., 2012; Lacouture et al., 2011; Potthoff et al., 2011; Ouwerkerk and Boers-Doets, 2010; Melosky et al., 2009), and most of them are based on uncontrolled trials or case series studies. However, the efficacy of preventive management strategies may be maximized (Lacouture et al., 2010; Jatoi et al., 2008; Scope et al., 2007), minimizing the need for dose reduction and delays that may compromise the benefits of EGFRIs.
The primary end-point was to describe the clinical course of monoclonal antibody-induced papulopustular rash (mAB-induced PPR), when patients alert health-care providers and the subsequent reactive measures employed. Exploring the predictors affecting PPR grading was the secondary end-point.
A multicentre retrospective study involving six Italian oncology outpatient departments was conducted. Thirty-nine patients with cancer undergoing cetuximab or panitumumab treatment were included. Information was collected through medical records and face-to-face interviews. mAB-induced PPR was scored by patients' self-reported Common Terminology Criteria for Adverse Eventsv4.02 and was defined as severe when the grade ≥3.
Thirty-five (89.7%) patients developed a rash, which was severe in nine cases. The rash usually appeared within the first week after starting the drug (22, 62.8%), peaked in severity during the first month (26, 74.3%) and resolved 4–8 weeks after the end of mABs therapy (15, 45.7%). At the time of the interviews, the rash was not still resolved in almost half (n = 16) of the patients. Twenty-six (74.3%) patients reported sequelae and the mostly common were erythema (21, 81%) and dry skin (14, 54%). Only half of the patients informed health-care professionals as soon as the rash appeared. All the patients treated the rash topically and mAB therapy was modified in 16 (45.7%) cases (reduction, n = 10; discontinuation, n = 9; withdrawal, n = 2). No association between male gender, age, fair skin, current smokers during therapy and PPR grading escalation was found.
The clinical course of the rash was pathognomonic. Patients should be further encouraged to communicate the onset of a rash to health-care professionals as soon as it appears to avoid grading escalation and sequelae. The adoption of CTCAE as a patient-reported outcome may become an instrument to help health-care providers in tailoring treatment measures.
First-line anti-EGFR monoclonal antibodies in panRAS wild-type metastatic colorectal cancer: A systematic review and meta-analysis
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When choosing the first-line treatment, these issues should be discussed with patients in order to take into account also their expectations. However, the potential occurrence of skin toxicity should not discourage from the use of anti-EGFR MoAbs since the prevention and an adequate early treatment of this adverse event may help to improve treatment tolerability and to maintain an adequate dose intensity of the first-line regimen [42]. Third, even if no significant difference in terms of ORR as measured by means of RECIST is observed, recent evidences underline the ability of anti-EGFR MoAbs in inducing tumour shrinkage earlier and more deeply than bevacizumab [30].
The use of anti-EGFR monoclonal antibodies (MoAbs) is restricted in Europe to RAS wild-type metastatic colorectal cancer (mCRC) patients. While up today these targeted agents have been mainly chosen as salvage treatment in later lines, their use in first-line in combination with chemotherapy is highly debated.
MEDLINE/PubMed, Cochrane Library, ASCO University, ESMO/ECCO conferences were searched for randomized controlled trials (RCTs) comparing first-line anti-EGFR MoAbs cetuximab or panitumumab plus chemotherapy to chemotherapy alone or with bevacizumab in patients with RAS wild-type colorectal cancer. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.
Seven eligible RCTs were identified. In the overall RAS wild-type population (N = 2719), anti-EGFR MoAbs significantly improved OS (HR = 0.81; 95%CI, 0.71–0.92; p = 0.002), PFS (HR = 0.77; 95%CI, 0.60–0.98; p = 0.03) and objective response rate (ORR) (RR = 1.33; 95%CI, 1.09–1.62; p = 0.004). The addition of an anti-EGFR MoAb to chemotherapy alone improved PFS (p < 0.001) and ORR (p < 0.001) with a trend toward longer OS (p = 0.07). As compared to bevacizumab, anti-EGFR MoAbs significantly improved OS (HR = 0.80; 95%CI, 0.69–0.92; p = 0.003), but not PFS (HR = 0.94; 95%CI, 0.74–1.19; p = 0.59) or ORR (RR = 1.10; 95%CI, 0.97–1.25; p = 0.12). No significant differences were found with respect to the chemotherapy backbone (oxaliplatin- versus irinotecan-based).
The choice of an anti-EGFR MoAb as first-line biologic is a valid option in RAS wild-type patients candidate to a doublet with infusional 5-FU. While attempting to further refine molecular selection, clinical considerations are crucial in planning the treatment strategy.
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Complications of TreatmentRecommendations on management of EGFR inhibitor-induced skin toxicity: A systematic review

Summary

Introduction

Section snippets

Objectives

Search methods

Results

Is the management of EGFR inhibitor-induced skin toxicity necessary?

Conflict of interest

Acknowledgement

Lancet

Eur J Cancer

Ann Oncol

J Invest Dermatol

J Am Acad Dermatol

Lancet Oncol

Radiother Oncol

Lancet Oncol

Lancet Oncol

Lancet Oncol

Eur J Cancer

J Am Acad Dermatol

Lancet

Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck

N Engl J Med

Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an eastern cooperative oncology group study

J Clin Oncol

Cetuximab for the treatment of colorectal cancer

N Engl J Med

EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer

J Clin Oncol

Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer

J Clin Oncol

Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer

N Engl J Med

Cutaneous adverse effects with HER1/EGFR-targeted agents: is there a silver lining?

J Clin Oncol

Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer

J Clin Oncol

Analysis of dermatologic events in patients with cancer treated with lapatinib

Breast Cancer Res Treat

Development of a functional assessment of side-effects to therapy (FAST) questionnaire to assess dermatology-related quality of life in patients treated with EGFR inhibitors (EGFRI): The FAST-EGFRI

J Clin Oncol

Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies

J Clin Oncol

Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial

JAMA

ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial

J Clin Oncol

The EGF receptor – an essential regulator of multiple epidermal functions

Eur J Dermatol

Mechanisms of cutaneous toxicities to EGFR inhibitors

Nat Rev Cancer

Cutaneous side-effects in cancer patients treated with the antiepidermal growth factor receptor antibody C225

Br J Dermatol

Pharmacodynamic evaluation of the epidermal growth factor receptor inhibitor OSI-774 in human epidermis of cancer patients

Clin Cancer Res

Follicular and epidermal alterations in patients treated with ZD1839 (Iressa), an inhibitor of the epidermal growth factor receptor

Br J Dermatol

Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: histopathologic and molecular consequences of receptor inhibition

J Clin Oncol

Staphylococcus coagulase-positive skin inflammation associated with epidermal growth factor receptor-targeted therapy: an early and a late phase of papulopustular eruptions

Oncologist

Inhibition of the epidermal growth factor receptor increases expression of genes that stimulate inflammation, apoptosis, and cell attachment

Mol Cancer Ther

Gefitinib-induced epidermal growth factor receptor (EGFR)-independent keratinocyte apoptosis is mediated by the JNK-activation pathway

Br J Dermatol

Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck

J Clin Oncol

Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck

J Clin Oncol

Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer

J Clin Oncol

Skin rash and good performance status (PS) predict impoved survival with gefitinib for patients with advanced non-small cell lung cancer (NSCLC)

J Clin Oncol

Clinical predictors of severe cetuximab-induced rash: observations from 933 patients enrolled in north central cancer treatment group study N0147

Oncology

Complications of Treatment
Recommendations on management of EGFR inhibitor-induced skin toxicity: A systematic review