Erlotinib-related skin toxicities: Treatment strategies in patients with metastatic non-small cell lung cancer
Authors: Yoshio Kiyohara, Naoya Yamazaki, Akiko Kishi
Journal: Journal of the American Academy of Dermatology (2013)

Skin toxicities are the most common side effects associated with the epidermal growth factor receptor inhibitor erlotinib, occurring in most patients receiving the drug. Clinical trials evaluating erlotinib for the treatment of non-small cell lung cancer have reported a range of skin disorders, the most common being acneiform rash, xeroderma (dry skin), pruritus, and paronychia. Although in the majority of cases these effects are mild and transient, they can have a considerable impact on a patient's quality of life and, if particularly severe and persistent, may necessitate treatment interruption or cessation and compromise treatment outcome. This coupled with recent evidence to suggest a positive correlation between the incidence and severity of rash and clinical outcome among erlotinib-treated patients with advanced or metastatic non-small cell lung cancer highlights the importance of adequately managing epidermal growth factor receptor inhibitor–related skin disorders. Clear treatment strategies are therefore necessary to ensure the prevention and optimal management of erlotinib-related skin toxicities thereby enabling patients to continue erlotinib treatment. In this review we present a practical approach for the treatment of erlotinib-related cutaneous side effects in Japanese patients with advanced non-small cell lung cancer providing details of specific treatment interventions, according to symptom severity, for each of the common skin disorders. In addition, the importance of preventive skin care measures–namely maintaining cleanliness, moisturization, and protection from external stimuli–in preventing the development of serious skin disorders is discussed and guidelines for the practice of proper skin care are presented. Skin toxicities are the most common side effects associated with the epidermal growth factor receptor inhibitor erlotinib, occurring in most patients receiving the drug. Clinical trials evaluating erlotinib for the treatment of non-small cell lung cancer have reported a range of skin disorders, the most common being acneiform rash, xeroderma (dry skin), pruritus, and paronychia. Although in the majority of cases these effects are mild and transient, they can have a considerable impact on a patient's quality of life and, if particularly severe and persistent, may necessitate treatment interruption or cessation and compromise treatment outcome. This coupled with recent evidence to suggest a positive correlation between the incidence and severity of rash and clinical outcome among erlotinib-treated patients with advanced or metastatic non-small cell lung cancer highlights the importance of adequately managing epidermal growth factor receptor inhibitor–related skin disorders. Clear treatment strategies are therefore necessary to ensure the prevention and optimal management of erlotinib-related skin toxicities thereby enabling patients to continue erlotinib treatment. In this review we present a practical approach for the treatment of erlotinib-related cutaneous side effects in Japanese patients with advanced non-small cell lung cancer providing details of specific treatment interventions, according to symptom severity, for each of the common skin disorders. In addition, the importance of preventive skin care measures–namely maintaining cleanliness, moisturization, and protection from external stimuli–in preventing the development of serious skin disorders is discussed and guidelines for the practice of proper skin care are presented. Capsule Summary•Skin toxicities are a common side effect of the epidermal growth factor receptor inhibitor erlotinib.•We present a practical approach for the treatment of erlotinib-related cutaneous side effects including treatment interventions according to symptom severity and the importance of preventive measures.•Skin toxicities impact quality of life and may necessitate treatment interruption. Ensuring the prevention and optimal management of erlotinib-related skin toxicities will enable erlotinib treatment continuation to gain the best outcome.In recent years, targeted therapy directed at the epidermal growth factor receptor (EGFR) has emerged as an important therapeutic option for the treatment of patients with a range of solid tumors including non-small cell lung cancer (NSCLC). Erlotinib is a highly selective oral tyrosine kinase inhibitor that targets EGFR to inhibit tumor cell growth and proliferation.1Bareschino M.A. Schettino C. Troiani T. Martinelli R. Morgillo F. Ciardiello F. Erlotinib in cancer treatment.Ann Oncol. 2007; 18: vi35-vi41Crossref PubMed Scopus (97) Google Scholar Based on the results of 1 international phase III study (BR.21) and 2 Japanese phase II studies, erlotinib monotherapy has received regulatory approval in Europe, the United States, and Japan for the treatment of patients with locally advanced or metastatic NSCLC who have failed at least 1 previous chemotherapy regimen.2Shepherd F.A. Rodrigues Pereira J. Ciuleanu T. Tan E.H. Hirsh V. Thongprasert S. et al.Erlotinib in previously treated non-small-cell lung cancer.N Engl J Med. 2005; 353: 123-132Crossref PubMed Scopus (5066) Google Scholar, 3Kubota K. Nishiwaki Y. Tamura T. Nakagawa K. Matsui K. Watanabe K. et al.Efficacy and safety of erlotinib monotherapy for Japanese patients with advanced non-small cell lung cancer: a phase II study.J Thorac Oncol. 2008; 3: 1439-1445Crossref PubMed Scopus (74) Google Scholar, 4Takahashi T. Yamamoto N. Nukiwa T. Mori K. Tsuboi M. Horai T. et al.Phase II study of erlotinib in Japanese patients with advanced non-small cell lung cancer.Anticancer Res. 2010; 30: 557-563PubMed Google ScholarDermatologic side effects are relatively common among patients treated with EGFR inhibitors.5Mitchell E.P. Perez-Soler R. Van Cutsem E. Lacouture M.E. Clinical presentation and pathophysiology of EGFRI dermatologic toxicities.Oncology (Williston Park). 2007; 21: 4-9PubMed Google Scholar, 6Parmar S. Schumann C. Rüdiger S. Boeck S. Heinemann V. Kächele V. et al.Pharmacogenetic predictors for EGFR-inhibitor-associated skin toxicity.Pharmacogenomics J. 2013; 13: 181-188Crossref PubMed Scopus (27) Google Scholar These skin disorders are generally mild or moderate in severity and can be managed by appropriate interventions or by reducing or interrupting the erlotinib dose. Appropriate and timely management make it possible to continue a patient's quality of life and maintain compliance; however if these adverse events (AEs) are not managed appropriately, and become more severe, treatment cessation may be warranted compromising clinical outcome. Evidence has emerged in recent years to suggest that the incidence and severity of rash are positively correlated with treatment outcome among patients receiving erlotinib (Fig 1).7Pérez-Soler R. Chachoua A. Hammond L.A. Rowinsky E.K. Huberman M. Karp D. et al.Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer.J Clin Oncol. 2004; 22: 3238-3247Crossref PubMed Scopus (1037) Google Scholar, 8Pérez-Soler R. Delord J.P. Halpern A. Kelly K. Krueger J. Sureda B.M. et al.HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the HER1/EGFR inhibitor rash management forum.Oncologist. 2005; 10: 345-356Crossref PubMed Scopus (256) Google Scholar, 9Pérez-Soler R. Cappuzzo F. Leon L. Wojtowicz-Praga S. Time course of cutaneous toxicity secondary to erlotinib therapy in patients with non-small cell lung cancer enrolled in the SATURN study [abstract].J Clin Oncol. 2011; 29: 502sGoogle Scholar, 10Soulieres D. Senzer N.N. Vokes E.E. Hidalgo M. Agarwala S.S. Siu L.L. 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. 2004; 22: 77-85Crossref PubMed Scopus (741) Google Scholar, 11Wacker B. Nagrani T. Weinberg J. Witt K. Clark G. Cagnoni P.J. Correlation between development of rash and efficacy in patients treated with epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies.Clin Cancer Res. 2007; 13: 3913-3921Crossref PubMed Scopus (357) Google Scholar, 12Okamoto H. Watanabe K. Goto K. Tamura T. Takahashi T. Ichinose Y. et al.Efficacy and safety of erlotinib monotherapy for Japanese patients with advanced non-small cell lung cancer: integrated analysis of two Japanese phase II studies.Nihon Kokyuki Gakkai Zasshi. 2012; 1: 190-196Google Scholar Strategies to improve the assessment and management of EGFR-related skin AEs are therefore essential to ensure compliance with anticancer therapy, thereby enabling patients to achieve optimal benefits. The purpose of this article is to describe the most common erlotinib-related skin disorders in patients with advanced/metastatic NSCLC and to provide treatment strategies for their management.Erlotinib-related skin disorders: symptoms and incidenceCommon skin disorders with erlotinibThe most frequently occurring skin disorders reported with erlotinib are acneiform rash, xeroderma (dry skin), pruritus, and paronychia (periungual inflammation). Skin disorders have been generally categorized by the Common Terminology Criteria for AEs v4.0 (Table I), with special criteria for paronychia being adopted because there is no Common Terminology Criteria for AEs category for paronychia. Erlotinib-related acneiform rash typically manifests as red papules and/or pustules on the face, chest, abdomen, or thighs (Fig 2). Several features distinguish an acneiform rash from acne vulgaris, including the absence of bacterial infection.13Common Terminology Criteria for Adverse Events [CTCAE] v4.0. US Department of Health and Human Services. National Institutes of Health. National Cancer Institute. May 28, 2009. Available from: URL:http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Accessed April 17, 2012.Google Scholar Xeroderma is characterized by dryness and roughness of the skin, and scaling (Fig 2). The scales may be associated with inflammatory erythema or pigmentation. As the condition progresses, fissures appear and the skin becomes itchy and similar to pityriasis, resembling fish scales; the fissures can cause considerable pain. Pruritus, or skin itching, usually develops with xeroderma or dermatitis; it is unusual for a patient to present with pruritus without a rash. Pruritus may cause patients to scratch, resulting in scratch marks, lichenification, and eczematous inflammation with hyperpigmentation and/or secondary infection. Paronychia manifests as dusky erythema around several fingernails and toenails (Fig 3). This results in the formation of painful fissures, swelling, and noninfectious granulation. Bleeding or exudation can result in crust formation, which may be extremely painful and severely impact quality of life. Secondary infection arising from paronychia is also a common problem.Table ISymptoms and interventions of most common erlotinib-related skin disorders by severityEventGrade 1Grade 2Grade 3∗Refer to dermatologist promptly.Grade 4∗Refer to dermatologist promptly.Acneiform rashPapules and/or pustules covering <10% BSA, with/without symptoms of pruritus or tendernessPapules and/or pustules covering 10%-30% BSA, with/without symptoms of pruritus or tenderness; associated with psychosocial impact, and limiting instrumental ADLPapules/pustules covering >30% BSA with/without symptoms of pruritus or tenderness; limiting self-care ADL associated with local superinfection with oral antibiotics indicatedPapules and/or pustules covering any percent of BSA with/without symptoms of pruritus or tenderness; associated with extensive superinfection with IV antibiotics indicated; life-threatening consequencesTopical steroids (twice daily)Face: medium/strong classOther areas: strong classTopical steroidsFace: strong classOther areas: at least very strong class + oral minocycline†Switch to macrolide antibiotic if dizziness occurs. (50 mg twice daily)Topical steroidsAll areas: at least very strong class + oral minocycline†Switch to macrolide antibiotic if dizziness occurs. + oral steroids (prednisolone 10 mg for 1 wk)Refer for admission to major hospital with dermatology specialistsNote: handling of cases such as Stevens-Johnson syndrome or toxic epidermal necrolysis requires specialist careGrade 1Grade 2Grade 3∗Refer to dermatologist promptly.Xeroderma (dry skin)Covering <10% BSA, without erythema or pruritusCovering 10%-30% BSA, with erythema or pruritus; limiting instrumental ADLCovering >30% BSA, with pruritus; limiting self-care ADLEmollients (heparinoids, petroleum jelly, urea preparations‡Can cause burning or stinging in areas with fissuring.)Emollients + Topical steroids (at least strong class)PruritusMild or localized; topical treatment requiredIntense or widespread; intermittent; skin changes caused by scratching (eg, edema, papulation, excoriations, lichenification, oozing/crusts); oral intervention indicated; limiting instrumental ADLIntense or widespread; constant; limiting self-care ADL or sleep; oral corticosteroids or immunosuppressants indicatedEmollients + topical steroids (at least strong class)Emollients + topical steroids (at least strong class) + oral antihistamines or oral antiallergy medicinesParonychia§If grade ≥2 refer to dermatologist promptly., //Paronychia severity is graded according to criteria prepared by editorial committee of Erlotinib Rash Management Overview and Specific Treatment Guidelines v3.0.Nailfold edema or erythema; disruption of cuticleLocalized intervention indicated; oral intervention indicated (eg, antibiotic, antifungal, antiviral); nailfold edema or erythema with pain; associated with discharge or nail plate separation; limiting instrumental ADLSurgical intervention or IV antibiotics indicated; limiting self-care ADLWashing + cooling¶Water or gel-type cooling agent should be used to cool entire area. + topical steroids (at least strong class) + emollients + tapingWashing + cooling + topical steroids (at least very strong class) + emollients + taping or cryotherapy (liquid nitrogen) + oral minocycline; if there is fissuring, flurandrenolide tapeWashing + coolingGrade 2 treatments/partial nail removal/artificial nail placementSkin disorders are graded according to Common Terminology Criteria for Adverse Events v4.0.13Common Terminology Criteria for Adverse Events [CTCAE] v4.0. US Department of Health and Human Services. National Institutes of Health. National Cancer Institute. May 28, 2009. Available from: URL:http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Accessed April 17, 2012.Google ScholarADL, Activities of daily living; BSA, body surface area; IV, intravenous.∗ Refer to dermatologist promptly.† Switch to macrolide antibiotic if dizziness occurs.‡ Can cause burning or stinging in areas with fissuring.§ If grade ≥2 refer to dermatologist promptly.// Paronychia severity is graded according to criteria prepared by editorial committee of Erlotinib Rash Management Overview and Specific Treatment Guidelines v3.0.¶ Water or gel-type cooling agent should be used to cool entire area. Open table in a new tab Fig 2Acneiform rash and xeroderma. Characteristic symptoms.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig 3Paronychia. Characteristic symptoms.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Incidence of the most common skin disordersData from a Japanese postmarketing surveillance study of erlotinib-treated patients with NSCLC (POLARSTAR; n = 3488) revealed a high incidence of rash (63%), with somewhat lower incidences for dry skin, pruritus, and paronychia (7.7%, 3.8%, and 6.0%, respectively).14Nakagawa K. Kudoh S. Ohe Y. Johkoh T. Ando M. Yamazaki N. et al.Postmarketing surveillance study of erlotinib in Japanese patients with non-small-cell lung cancer (NSCLC): an interim analysis of 3488 patients (POLARSTAR).J Thorac Oncol. 2012; 7: 1296-1303Crossref PubMed Scopus (65) Google Scholar The majority of the skin disorders were grade 1 (mild) or grade 2 (moderate) in severity; just 6.7% of rash cases were grade 3 or higher, and 0.2% of dry skin and pruritus episodes and 0.7% of paronychia cases were grade 3 or higher in the surveillance study (Table II).14Nakagawa K. Kudoh S. Ohe Y. Johkoh T. Ando M. Yamazaki N. et al.Postmarketing surveillance study of erlotinib in Japanese patients with non-small-cell lung cancer (NSCLC): an interim analysis of 3488 patients (POLARSTAR).J Thorac Oncol. 2012; 7: 1296-1303Crossref PubMed Scopus (65) Google Scholar, 15US Department of Health and Human Services. National Institutes of Health. National Cancer Institute. Common Terminology Criteria for Adverse Events [CTCAE] v3.0. August 9, 2006. Available from: URL:http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. Accessed April 17, 2012.Google ScholarTable IIIncidence and time to onset of most common skin disorders in postmarketing surveillance study of advanced non-small cell lung cancer (analysis of 3488 patients in safety data set)14Nakagawa K. Kudoh S. Ohe Y. Johkoh T. Ando M. Yamazaki N. et al.Postmarketing surveillance study of erlotinib in Japanese patients with non-small-cell lung cancer (NSCLC): an interim analysis of 3488 patients (POLARSTAR).J Thorac Oncol. 2012; 7: 1296-1303Crossref PubMed Scopus (65) Google ScholarEventIncidence, % (n)Time to onset, dAll grades∗Common Terminology Criteria for Adverse Events v3.0.15Grade ≥3Median (range)Rash63.0 (2199)6.7 (234)8 (1-494)Dry skin7.7 (270)0.2 (8)15 (1-185)Pruritus3.8 (132)0.2 (6)11 (1-220)Paronychia6.0 (210)0.7 (23)32 (2-558)If patient experienced multiple events in same category, grade of most serious episode was used.∗ Common Terminology Criteria for Adverse Events v3.0.15US Department of Health and Human Services. National Institutes of Health. National Cancer Institute. Common Terminology Criteria for Adverse Events [CTCAE] v3.0. August 9, 2006. Available from: URL:http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. Accessed April 17, 2012.Google Scholar Open table in a new tab Time of onset typically varies according to the type of skin disorder. In the POLARSTAR study, median time to onset was shortest for rash (8 days, range 1-494) and longest for paronychia (32 days, range 2-558); median time to onset for dry skin and pruritus were 15 days and 11 days, respectively (Table II).14Nakagawa K. Kudoh S. Ohe Y. Johkoh T. Ando M. Yamazaki N. et al.Postmarketing surveillance study of erlotinib in Japanese patients with non-small-cell lung cancer (NSCLC): an interim analysis of 3488 patients (POLARSTAR).J Thorac Oncol. 2012; 7: 1296-1303Crossref PubMed Scopus (65) Google Scholar These findings are generally comparable with those from the 2 phase II studies for rash (median 6 days), pruritus (median 7 and 9 days), dry skin (12 and 23 days), and paronychia (41.5 and 49.5 days).16Rash management Ver.3, 2011. Yoshio Kiyohara, Naoya Yamazazki, Chugai Pharmaceutical Co Ltd.Google ScholarTreatment strategies for erlotinib-related rashPublished evidenceFew randomized controlled trials have been conducted in the management of EGFR-related skin disorders; 5 have been published to date although each study is small.17Scope A. Agero A.L. Dusza S.W. Myskowski P.L. Lieb J.A. Saltz L. et al.Randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab-associated acne-like eruption.J Clin Oncol. 2007; 25: 5390-5396Crossref PubMed Scopus (244) Google Scholar, 18Jatoi A. Rowland K. Sloan J.A. Gross H.M. Fishkin P.A. Kahanic S.P. et al.Tetracycline to prevent epidermal growth factor receptor-inhibitor skin rashes: results of a placebo-controlled trial from North Central Cancer Treatment Group (NO3CB).Cancer. 2008; 113: 847-853Crossref PubMed Scopus (151) Google Scholar, 19Scope A. Lieb J.A. Disza S.W. Phelan D.L. Myskowski P.L. Saltz L. et al.A prospective randomized trial of topical pimecrolimus for cetuximab-associated acnelike eruption.J Am Acad Dermatol. 2009; 61: 614-620Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 20Jatoi A. Thrower A. Sloan J.A. Flynn P.J. Wentworth-Hartung N.L. Dakhil S.R. et al.Does sunscreen prevent epidermal growth factor receptor (EGFR) inhibitor-induced rash? Results of a placebo-controlled trial from North Central Cancer Treatment Group (N05C4).Oncologist. 2010; 15: 1016-1022Crossref PubMed Scopus (45) Google Scholar, 21Lacouture M.E. Mitchell E.P. Piperdi B. Pillai M.V. Shearer H. Iannotti N. et al.Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer.J Clin Oncol. 2010; 28: 1351-1357Crossref PubMed Scopus (351) Google Scholar The studies were in different cancer types (including lung) with a range of EGFR inhibitors (cetuximab, panitumumab, erlotinib, gefitinib) and investigated the use of prophylactic or reactive treatments (Table III). Of these studies, 2 generated positive findings.Table IIIRandomized controlled trials on management of epidermal growth factor receptor-related skin disordersStudyEGFR inhibitorTumor typeTreatmentResultsScope et al,17Scope A. Agero A.L. Dusza S.W. Myskowski P.L. Lieb J.A. Saltz L. et al.Randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab-associated acne-like eruption.J Clin Oncol. 2007; 25: 5390-5396Crossref PubMed Scopus (244) Google Scholar 2007CetuximabCRCProphylactic oral minocycline 100 mg od vs placebo for 8 wkDecreased mild/moderate lesion count with minocycline at wk 4 (P = .005)Prophylactic tazarotene 0.05% od on left or right side of face for 8 wkNo difference between groupsJatoi et al,18Jatoi A. Rowland K. Sloan J.A. Gross H.M. Fishkin P.A. Kahanic S.P. et al.Tetracycline to prevent epidermal growth factor receptor-inhibitor skin rashes: results of a placebo-controlled trial from North Central Cancer Treatment Group (NO3CB).Cancer. 2008; 113: 847-853Crossref PubMed Scopus (151) Google Scholar 2008VariousVariousProphylactic oral tetracycline 500 mg bd vs placebo for 4 wkDecrease in grade 2 rash with tetracycline at wk 4 (P = .01); no difference between groups at wk 8 (P = .61)Scope et al,19Scope A. Lieb J.A. Disza S.W. Phelan D.L. Myskowski P.L. Saltz L. et al.A prospective randomized trial of topical pimecrolimus for cetuximab-associated acnelike eruption.J Am Acad Dermatol. 2009; 61: 614-620Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar 2009CetuximabCRCReactive topical pimecrolimus 1% bd for 5 wk on left or right sides of face vs no pimecrolimusGreater decrease in lesion count with pimecrolimus (P < .05)∗Lesions on both sides of face decreased significantly over study duration, therefore effect was considered not clinically relevant.Jatoi et al,20Jatoi A. Thrower A. Sloan J.A. Flynn P.J. Wentworth-Hartung N.L. Dakhil S.R. et al.Does sunscreen prevent epidermal growth factor receptor (EGFR) inhibitor-induced rash? Results of a placebo-controlled trial from North Central Cancer Treatment Group (N05C4).Oncologist. 2010; 15: 1016-1022Crossref PubMed Scopus (45) Google Scholar 2010VariousVariousSunscreen (SPF 60) bd vs placebo for 28 dNo difference between treatment groups (P = .36)Lacouture et al,21Lacouture M.E. Mitchell E.P. Piperdi B. Pillai M.V. Shearer H. Iannotti N. et al.Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer.J Clin Oncol. 2010; 28: 1351-1357Crossref PubMed Scopus (351) Google Scholar 2010PanitumumabCRCProphylactic treatment†Including skin moisturizer, sunscreen, topical steroid, and oral doxycycline. vs reactive treatment‡Any treatment as determined by physician.Decrease in grade ≥2 skin toxicity with prophylaxis (29% vs 62%)bd, Twice a day; CRC, colorectal cancer; od, daily; SPF, sun protection factor.∗ Lesions on both sides of face decreased significantly over study duration, therefore effect was considered not clinically relevant.† Including skin moisturizer, sunscreen, topical steroid, and oral doxycycline.‡ Any treatment as determined by physician. Open table in a new tab The most persuasive results were seen in the open-label phase II Skin Toxicity Evaluation Protocol with Panitumumab (STEPP) trial in patients with metastatic colorectal cancer. Patients receiving therapy including the EGFR inhibitor panitumumab were randomized to pre-emptive treatment (n = 48, comprising emollients, sunscreen, topical steroid, and doxycycline) or reactive treatment (n = 47) after skin toxicity developed. Notably, the primary endpoint, the incidence of specific grade 2 or higher skin toxicities during the 6-week skin treatment period, was reduced by more than 50% in the pre-emptive group compared with the reactive group (62% vs 29%; odds ratio 0.3; 95% confidence interval 0.1-0.6) (Fig 4).21Lacouture M.E. Mitchell E.P. Piperdi B. Pillai M.V. Shearer H. Iannotti N. et al.Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer.J Clin Oncol. 2010; 28: 1351-1357Crossref PubMed Scopus (351) Google ScholarFig 4Grade ≥2 skin toxicity in patients with metastatic colorectal cancer (Skin Toxicity Evaluation Protocol with Panitumumab [STEPP] study), time to first occurrence.21Lacouture M.E. Mitchell E.P. Piperdi B. Pillai M.V. Shearer H. Iannotti N. et al.Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer.J Clin Oncol. 2010; 28: 1351-1357Crossref PubMed Scopus (351) Google Scholar CI, Confidence interval; NR, not reached.Reprinted from Lacouture ME et al, Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II open-label, randomized trial evaluating the impact of a pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer, Journal of Clinical Oncology 28(8):1351-7, with permission. © (2010) American Society of Clinical Oncology. All rights reserved.View Large Image Figure ViewerDownload Hi-res image Download (PPT)In a randomized, double-blind trial of prophylactic oral minocycline in patients with metastatic colorectal cancer, patients receiving cetuximab were randomized to receive oral minocycline 100 mg once daily or placebo for the first 8 weeks of therapy. Up to week 4, mean lesion count in the oral minocycline group was half that of the placebo group (P = .005), but by week 8 the placebo group had spontaneously improved, suggesting the effects of prophylactic oral minocycline were most effective on early symptoms.17Scope A. Agero A.L. Dusza S.W. Myskowski P.L. Lieb J.A. Saltz L. et al.Randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab-associated acne-like eruption.J Clin Oncol. 2007; 25: 5390-5396Crossref PubMed Scopus (244) Google ScholarSeveral reports into the use of topical retinoids in the treatment of EGFR-induced skin disorders have been published.22Pomerantz R.G. Chirinos R.E. Falo Geskin L.J. Acitretin for treatment of EGFR inhibitor-induced cutaneous toxic effects.Arch Dermatol. 2008; 144: 949-950Crossref PubMed Scopus (17) Google Scholar, 23DeWitt C.A. Siroy A.E. Stone S.P. Acneiform eruptions associated with epidermal growth factor receptor-targeted chemotherapy.J Am Acad Dermatol. 2007; 56: 500-505Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 24Gutzmer R. Werfel T. Mao R. Kapp A. Elsner J. Successful treatment with oral isotretinoin of acneiform skin lesions associated with cetuximab therapy.Br J Dermatol. 2005; 153: 849-851Crossref PubMed Scopus (66) Google Scholar, 25Hachisuka J. Yunotani S. Shidahara S. Moroi Y. Furue M. Effect of adapalene on cetuximab-induced painful periungual inflammation.J Am Acad Dermatol. 2011; 64: e20-e21Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 26Hachisuka J. Doi K. Moroi Y. Furue M. Successful treatment of epidermal growth factor receptor inhibitor-induced periungual inflammation with adapalene.Case Rep Dermatol. 2011; 3: 130-136Crossref PubMed Scopus (10) Google Scholar One agent, adapalene (a topical retinoid) has been used successfully to treat paronychia in patients receiving EGFR inhibitors (gefitinib, erlotinib, cetuximab).25Hachisuka J. Yunotani S. Shidahara S. Moroi Y. Furue M. Effect of adapalene on cetuximab-induced painful periungual inflammation.J Am Acad Dermatol. 2011; 64: e20-e21Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 26Hachisuka J. Doi K. Moroi Y. Furue M. Successful treatment of epidermal growth factor receptor