This Article Abstract Full Text (PDF) Supplemental Data eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lynch, T. J. Articles by Lacouture, M. E. Search for Related Content PubMed PubMed Citation Articles by Lynch, T. J., Jr. Articles by Lacouture, M. E.

Symptom Management and Supportive Care

Epidermal Growth Factor Receptor Inhibitor–Associated Cutaneous Toxicities: An Evolving Paradigm in Clinical Management

^aMassachusetts General Hospital, Boston, Massachusetts, USA; ^bMD Anderson Cancer Center, Houston, Texas, USA; ^cUniversity of Pennsylvania, Philadelphia, Pennsylvania, USA; ^dNorthwestern University, Chicago, Illinois, USA

Key Words. EGFR • Erlotinib • Cetuximab • Panitumumab • Cutaneous toxicity • Pathobiology Forum Consensus

Correspondence: Thomas J. Lynch, Jr., M.D., Massachusetts General Hospital, 55 Fruit Street, YAW7, Boston, Massachusetts 02114, USA. Telephone: 617-726-2408; Fax: 617-724-1137; e-mail: tlynch{at}partners.org

Received March 9, 2007; accepted for publication April 18, 2007.

	ABSTRACT

Top Abstract Introduction EGFRIs in the Treatment... Clinical Features and Incidence... Pathobiology of EGFRI-Associated... EGFRI Efficacy and Association... Recommendations for Management... Conclusions Disclosure of Potential... Acknowledgments References

 
Epidermal growth factor receptor inhibitors (EGFRIs) have demonstrated improved overall survival in patients with non-small cell lung cancer, pancreatic cancer, and colorectal cancer; however, their use is associated with dermatologic reactions of varying severity. The similar spectrum of events observed with monoclonal antibodies and tyrosine kinase inhibitors suggests such toxicities are a class effect. While such reactions do not necessarily require any alteration in EGFRI treatment, being best addressed through symptomatic treatment, there is limited evidence on which to base such therapies. In October 2006, at an international and interdisciplinary EGFRI dermatologic toxicity forum, the underlying mechanisms of these toxicities were discussed and commonly used therapeutic interventions were evaluated. Our aim was to reach a current consensus on management strategies. A three-tiered, EGFRI-focused toxicity grading system is suggested for the purposes of therapeutic decision making, and as a framework on which to build a stepwise approach to intervention. This approach to successful management is specifically tailored to accurately categorize dermatologic toxicity associated with EGFRIs, and can be easily applied by all health care professionals. The goal is to maximize quality of life in patients who are being treated with these agents—many of whom will be on these drugs for several months or even years.

Disclosure of potential conflicts of interest is found at the end of this article.

	INTRODUCTION

Top Abstract Introduction EGFRIs in the Treatment... Clinical Features and Incidence... Pathobiology of EGFRI-Associated... EGFRI Efficacy and Association... Recommendations for Management... Conclusions Disclosure of Potential... Acknowledgments References

 
Targeted therapies that interfere with specific molecular pathways critical to cancer evolution have now been developed as treatment approaches to various tumors [1]. Most notably, agents that target the epidermal growth factor receptor (EGFR) have demonstrated clinical activity in patients with non-small cell lung cancer (NSCLC), pancreatic cancer, and colorectal cancer (CRC), and are in clinical development for a range of other solid tumors [2–5]. However, the tolerability profile of EGFR inhibitors (EGFRIs) is impacted by a unique group of skin, hair, and nail reactions [6, 7] that have significant potential to disrupt the optimal dosing of these agents, leading to detrimental effects on patient quality of life [8] and tumor response [2].

An EGFRI dermatologic toxicity forum was held on October 29, 2006 in Chicago, Illinois to discuss the underlying mechanisms of these dermatologic toxicities and to evaluate existing therapeutic interventions. This was an international and interdisciplinary meeting, attended by oncologists, oncology nurses, pharmacists, and dermatologists with expertise in the management of cutaneous toxicities associated with EGFRIs. The primary objective of this meeting was to reach a current consensus on management strategies; this article delivers an overview of the outcomes from the forum.

	EGFRIS IN THE TREATMENT OF SOLID TUMORS

Top Abstract Introduction EGFRIs in the Treatment... Clinical Features and Incidence... Pathobiology of EGFRI-Associated... EGFRI Efficacy and Association... Recommendations for Management... Conclusions Disclosure of Potential... Acknowledgments References

 
Aberrant cell signaling, mediated through EGFR, plays a pivotal role in tumorigenesis and disease progression. EGFR belongs to the human epidermal growth factor receptor (HER) family, a group of four known transmembrane receptors, which also includes HER-2/neu, HER-3, and HER-4 [9]. Activation of EGFR by ligands, such as EGF, leads to receptor dimerization (either with a second EGFR or with another member of the HER family) and activation of intrinsic tyrosine kinase (TK) activity [10]. This initiates downstream signaling pathways, including the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol-3-OH kinase (PI3K/Akt) pathway, modulating gene transcription and protein translation and ultimately stimulating tumor-cell proliferation, migration, adhesion, and angiogenesis, and inhibiting apoptosis [11]. EGFR is dysregulated in various tumor types [12–14], and its overexpression has been correlated with disease progression, poor prognosis, and a reduced sensitivity to chemotherapy [15, 16]. In NSCLC, amplification and mutation of EGFR have been implicated as major mechanisms in the pathogenesis of lung tumors [17, 18].

Agents that target EGFR therefore have the potential to profoundly impact cancer treatment. Several approaches are being developed by which EGFR may be targeted, but small-molecule TK inhibitors (TKIs) and monoclonal antibodies (mAbs) are the most advanced [19]. TKIs are orally administered, low molecular weight compounds that block the intracytoplasmic ATP-biding site on the receptor, preventing downstream signal transduction [11]. mAbs block the extracellular domain of the receptor, preventing ligand-dependent activation and downstream signaling [20].

Three EGFRIs—erlotinib (Tarceva®; Genentech, Inc., South San Francisco, CA; OSI Pharmaceuticals Inc., Melville, NY; F. Hoffmann-La Roche Ltd, Basel, Switzerland), cetuximab (Erbitux®; Bristol-Myers Squibb, Princeton, NJ), and panitumumab (Vectibix^TM; Amgen Inc., Thousand Oaks, CA)—are currently approved in the European Union (EU) and/or the U.S. (Table 1).

Cetuximab is a chimeric IgG1 mAb that is currently approved in combination with irinotecan in the EU and U.S. for EGFR-expressing metastatic CRC in patients who are refractory to irinotecan-based chemotherapy, and as monotherapy in the U.S. in patients who are intolerant to irinotecan-based chemotherapy [3, 23]. It is also approved for locally or regionally advanced head and neck squamous cell carcinoma (HNSCC) in combination with radiation therapy in the EU and U.S., and metastatic or recurrent HNSCC that is refractory to platinum-based therapy, in the U.S. [3, 23].

Panitumumab, a human IgG2 mAb, is currently approved in the U.S. for EGFR-expressing, metastatic CRC with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens [4].

A fourth agent, the TKI gefitinib (Iressa®; AstraZeneca, London, UK), is also currently approved in the U.S. as a third-line option for patients with NSCLC, but with restrictions. Although this accelerated approval is based on the results of a randomized phase II trial [24], data from a phase III confirmatory trial failed to show a survival benefit [25]. As a result, the use of gefitinib is at present restricted to patients currently or previously benefiting from it, and to patients enrolled in clinical studies in the U.S. [26]. In addition, it is currently approved for the treatment of inoperable or recurrent NSCLC in Japan and several other Asian countries.

Other agents that inhibit the activity of EGFR are in clinical development. Unlike those that have already received U.S. Food and Drug Administration (FDA) approval, most of these drugs target more than one receptor (i.e., do not exclusively target EGFR). These agents are summarized in Table 2.

	CLINICAL FEATURES AND INCIDENCE OF EGFRI-ASSOCIATED CUTANEOUS TOXICITIES

Top Abstract Introduction EGFRIs in the Treatment... Clinical Features and Incidence... Pathobiology of EGFRI-Associated... EGFRI Efficacy and Association... Recommendations for Management... Conclusions Disclosure of Potential... Acknowledgments References

 
Dermatologic toxicities are the most common adverse events associated with EGFRIs, occurring, on average, in >50% of patients who receive treatment [27].

To date, clinical trials evaluating EGFRIs have reported a range of adverse cutaneous reactions with variable severity (Table 3). Xerosis (dry skin), pruritus, nail/periungual alterations (usually manifested as paronychia), regulatory abnormalities of hair growth (usually manifested as alopecia of the scalp and trichomegaly of the eyelashes/hypertrichosis of the face), and telangiectasia (dilatation of capillaries and small blood vessels and hyperpigmentation) have all been observed [28, 29]. However, the most commonly reported toxicity is a papulopustular reaction (also variously described as acne or acneiform rash). This usually develops on the face and/or upper trunk and, in a majority of cases, peaks in severity during the first 1–2 weeks of therapy, stabilizing during the following weeks [30]. More specifically, the rash commonly develops in the following phases: sensory disturbance with erythema and edema (week 0–1), papulopustular eruption (weeks 1–3), crusting (weeks 3–5), and ending with erythematotelangiectasias (weeks 5–8). Usually, if the rash has resolved or greatly diminished during the second month (weeks 4–6), erythema and dry skin remain in areas previously dominated by the papulopustular eruption [28] (ME Lacouture, personal communication).

	PATHOBIOLOGY OF EGFRI-ASSOCIATED CUTANEOUS TOXICITIES

Top Abstract Introduction EGFRIs in the Treatment... Clinical Features and Incidence... Pathobiology of EGFRI-Associated... EGFRI Efficacy and Association... Recommendations for Management... Conclusions Disclosure of Potential... Acknowledgments References

 
Mechanisms that underlie EGFRI-associated cutaneous toxicities remain incompletely characterized; however, interference with the follicular and interfollicular epidermal-growth signaling pathway is considered critical.

Within the epidermis, EGFR plays a critical role, stimulating epidermal growth, inhibiting differentiation, protecting against UV-induced damage, inhibiting inflammation, and accelerating wound healing [33]. EGFR is known to be expressed in epidermal keratinocytes, sebaceous and eccrine glands, and hair follicle epithelium [34], and the greatest expression occurs in proliferating and undifferentiated keratinocytes, which are located in the basal and suprabasal layers of the epidermis and outer root sheath of the hair follicle [35]. Drug-induced inhibition of EGFR is thought to alter keratinocyte proliferation, differentiation, migration, and attachment [36, 37], and this may help to explain the papulopustular reaction and xerosis.

Histological specimens taken from the skin of patients with EGFRI-associated rash reveal a mixed inflammatory infiltrate surrounding the upper areas of the dermis (especially around follicles), follicular rupture, and epithelial acantholysis [32].

Immunohistochemical studies show that, during treatment with EGFRIs, expression of key markers is altered in the skin. In normal skin, phosphorylated EGFR is expressed in the basal and suprabasal layers, and MAPK is observed in the basal layer. Treatment with EGFRIs leads to abolishment of phosphorylated EGFR in all epidermal cells and reduced expression of MAPK [38]. Inhibition of EGFR in basal keratinocytes leads to growth arrest and premature differentiation. This is demonstrated by upregulated expression of cyclin-dependent-kinase inhibitor p27, keratin-1, and signal transducer and activator of transcription-3 in the basal layer, markers of differentiation that are normally only observed within the suprabasal layer [38].

These changes are accompanied in vitro by release of inflammatory cell chemoattractants that recruit leukocytes. These leukocytes are able to release enzymes that result in keratinocyte apoptosis, and accumulation of these nonviable cells in the underlying dermis results in additional cutaneous injury, which is thought to account for a majority of symptoms, including tenderness, papulopustules, and periungual inflammation [28]. These changes may also favor bacterial overgrowth, thus exacerbating inflammation, and have also been observed in histological specimens from skin of treated patients. Eventually, a decrease in thickness of the epidermis is observed, demonstrating a thin stratum corneum that lacks its characteristic basketweave configuration (an indication of abnormal differentiation) [38].

Interestingly, it has been shown, in patients who have received radiotherapy prior to EGFRI administration, that areas of skin having undergone prior irradiation tend not to develop a rash during erlotinib therapy [39]. This is thought to be a result of depletion of EGFR-expressing cells or alterations in the microvasculature in the skin covering irradiated areas. It is also important to note that inhibition of EGFR can lead to radiosensitization in malignant tissues, which may be therapeutically advantageous, but may result in aggravation of rash in skin overlying irradiated areas in patients simultaneously treated with EGFRIs (ME Lacouture, personal communication).

	EGFRI EFFICACY AND ASSOCIATION WITH SEVERITY OF SKIN RASH

Top Abstract Introduction EGFRIs in the Treatment... Clinical Features and Incidence... Pathobiology of EGFRI-Associated... EGFRI Efficacy and Association... Recommendations for Management... Conclusions Disclosure of Potential... Acknowledgments References

 
There is some evidence to suggest that the appearance of skin rash may be useful as a surrogate marker of EGFRI efficacy. This relationship has been most extensively studied with erlotinib, for which several trials have demonstrated a relationship between severity of the skin reaction and treatment efficacy. In a phase II study, in which 57 patients with advanced NSCLC received erlotinib (50 mg/day), patients with grade 0 rashes, assessed by The National Cancer Institute Common Toxicity Criteria (NCI-CTC) [40], had a median survival duration of 1.5 months. In contrast, patients with a grade 1 rash had a median survival time of 8.5 months and patients with a grade 2–3 rash had a 19.6-month survival duration [41]. This relationship has also been observed in other phase II trials of single-agent erlotinib in patients with head and neck cancer and ovarian cancer; survival rates for patients with skin rash (80% of patients) were significantly higher than for those without skin rash [42]. This correlation between rash and efficacy also appears, in an unplanned retrospective analysis, to have been an important predictive factor in the pivotal phase III trial of erlotinib in previously treated patients with advanced NSCLC. Patients who developed a rash (75%) had a significantly longer survival time than those who did not: 8.5 months for patients with grade 1 rash and 19.6 months for patients with grade 2 or 3 rash, versus 1.5 months for patients who did not develop any rash (p < .0001) [43].

Phase II trials of cetuximab in CRC, HNSCC, pancreatic cancer, and NSCLC have also shown that patients who develop rash live longer than those who do not [44, 45]. In the pivotal randomized phase II trial of cetuximab plus irinotecan versus cetuximab alone in patients with metastatic CRC, the response rates in patients with skin reactions after cetuximab treatment were higher than those in patients without skin reactions (25.8% versus 6.3% in the combination arm, p = .005, and 13.0% versus 0% in the monotherapy arm) [46]. In addition, in the phase III randomized trial of cetuximab plus cisplatin versus cisplatin plus placebo in metastatic/recurrent HNSCC, the response rate for patients on the cetuximab arm who developed skin toxicity was 33%, compared with 7% for patients who did not develop skin toxicity [47]. This difference was not statistically significant, although the study was not designed to test this comparison [47].

Similar correlations have also been observed with gefitinib in patients with HNSCC and NSCLC; for a full review of the available data please refer to Perez-Soler [43] and Saltz et al. [44].

These correlations remain to be validated in prospective trials, and it should not be assumed that EGFRIs are ineffective in patients who do not develop rash. However, these observations have led to the initiation of trials investigating dose-escalation protocols of EGFRIs. Ongoing studies are attempting to elicit characteristic target rashes in patients that may correlate with a better response.

	RECOMMENDATIONS FOR MANAGEMENT OF EGFRI-ASSOCIATED CUTANEOUS TOXICITY

Top Abstract Introduction EGFRIs in the Treatment... Clinical Features and Incidence... Pathobiology of EGFRI-Associated... EGFRI Efficacy and Association... Recommendations for Management... Conclusions Disclosure of Potential... Acknowledgments References

 
To date, no controlled clinical studies that have investigated treatment options for EGFRI-associated dermatologic reactions have been fully reported and, as a result, evidence-based treatment recommendations are not yet possible. Current techniques for management of these toxicities rely on qualitative, rather than quantitative, evidence, and upon expert opinion [48, 49].

The following recommendations represent a consensus approach to the grading and treatment of EGFRI-associated dermatologic toxicities and reflect an international approach to rash management.

Gradation of EGFRI-Associated Cutaneous Toxicities
Effective treatment of EGFRI-associated dermatologic reactions depends to a large degree on accurate grading, allowing for an appropriate level of intervention.

The NCI-CTC [40, 50] are most commonly used to grade adverse events in clinical trials, and criteria include several categories that are relevant to EGFRI-associated events (Table 5). However, the NCI-CTC is designed primarily as a surveillance tool, and its value as an aid to selecting interventions and predicting their effectiveness is questionable. Furthermore, there are limitations to its use in monitoring EGFR-targeted agents. Certain grading criteria, for example, basing rash severity on body surface area coverage, are misleading because EGFRI-associated rashes are generally confined to the face and upper trunk, and can be of high severity at such anatomic sites. In addition, discoloration, pitting, and ridging associated with grade 1 nail changes do not occur in response to EGFRI treatment.

Mild toxicity: Generally localized papulopustular reaction that is minimally symptomatic, with no sign of superinfection, and no impact on daily activities.

Moderate toxicity: Generalized papulopustular reaction, accompanied by mild pruritus or tenderness, with minimal impact upon daily activities and no signs of superinfection.

Severe toxicity: Generalized papulopustular reaction, accompanied by severe pruritus or tenderness, that has a significant impact upon daily activity and has the potential for or has become superinfected.

This simplified system is specifically tailored to describe dermatologic toxicity associated with EGFRIs, and can be easily applied by all health care professionals (examples of mild, moderate, and severe EGFRI-associated dermatologic toxicity are shown in Figure 1). In addition, this three-tiered grading-system is an appropriate framework on which to build a stepwise approach to intervention, using available treatments.

View larger version (72K): [in this window] [in a new window]   Figure 1. Examples of epidermal growth factor receptor inhibitor–associated dermatologic toxicity. (A): Mild toxicity: Generally localized papulopustular reaction that is minimally symptomatic, with no sign of superinfection and no impact on daily activities. (B): Moderate toxicity: Generalized papulopustular reaction, accompanied by mild pruritus or tenderness, with minimal impact upon daily activities and no signs of superinfection. (C): Severe toxicity: Generalized papulopustular reaction, accompanied by severe pruritus or tenderness, that has a significant impact upon daily activity and has the potential for or has become superinfected.

View larger version (57K): [in this window] [in a new window]   Figure 2. Proposed therapy algorithm for the management of cutaneous toxicities associated with EGFR inhibitors. Abbreviations: ADL, activities of daily life; bid, twice a day; EGFR, epidermal growth factor receptor; SPF, sun protection factor.

If patients develop EGFRI-associated dermatologic toxicity, the following interventions are suggested, based on severity of the reaction:

Mild toxicities: Patients may not require any form of intervention; however, it may be appropriate to treat some mild toxicities with topical hydrocortisone (1% or 2.5% cream) or clindamycin (1% gel). The EGFRI dosage should not be altered for mild toxicities.

Moderate toxicities: Treatment is hydrocortisone (2.5% cream), clindamycin (1% gel), or pimecrolimus (Elidel®; Novartis Pharmaceuticals Corporation, East Hanover, NJ) (1% cream), with the addition of either doxycycline (100 mg, po twice a day [bid]) or minocycline (100 mg, po bid) [8, 53, 54]. The EGFRI dosage should not be altered for moderate toxicities.

Severe toxicities: A reduction in the EGFRI dose is recommended. Concomitant intervention is the same as for moderate toxicities—i.e., hydrocortisone (2.5% cream), clindamycin (1% gel), or pimecrolimus (1% cream), with the addition of either doxycycline (100 mg, po bid) or minocycline (100 mg, po bid)—but with the addition of methylprednisolone dose pack. If toxicities do not sufficiently abate at 2–4 weeks, despite treatment, then interruption of EGFRI therapy is recommended, in accordance with prescribing information.

It is important to note that intervention for cutaneous toxicities needs to be maintained even when EGFRI therapy is decreased or is interrupted, because EGFRI-associated toxicities may have a very long duration, analogous to the prolonged tissue half-life of EGFRIs. Once the cutaneous reactions have sufficiently diminished in severity, or resolved, then EGFRI therapy may typically be re-escalated or restarted with a good degree of confidence that cutaneous toxicities may be more easily managed.

Considerations in the Management of EGFRI-Associated Cutaneous Toxicities
Application of topical agents (steroids, immunomoduators, or antibiotics) should continue for up to 7 days beyond abatement of the dermatologic toxicity. However, uninterrupted use of topical corticosteroids can cause dermal toxicity and increase the risk for bacterial or viral superinfection, so they should not be used for >14 days without interruption. Pulsed application of topical corticosteroids (e.g., 14 days on treatment then 7 days off treatment) is often recommended.

The decision on whether to use doxycycline or minocycline should be based on caregiver or institutional preference; both agents have been used to treat EGFRI-associated cutaneous toxicities. Doxycycline is preferred for patients with renal impairment and does not induce lupus-like autoimmune reactivity as does minocycline, but doxycycline is a more potent photosensitizer, and these factors should be taken into consideration when deciding treatment (ME Lacouture, personal communication).

In some areas of the EU (e.g., Germany), topical clindamycin is not readily available. In these instances gentamicin may be used as an alternative.

Pimecrolimus cream is not approved for use in the EU; however, a similar topical calcineurin inhibitor, tacrolimus (Protopic®; Astellas Pharma Inc, Deerfield, IL) ointment, is available [55]. Pimecrolimus is being investigated for the treatment of EGFR-associated cutaneous reactions at a number of institutions in the U.S., but there are no reports of successful topical tacrolimus use as of yet. In addition, if used systemically, these agents are immunomodulators and, while a causal relationship is not established, rare cases of skin malignancies and lymphoma have been observed in patients treated with topical calcineurin inhibitors [55, 56]. These malignancies are most likely associated with long-term use; however, these agents are not recommended in immunosuppressed individuals [55, 56], and this should be taken into consideration prior to the use of these agents in EGFRI-treated cancer patients.

Referral to a dermatologist is advocated in those cases in which suggested therapeutic interventions have not yielded satisfactory therapeutic responses and/or when clinical presentation is atypical.

	CONCLUSIONS

Top Abstract Introduction EGFRIs in the Treatment... Clinical Features and Incidence... Pathobiology of EGFRI-Associated... EGFRI Efficacy and Association... Recommendations for Management... Conclusions Disclosure of Potential... Acknowledgments References

 
EGFRIs play a significant role in the treatment of some cancers. However, their use is commonly associated with a generalized class effect: dermatologic reactions of varying severity.

The majority of these reactions are best addressed through symptomatic treatment and do not necessitate alteration in the course of EGFRI treatment. Unfortunately, at present, there is limited controlled, clinical evidence on which to base such symptomatic treatment, and of necessity, current "best practice" is employed.

Although controlled studies are required to investigate the utility of any algorithm and its various components, until such data are available, educational tools such as this algorithm serve an unmet need, that is, to better inform health care professionals and patients about the pathology behind EGFRI-associated dermatologic reactions, and the logic behind their management.

While the concerns of patients and health care professionals regarding rash require empathetic handling, it is important to emphasize that, in the majority of cases, there is no clinical need to withdraw EGFRI treatment. Even in worst-case scenarios, suspension of EGFRI treatment often needs only to be temporary, simply allowing for diminution of the rash.

One important goal is to ensure that health care professionals and patients see EGFRI-associated dermatologic toxicity as manageable, thereby optimizing clinical benefit (wherever possible) from continued and uninterrupted use of EGFRIs when possible.

	DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

Top Abstract Introduction EGFRIs in the Treatment... Clinical Features and Incidence... Pathobiology of EGFRI-Associated... EGFRI Efficacy and Association... Recommendations for Management... Conclusions Disclosure of Potential... Acknowledgments References

 
T.J.L. has acted as a consultant to Genentech, OSI, ImClone, and Sanofi-Aventis, and he has a financial interest in Genentech and Sanofi-Aventis. M.E.L. has acted as a consultant to ImClone, Genentech, and Bristol-Myers Squibb, and he has a financial interest in ImClone. D.P.W. has performed contract work for Genentech and Amgen. B.E. has acted as a consultant to and performed contract work for Merck, Amgen, and Oncology Education Centers (supported by a grant from Genentech). E.S.K. has acted as a consultant to Sanofi-Aventis, Genentech, and Eli Lilly. J.G. has acted as a consultant to Genentech.

	ACKNOWLEDGMENTS

Top Abstract Introduction EGFRIs in the Treatment... Clinical Features and Incidence... Pathobiology of EGFRI-Associated... EGFRI Efficacy and Association... Recommendations for Management... Conclusions Disclosure of Potential... Acknowledgments References

 
The authors would like to acknowledge the contribution of the other attendees of the EGFRI dermatologic toxicity forum: Anne Culkin (Memorial Sloan-Kettering Cancer Center, New York); Jean Pierre DeLord (Institut Claudius Regaud, Toulouse, France); Giuseppe Giaccone (VU University Medical Center, Amsterdam, The Netherlands; current affiliation: National Cancer Institute, Bethesda, MD); Patricia LoRusso (Hudson-Webber Cancer Research Center, Detroit, MI); Barbara Melosky (British Columbia Cancer Agency, Vancouver, Canada); Martin Reck (Hospital Grosshansdorf, Grosshansdorf, Germany); Roman Perez-Soler (Montefiore Medical Center, Bronx, NY); Jennifer Temel (Massachusetts General Hospital, Boston, MA).

Medical writing assistance for this article was provided by Genentech, Inc. and F. Hoffmann-La Roche Ltd.

	REFERENCES

Top Abstract Introduction EGFRIs in the Treatment... Clinical Features and Incidence... Pathobiology of EGFRI-Associated... EGFRI Efficacy and Association... Recommendations for Management... Conclusions Disclosure of Potential... Acknowledgments References

 

1. Dancey J, Sausville EA. Issues and progress with protein kinase inhibitors for cancer treatment. Nat Rev Drug Discov 2003;2:296–313.[CrossRef][Medline]
2. OSI Pharmaceuticals Inc. Tarceva® [prescribing information]. 2007. Available at http://www.gene.com/gene/products/information/oncology/tarceva/insert.jsp. Accessed February 19, 2007.
3. ImClone Systems, Bristol-Myers Squibb. Erbitux® [prescribing information]. Available at http://www.erbitux.com/erb/pdf/PI.pdf. Accessed February 19, 2007.
4. Amgen Inc. Vectibix^TM [prescribing information]. Available at http://www.vectibix.com/prescribing_information/prescribing_information.html. Accessed February 19, 2007.
5. Hynes NE, Lane HA. ERBB receptors and cancer: The complexity of targeted inhibitors. Nat Rev Cancer 2005;5:341–354.[CrossRef][Medline]
6. Robert C, Soria JC, Spatz A et al. Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol 2005;6:491–500.[CrossRef][Medline]
7. Rhee J, Oishi K, Garey J et al. Management of rash and other toxicities in patients treated with epidermal growth factor receptor-targeted agents. Clin Colorectal Cancer 2005;5(suppl 2):S101–S106.[Medline]
8. Molinari E, De Quatrebarbes J, Andre T et al. Cetuximab-induced acne. Dermatology 2005;211:330–333.[CrossRef][Medline]
9. Wells A. EGF receptor. Int J Biochem Cell Biol 1999;31:637–643.[CrossRef][Medline]
10. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001;2:127–137.[CrossRef][Medline]
11. Arteaga CL. The epidermal growth factor receptor: From mutant oncogene in nonhuman cancers to therapeutic target in human neoplasia. J Clin Oncol 2001;19;(18) (suppl):32S–40S.
12. Salomon DS, Brandt R, Ciardiello F et al. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995;19:183–232.[Medline]
13. Greatens TM, Niehans GA, Rubins JB et al. Do molecular markers predict survival in non-small-cell lung cancer? Am J Respir Crit Care Med 1998;157:1093–1097.[Abstract/Free Full Text]
14. Ohsaki Y, Tanno S, Fujita Y et al. Epidermal growth factor receptor expression correlates with poor prognosis in non-small cell lung cancer patients with p53 overexpression. Oncol Rep 2000;7:603–607.[Medline]
15. Nicholson RI, Gee JM, Harper ME. EGFR and cancer prognosis. Eur J Cancer 2001;37(suppl 4):S9–S15.[Medline]
16. Cooke T, Reeves J, Lannigan A et al. The value of the human epidermal growth factor receptor-2 (HER2) as a prognostic marker. Eur J Cancer 2001;37(suppl 1):S3–S10.
17. Lynch TJ, Bell DW, Sordella R et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129–2139.[Abstract/Free Full Text]
18. Tsao M, Sakurada A, Cutz JC et al. Erlotinib in lung cancer – molecular and clinical predictors of outcome. N Engl J Med 2005;353:133–144.[Abstract/Free Full Text]
19. Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 2003;21:2787–2799.[Abstract/Free Full Text]
20. Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene 2000;19:6550–6565.[CrossRef][Medline]
21. European Agency for the Evaluation of Medicinal Products (EMEA). Tarceva® [European product information]. Available at http://www.emea.europa.eu/humandocs/PDFs/EPAR/tarceva/H-618-PI-en.pdf. Accessed February 19, 2007.
22. F. Hoffmann-La Roche Ltd. Tarceva®: European Approval for Pancreatic Cancer Treatment. Available at http://www.roche.com/med-cor-2007–01-29. Accessed February 19, 2007.
23. European Agency for the Evaluation of Medicinal Products (EMEA). Erbitux] [European product information]. Available at http://www.emea.europa.eu/humandocs/PDFs/EPAR/erbitux/H-558-PI-en.pdf. Accessed February 19, 2007.
24. Kris MG, Natale RB, Herbst RS et al. 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 2003;290:2149–2158.[Abstract/Free Full Text]
25. Thatcher N, Chang A, Parikh P et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: Results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005;366:1527–1537.[CrossRef][Medline]
26. U.S. Food Drug Administration (FDA). Patient Information Sheet Gefitinib (Marketed as Iressa®). Available at http://www.fda.gov/cder/drug/InfoSheets/patient/gefitinibPIS.htm. Accessed February 19, 2007.
27. Agero AL, Dusza SW, Benvenuto-Andrade C et al. Dermatologic side effects associated with the epidermal growth factor receptor inhibitors. J Am Acad Dermatol 2006;55:657–670.[CrossRef][Medline]
28. Lacouture ME, Lai SE. The PRIDE (Papulopustules and/or paronychia, Regulatory abnormalities of hair growth, Itching, and Dryness due to Epidermal growth factor receptor inhibitors) syndrome. Br J Dermatol 2006;155:852–854.[CrossRef][Medline]
29. Segaert S, Van Cutsem E. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol 2005;16:1425–1433.[Abstract/Free Full Text]
30. Busam KJ, Capodieci P, Motzer R et al. Cutaneous side-effects in cancer patients treated with the antiepidermal growth factor receptor antibody C225. Br J Dermatol 2001;144:1169–1176.[CrossRef][Medline]
31. Bruno R, Mass RD, Jones C et al. Preliminary population pharmacokinetics (PPK) and exposure-safety (E-S) relationships of erlotinib HCI in patients with metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 2003;22:205.
32. Sipples R. Common side effects of anti-EGFR therapy: Acneform rash. Semin Oncol Nurs 2006;22(suppl 1):28–34.[CrossRef][Medline]
33. Jost M, Kari C, Rodeck U. The EGF receptor – an essential regulator of multiple epidermal functions. Eur J Dermatol 2000;10:505–510.[Medline]
34. Nanney LB, Stoscheck CM, King LE Jr et al. Immunolocalization of epidermal growth factor receptors in normal developing human skin. J Invest Dermatol 1990;94:742–748.[CrossRef][Medline]
35. Fox LP. Pathology and management of dermatologic toxicities associated with anti-EGFR therapy. Oncology (Williston Park) 2006;20(suppl 2):26–34.
36. Peus D, Hamacher L, Pittelkow MR. EGF-receptor tyrosine kinase inhibition induces keratinocyte growth arrest and terminal differentiation. J Invest Dermatol 1997;109:751–756.[CrossRef][Medline]
37. Woodworth CD, Michael E, Marker D et al. Inhibition of the epidermal growth factor receptor increases expression of genes that stimulate inflammation, apoptosis, and cell attachment. Mol Cancer Ther 2005;4:650–658.[Abstract/Free Full Text]
38. Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer 2006;6:803–812.[CrossRef][Medline]
39. Mitra SS, Simcock R. Erlotinib induced skin rash spares skin in previous radiotherapy field. J Clin Oncol 2006;24:e28–e29.[Free Full Text]
40. National Cancer Institute (NCI). Common Toxicity Criteria (CTC) Version 2.0. Available at http://ctep.cancer.gov/forms/CTCv20_4–30-992.pdf. Accessed February 14, 2007.
41. Perez-Soler R, Chachoua A, Hammond LA et al. Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer. J Clin Oncol 2004;22:3238–3247.[Abstract/Free Full Text]
42. Clarke G, Perez-Soler R, Siu L et al. Rash severity is predictive of increased survival with erlotinib HCI. Proc Am Soc Clin Oncol 2003;22:196.
43. Perez-Soler R. Rash as a surrogate marker for efficacy of epidermal growth factor receptor inhibitors in lung cancer. Clin Lung Cancer 2006;8(suppl 1):S7–S14.[Medline]
44. Saltz L, Kies M, Abbruzzese J et al. The presence and intensity of the cetuximab-induced acne-like rash predicts increased survival in studies across multiple malignancies. Proc Am Soc Clin Oncol 2003;22:204.
45. Rosell R, Daniel C, Ramlau R et al. Randomized phase II study of cetuximab in combination with cisplatin (C) and vinorelbine (V) vs. CV alone in the first-line treatment of patients (pts) with epidermal growth factor receptor (EGFR)-expressing advanced non small-cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2004;23:618.
46. Cunningham D, Humblet Y, Siena S et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337–345.[Abstract/Free Full Text]
47. Burtness B, Goldwasser MA, Flood W et al. 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 2005;23:8646–8654.[Abstract/Free Full Text]
48. Lacouture ME, Basti S, Patel J et al. The SERIES clinic: An interdisciplinary approach to the management of toxicities of EGFR inhibitors. J Support Oncol 2006;4:236–238.[Medline]
49. Perez-Soler R, Delord JP, Halpern A et al. HER1/EGFR inhibitor-associated rash: Future directions for management and investigation outcomes from the HER1/EGFR inhibitor rash management forum. The Oncologist 2005;10:345–356.[Abstract/Free Full Text]
50. National Cancer Institute (NCI). Common Terminology Criteria for Adverse Events v3.0 (CTCAE). Available at http://ctep.cancer.gov/forms/CTCAEv3.pdf. Accessed February 14, 2007.
51. Herbst RS, LoRusso PM, Purdom M et al. Dermatologic side effects associated with gefitinib therapy: Clinical experience and management. Clin Lung Cancer 2003;4:366–369.[Medline]
52. Jacot W, Bessis D, Jorda E et al. Acneiform eruption induced by epidermal growth factor receptor inhibitors in patients with solid tumours. Br J Dermatol 2004;151:238–241.[CrossRef][Medline]
53. Micantonio T, Fargnoli MC, Ricevuto E et al. Efficacy of treatment with tetracyclines to prevent acneiform eruption secondary to cetuximab therapy. Arch Dermatol 2005;141:1173–1174.[Free Full Text]
54. Sapadin AN, Fleischmajer R. Tetracyclines: nonantibiotic properties and their clinical implications. J Am Acad Dermatol 2006;54:258–265.[CrossRef][Medline]
55. Astellas Pharma Inc. Protopic® [prescribing information]. Available at http://www.astellas.us/docs/protopic.pdf. Accessed April 2, 2007.
56. Novartis Pharmaceuticals Corporation. Elidel® [prescribing information]. Available at http://www.pharma.us.novartis.com/product/pi/pdf/elidel.pdf. Accessed February 22, 2007.
57. AstraZeneca. Iressa® [prescribing information]. Available at http://www.astrazeneca-us.com/pi/iressa.pdf. Accessed February 19, 2007.
58. Thomson Scientific Ltd. Investigational Drugs Database. Available at http://www.iddb.com. Accessed February 26, 2007.

This article has been cited by other articles:

				R. E. Eilers Jr, M. Gandhi, J. D. Patel, M. F. Mulcahy, M. Agulnik, T. Hensing, and M. E. Lacouture Dermatologic Infections in Cancer Patients Treated With Epidermal Growth Factor Receptor Inhibitor Therapy J Natl Cancer Inst, January 6, 2010; 102(1): 47 - 53. [Abstract] [Full Text] [PDF]

				J. Schwartz Current combination chemotherapy regimens for metastatic breast cancer Am. J. Health Syst. Pharm., December 1, 2009; 66(23_Supplement_6): S3 - S8. [Abstract] [Full Text] [PDF]

				E. H. Tan and A. Chan Evidence-Based Treatment Options for the Management of Skin Toxicities Associated with Epidermal Growth Factor Receptor Inhibitors Ann. Pharmacother., October 1, 2009; 43(10): 1658 - 1666. [Abstract] [Full Text] [PDF]

				H. Piessevaux, M. Buyse, W. De Roock, H. Prenen, M. Schlichting, E. Van Cutsem, and S. Tejpar Radiological tumor size decrease at week 6 is a potent predictor of outcome in chemorefractory metastatic colorectal cancer treated with cetuximab (BOND trial) Ann. Onc., August 1, 2009; 20(8): 1375 - 1382. [Abstract] [Full Text] [PDF]

				N. Thatcher, M. Nicolson, R. W. Groves, J. Steele, B. Eaby, J. Dunlop, J. McPhelim, R. Nijjar, I. Ukachukwu, and U.K. Erlotinib Skin Toxicity Management Consensus Expert Consensus on the Management of Erlotinib-Associated Cutaneous Toxicity in the U.K. Oncologist, August 1, 2009; 14(8): 840 - 847. [Abstract] [Full Text] [PDF]

				B. Burtness, M. Anadkat, S. Basti, M. Hughes, M. E. Lacouture, J. S. McClure, P. L. Myskowski, J. Paul, C. S. Perlis, L. Saltz, et al. NCCN Task Force Report: Management of Dermatologic and Other Toxicities Associated With EGFR Inhibition in Patients With Cancer J Natl Compr Canc Netw, May 1, 2009; 7(Suppl_1): S-5 - S-21. [Abstract] [PDF]

				C.-H. Kohne and H.-J. Lenz Chemotherapy with Targeted Agents for the Treatment of Metastatic Colorectal Cancer Oncologist, May 1, 2009; 14(5): 478 - 488. [Abstract] [Full Text] [PDF]

				J. A. Wolfram, D. Diaconu, D. A. Hatala, J. Rastegar, D. A. Knutsen, A. Lowther, D. Askew, A. C. Gilliam, T. S. McCormick, and N. L. Ward Keratinocyte but Not Endothelial Cell-Specific Overexpression of Tie2 Leads to the Development of Psoriasis Am. J. Pathol., April 1, 2009; 174(4): 1443 - 1458. [Abstract] [Full Text] [PDF]

				N. A. Pennell and T. J. Lynch Jr. Combined Inhibition of the VEGFR and EGFR Signaling Pathways in the Treatment of NSCLC Oncologist, April 1, 2009; 14(4): 399 - 411. [Abstract] [Full Text] [PDF]

				R. S. Herbst and A. Sandler Bevacizumab and Erlotinib: A Promising New Approach to the Treatment of Advanced NSCLC Oncologist, November 1, 2008; 13(11): 1166 - 1176. [Abstract] [Full Text] [PDF]

				R. G. Pomerantz, R. E. Chirinos, L. D. Falo Jr, and L. J. Geskin Acitretin for Treatment of EGFR Inhibitor-Induced Cutaneous Toxic Effects Arch Dermatol, July 1, 2008; 144(7): 949 - 950. [Full Text] [PDF]

				H. Burris III and C. Rocha-Lima New Therapeutic Directions for Advanced Pancreatic Cancer: Targeting the Epidermal Growth Factor and Vascular Endothelial Growth Factor Pathways Oncologist, March 1, 2008; 13(3): 289 - 298. [Abstract] [Full Text] [PDF]

				C. Widakowich, G. de Castro Jr., E. de Azambuja, P. Dinh, and A. Awada Review: Side Effects of Approved Molecular Targeted Therapies in Solid Cancers Oncologist, December 1, 2007; 12(12): 1443 - 1455. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Supplemental Data eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lynch, T. J. Articles by Lacouture, M. E. Search for Related Content PubMed PubMed Citation Articles by Lynch, T. J., Jr. Articles by Lacouture, M. E.