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Treatment of gefitinib-associated folliculitis
CASE
REPORTS
Treatment of gefitinib-associated folliculitis Patricia Matheis, MD,a Mark A. Socinski, MD,b Craig Burkhart, MD,a Simon Warren, MD,a and Nancy E. Thomas, MD, PhDa Chapel Hill, North Carolina Gefitinib (Iressa), an epidermal growth factor inhibitor approved for treatment of advanced nonsmall cell lung carcinoma, is associated with an acneiform distributed folliculitis. Treatment attempts for this folliculitis have been noted in the literature, but photodocumentation of results has not been reported. We report 3 consecutive cases of gefitinib-associated folliculitis with photodocumentation of their treatment responses to combination therapy with topical metronidazole and oral tetracyclines. ( J Am Acad Dermatol 2006;55:710-3.)
G
efitinib (Iressa, ZD1839), an anilinoquinazoline, is an epidermal growth factor receptor (EGFR) inhibitor approved for use as chronic suppressive therapy for the treatment of locally advanced or metastatic nonsmall cell lung cancer (NSCLC) that has failed both platinum-based and docetaxel chemotherapies. We report clinical and photographic response to treatment of 3 consecutive patients presenting to the dermatology clinic with stage IV NSCLC who experienced an acneiform distributed folliculitis after onset of gefitinib therapy. All 3 patients experienced significant improvement of their cutaneous eruptions without scarring while continuing on gefitinib therapy without dose reduction.
CASE 1 After 17 days of gefitinib therapy at a dose of 250 mg/d, a 59-year-old Caucasian man developed pruritic papules and pustules on the central aspect of his face, neck, upper aspect of his back, and anterior aspect of his chest, considered grade-2 toxicity (Fig 1, A).1 The patient was considering discontinuing gefitinib, because he thought his appearance would discourage him from attending his son’s wedding. Pathologic examination showed a dense perifollicular infiltrate with dilated follicles filled
From the Departments of Dermatologya and Oncology,b University of North Carolina at Chapel Hill. Funding sources: None. Conflicts of interest: None identified. Reprint requests: Nancy E. Thomas, MD, PhD, Department of Dermatology, University of North Carolina at Chapel Hill, 3100 Thurston Bowles Bldg, CB No. 7287, Chapel Hill, NC 27599. E-mail: [email protected]. 0190-9622/$32.00 ª 2006 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2006.06.034
710
with keratin debris, whereas gram stain showed gram-positive cocci (Fig 1, B and C ). Aerobic culture of a pustule grew no pathologic organisms. He was treated with metronidazole 0.75% cream twice daily with nearly complete resolution after 2 weeks of therapy. Because of a few residual pustules, selenium sulfide 10% combined with sulfa 5% wash with daily use was added at 2 weeks. He was pleased with the results at 1 month (Fig 1, D) and remained on this therapy throughout treatment with getifinib. In addition, at this time he developed generalized xerosis and fine flakes over his body with severe eczematization on the shins, consistent with eczema craquele´ (Fig 1, E ). This responded within 1 month to twice daily application of topical triamcinolone 0.1% compounded with Eucerin (50:50) (Fig 1, F ). Gefitinib therapy was discontinued after 7 months because of disease progression of NSCLC.
CASE 2 Nine days after starting gefitinib at a dose of 250 mg/d, a 70-year-old Caucasian man noted excessive dryness and fissuring on his face in the nasolabial folds and 1 day later had onset of multiple papules and pustules that started on his nose and spread to other areas over 4 to 5 days. Fourteen days after initiation of gefitinib, the patient presented with pruritic papules and pustules on the central aspect of his face, scalp, neck, ears, and upper aspects of chest and back, considered grade-2 toxicity (Fig 2, A and B). Histology showed suppurative folliculitis with follicular hyperkeratosis, whereas gram stain of the tissue identified mixed flora including gramnegative rods and gram-positive coccobacilli (Fig 2, C and D). Aerobic and anaerobic cultures of pustules grew only probable coagulase-negative Staphylococcus species. Metronidazole 0.75% gel twice daily was initiated along with a moisturizer and cleansing
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Fig 1. Case 1. A, Papules, pustules, and telangiectasias on face of man taking gefitinib before treatment. B, Histology of pustule showed suppurative folliculitis and perifolliculitis with keratin-plugged follicle and atrophic sebaceous glands. (Hematoxylin-eosin stain; original magnification 34.) C, Gram-positive cocci were seen on gram stain. (Original magnification 1003 oil immersion.) D, Same man 1 month after initiation of metronidazole 0.75% cream twice daily and selenium sulfide 10% combined with sulfa 5% wash daily. E, Eczema craquele´ on shins while on gefitinib. F, Shins after 1 month of treatment with topical triamcinolone 0.1% compounded with Eucerin (50:50) twice daily.
Fig 2. Case 2. Pustules and crusting on face (A) and scalp (B) of man taking gefitinib at baseline. C, Suppurative folliculitis and perifolliculitis with keratin-plugged follicle and atrophic sebaceous glands. (Hematoxylin-eosin stain; original magnification 34.) D, Gramnegative rods and gram-positive coccobacilli were seen on gram stain. (Original magnification 1003 oil immersion.) E, Severely inflamed cyst on back while on genfitinib. F and G, Same man after 1 month of metronidazole 0.75% gel and doxycycline (100 mg orally) twice daily.
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Fig 3. Case 3. Papules and pustules on face (A) and chest (B) of man after 60 days of gefitinib. C and D, Same individual after 1 month of metronidazole 0.75% lotion and minocycline (100 mg orally) twice daily.
lotion. There was minimal response in 2 weeks and, at that time, the patient noted that a long-standing quiescent cyst on his back had become severely inflamed and was draining purulent material (Fig 2, E ). Culture of the cyst grew only Lactobacillus species. The patient was considering discontinuing gefitinib because of his appearance, pruritus from the eruption, and pain from the cyst. Doxycycline (100 mg orally twice daily) was added and, 1 month later, a significant reduction in the number of pustules was noted, decreasing to grade-1 toxicity (Fig 2, F and G). The cyst was also significantly less inflamed. However, the patient had developed generalized xerosis and fine flakes over his body consistent with asteatotic eczema. This was treated with topical triamcinolone 0.1% compounded with Eucerin (50:50) twice daily with improvement. The patient had stable disease of NSCLC after 2 months of getifinib.
CASE 3 Thirty days after starting gefitinib at a dose of 250 mg/d orally, a 42-year-old Caucasian man noted onset of a pustular rash on his chest and back. He presented 60 days after initiation of gentifinib with
pruritic papules and pustules on his face, scalp, neck, and upper aspects of his chest and back, considered grade-2 toxicity (Fig 3, A and B). Metronidazole 0.75% lotion twice daily was initiated; however, 2 weeks later the eruption had progressed to involve the upper aspect of his thighs, and the patient was considering discontinuing gefitinib because of his overall appearance. Minocycline (100 mg twice daily) was started, and the patient had significant improvement at 1 month with the folliculitis decreasing to grade-1 toxicity (Fig 3, C and D). The patient’s NSCLC has had a dramatic response to gefitinib.
DISCUSSION Several EGFR inhibitors are currently approved for use in a variety of neoplasms: gefitinib (Iressa) and erlotinib (Tarceva) for lung cancer, trastuzumab (Herceptin) for metastatic breast cancer, and cetuximab (Erbitux) for advanced colorectal cancer. Skin toxicity including folliculitis has also been associated with administration of other EGFR inhibitors, including cetuximab (Erbitux) and erlotinib (Tarceva).2-4 Of 216 patients who received gefitinib for NSCLC at the 250- to 500-mg daily dose, acneiform eruption, rash, and dry skin were reported in 25% to 33%, 43%
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to 54%, and 13% to 18% of patients, respectively.5 These observations are consistent with the recognized cutaneous loci of EGFR expression: basal keratinocytes, outer root sheath cells, sebocytes, and occasional endothelial cells.6 The time lag between initiation of therapy and mean time to onset of rash varies between 10 to 46 days, possibly reflecting differences in dose and schedule.7,8 The incidence of the acneiform eruption with getifinib may be dose dependent.9,10 The onset of xerosis has been reported to be about 20 days.8,10 The folliculitis can resolve with continuation of or within a few days of stopping the EGFR inhibitor.11,12 Variable and, at times, only partial success for treatment of the folliculitis while remaining on an EGFR inhibitor has been reported.4,5,7,11,13,14 EGFR slows cell growth of multiple cell types within the hair follicle, and some investigations have noted keratin plugs and dilated infundibula with micro-organisms as the predominant histopathologic finding of EGFR inhibition.15 EGFR also has a central role in controlling the inflammatory response in the skin. EGFR blockade increases expression of the proinflammatory chemokines CCL2, CCL5, and CXCL10 after stimulation with tumor necrosis factorealpha and interferon gamma.16 Conceivably, the getifinib-induced folliculitis could result from a combination of these effects on the hair follicle. The severe folliculitis associated with getifinib created psychologic distress for our patients. In addition, all patients had significant pruritus. Treatment of this eruption should improve quality of life for individuals who experience this complication. Although treatment did not result in complete resolution for all the patients, improvement was achieved. In addition, two patients who developed xerosis and eczematous eruptions were treated successfully with topical triamcinolone compounded with Eucerin. With expanding clinical use of EGFR inhibitors, increasing numbers of patients are likely to present with associated cutaneous side effects. Moreover, development of a suppurative folliculitis may correlate with higher EGFR treatment responses.2,3 Establishing reliable treatment options for these eruptions is necessary for patients to maintain satisfactory quality of life during the course and complete their treatment regimens. In addition, protocols for treatment of EGFR inhibitor—associated cutaneous eruptions should be specified in future clinical trials.
REFERENCES 1. National Cancer Institute. Common toxicity criteria. Version 2.0. Available at: http://ctep.cancer.gov/reporting/ctc_archive. html. Published April 1999. 2. Busam KJ, Capodieci P, Motzer R, Kiehn T, Phelan D, Halpern AC. Cutaneous side effects in cancer patients treated with the antiepidermal growth factor receptor antibody C225. Br J Dermatol 2001;144:1169-76. 3. Needle MN. Safety experience with IMC-C225, an antiepidermal growth factor receptor antibody. Semin Oncol 2002; 29(Suppl):55-60. 4. Perez-Soler R. Phase II clinical trial data with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib (OSI-774) in non-small-cell lung cancer. Clin Lung Cancer 2004;6(suppl 1):S20-3. 5. Physicians’ desk reference, 59 ed. Montvale, NJ: Medical Economics Production Company; 2005. p. 657. 6. Nanney LB, Magrid M, Stoscheck CM, King LE Jr. Comparison of epidermal growth factor binding and receptor distribution in normal human epidermis and epidermal appendages. J Invest Dermatol 1984;83:385-93. 7. Herbst RS, LoRusso PM, Purdom M, Ward D. Dermatologic side effects associated with gefitnib therapy: clinical experience and management. Clin Lung Cancer 2003;6:366-9. 8. Lee MW, Seo CW, Kim SW, Yang HJ, Lee HW, Choi JH, et al. Cutaneous side effects in non-small cell lung cancer patients treated with Iressa (ZD1839), an inhibitor of epidermal growth factor. Acta Derm Venereol 2004;84:23-6. 9. Baselga J, Rischin D, Ranson M, Calvert H, Raymond E, Kieback DG, et al. Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol 2002;20:4292-302. 10. Segaert S, van Custem E. Clinical signs, pathophysiology, and management of skin toxicity during therapy with epidermal growth factor inhibitors. Ann Oncol 2005;16:1425-33. 11. Fernandez-Galar M, Espana A, Lopez-Picazo JM. Acneiform lesions secondary to ZD1839, an inhibitor of the epidermal growth factor receptor. Clin Exp Dermatol 2004;29:138-40. 12. Herbst RS, Maddox AM, Rothenberg ML, Small EJ, Rubin EH, Baselga J, et al. Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD 1839 is generally welltolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a phase one trial. J Clin Oncol 2002;20:3815-25. 13. Jacot W, Bessis D, Jorda E, Ychou M, Fabbro M, Pujol JL, et al. Acneiform eruption induced by epidermal growth factor receptor inhibitors in patients with solid tumors. Br J Dermatol 2004;151:238-41. 14. Van Doorn R, Kirtschig G, Scheffer E, Stoof TJ, Giaccone G. Follicular and epidermal alterations in patients treated with ZD 1839 (Iressa), an inhibitor of the epidermal growth factor receptor. Br J Dermatol 2002;147:598-601. 15. Albanell J, Rojo F, Averbuch S, Feyereislova A, Mascaro JM, Herbst R, et al. Pharmacodynamic studies of the epidermal growth factor inhibitor ZD1839 in skin from cancer patients: histopathologic and molecular consequences of receptor inhibition. J Clin Oncol 2001;20:110-24. 16. Mascia F, Mariani V, Girolomoni G, Pastore S. Blockade of the EGF receptor induces a deranged chemokine expression in keratinocytes leading to enhanced skin inflammation. Am J Pathol 2003;163:303-12.
REPORTS
Treatment of gefitinib-associated folliculitis Patricia Matheis, MD,a Mark A. Socinski, MD,b Craig Burkhart, MD,a Simon Warren, MD,a and Nancy E. Thomas, MD, PhDa Chapel Hill, North Carolina Gefitinib (Iressa), an epidermal growth factor inhibitor approved for treatment of advanced nonsmall cell lung carcinoma, is associated with an acneiform distributed folliculitis. Treatment attempts for this folliculitis have been noted in the literature, but photodocumentation of results has not been reported. We report 3 consecutive cases of gefitinib-associated folliculitis with photodocumentation of their treatment responses to combination therapy with topical metronidazole and oral tetracyclines. ( J Am Acad Dermatol 2006;55:710-3.)
G
efitinib (Iressa, ZD1839), an anilinoquinazoline, is an epidermal growth factor receptor (EGFR) inhibitor approved for use as chronic suppressive therapy for the treatment of locally advanced or metastatic nonsmall cell lung cancer (NSCLC) that has failed both platinum-based and docetaxel chemotherapies. We report clinical and photographic response to treatment of 3 consecutive patients presenting to the dermatology clinic with stage IV NSCLC who experienced an acneiform distributed folliculitis after onset of gefitinib therapy. All 3 patients experienced significant improvement of their cutaneous eruptions without scarring while continuing on gefitinib therapy without dose reduction.
CASE 1 After 17 days of gefitinib therapy at a dose of 250 mg/d, a 59-year-old Caucasian man developed pruritic papules and pustules on the central aspect of his face, neck, upper aspect of his back, and anterior aspect of his chest, considered grade-2 toxicity (Fig 1, A).1 The patient was considering discontinuing gefitinib, because he thought his appearance would discourage him from attending his son’s wedding. Pathologic examination showed a dense perifollicular infiltrate with dilated follicles filled
From the Departments of Dermatologya and Oncology,b University of North Carolina at Chapel Hill. Funding sources: None. Conflicts of interest: None identified. Reprint requests: Nancy E. Thomas, MD, PhD, Department of Dermatology, University of North Carolina at Chapel Hill, 3100 Thurston Bowles Bldg, CB No. 7287, Chapel Hill, NC 27599. E-mail: [email protected]. 0190-9622/$32.00 ª 2006 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2006.06.034
710
with keratin debris, whereas gram stain showed gram-positive cocci (Fig 1, B and C ). Aerobic culture of a pustule grew no pathologic organisms. He was treated with metronidazole 0.75% cream twice daily with nearly complete resolution after 2 weeks of therapy. Because of a few residual pustules, selenium sulfide 10% combined with sulfa 5% wash with daily use was added at 2 weeks. He was pleased with the results at 1 month (Fig 1, D) and remained on this therapy throughout treatment with getifinib. In addition, at this time he developed generalized xerosis and fine flakes over his body with severe eczematization on the shins, consistent with eczema craquele´ (Fig 1, E ). This responded within 1 month to twice daily application of topical triamcinolone 0.1% compounded with Eucerin (50:50) (Fig 1, F ). Gefitinib therapy was discontinued after 7 months because of disease progression of NSCLC.
CASE 2 Nine days after starting gefitinib at a dose of 250 mg/d, a 70-year-old Caucasian man noted excessive dryness and fissuring on his face in the nasolabial folds and 1 day later had onset of multiple papules and pustules that started on his nose and spread to other areas over 4 to 5 days. Fourteen days after initiation of gefitinib, the patient presented with pruritic papules and pustules on the central aspect of his face, scalp, neck, ears, and upper aspects of chest and back, considered grade-2 toxicity (Fig 2, A and B). Histology showed suppurative folliculitis with follicular hyperkeratosis, whereas gram stain of the tissue identified mixed flora including gramnegative rods and gram-positive coccobacilli (Fig 2, C and D). Aerobic and anaerobic cultures of pustules grew only probable coagulase-negative Staphylococcus species. Metronidazole 0.75% gel twice daily was initiated along with a moisturizer and cleansing
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Fig 1. Case 1. A, Papules, pustules, and telangiectasias on face of man taking gefitinib before treatment. B, Histology of pustule showed suppurative folliculitis and perifolliculitis with keratin-plugged follicle and atrophic sebaceous glands. (Hematoxylin-eosin stain; original magnification 34.) C, Gram-positive cocci were seen on gram stain. (Original magnification 1003 oil immersion.) D, Same man 1 month after initiation of metronidazole 0.75% cream twice daily and selenium sulfide 10% combined with sulfa 5% wash daily. E, Eczema craquele´ on shins while on gefitinib. F, Shins after 1 month of treatment with topical triamcinolone 0.1% compounded with Eucerin (50:50) twice daily.
Fig 2. Case 2. Pustules and crusting on face (A) and scalp (B) of man taking gefitinib at baseline. C, Suppurative folliculitis and perifolliculitis with keratin-plugged follicle and atrophic sebaceous glands. (Hematoxylin-eosin stain; original magnification 34.) D, Gramnegative rods and gram-positive coccobacilli were seen on gram stain. (Original magnification 1003 oil immersion.) E, Severely inflamed cyst on back while on genfitinib. F and G, Same man after 1 month of metronidazole 0.75% gel and doxycycline (100 mg orally) twice daily.
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Fig 3. Case 3. Papules and pustules on face (A) and chest (B) of man after 60 days of gefitinib. C and D, Same individual after 1 month of metronidazole 0.75% lotion and minocycline (100 mg orally) twice daily.
lotion. There was minimal response in 2 weeks and, at that time, the patient noted that a long-standing quiescent cyst on his back had become severely inflamed and was draining purulent material (Fig 2, E ). Culture of the cyst grew only Lactobacillus species. The patient was considering discontinuing gefitinib because of his appearance, pruritus from the eruption, and pain from the cyst. Doxycycline (100 mg orally twice daily) was added and, 1 month later, a significant reduction in the number of pustules was noted, decreasing to grade-1 toxicity (Fig 2, F and G). The cyst was also significantly less inflamed. However, the patient had developed generalized xerosis and fine flakes over his body consistent with asteatotic eczema. This was treated with topical triamcinolone 0.1% compounded with Eucerin (50:50) twice daily with improvement. The patient had stable disease of NSCLC after 2 months of getifinib.
CASE 3 Thirty days after starting gefitinib at a dose of 250 mg/d orally, a 42-year-old Caucasian man noted onset of a pustular rash on his chest and back. He presented 60 days after initiation of gentifinib with
pruritic papules and pustules on his face, scalp, neck, and upper aspects of his chest and back, considered grade-2 toxicity (Fig 3, A and B). Metronidazole 0.75% lotion twice daily was initiated; however, 2 weeks later the eruption had progressed to involve the upper aspect of his thighs, and the patient was considering discontinuing gefitinib because of his overall appearance. Minocycline (100 mg twice daily) was started, and the patient had significant improvement at 1 month with the folliculitis decreasing to grade-1 toxicity (Fig 3, C and D). The patient’s NSCLC has had a dramatic response to gefitinib.
DISCUSSION Several EGFR inhibitors are currently approved for use in a variety of neoplasms: gefitinib (Iressa) and erlotinib (Tarceva) for lung cancer, trastuzumab (Herceptin) for metastatic breast cancer, and cetuximab (Erbitux) for advanced colorectal cancer. Skin toxicity including folliculitis has also been associated with administration of other EGFR inhibitors, including cetuximab (Erbitux) and erlotinib (Tarceva).2-4 Of 216 patients who received gefitinib for NSCLC at the 250- to 500-mg daily dose, acneiform eruption, rash, and dry skin were reported in 25% to 33%, 43%
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VOLUME 55, NUMBER 4
to 54%, and 13% to 18% of patients, respectively.5 These observations are consistent with the recognized cutaneous loci of EGFR expression: basal keratinocytes, outer root sheath cells, sebocytes, and occasional endothelial cells.6 The time lag between initiation of therapy and mean time to onset of rash varies between 10 to 46 days, possibly reflecting differences in dose and schedule.7,8 The incidence of the acneiform eruption with getifinib may be dose dependent.9,10 The onset of xerosis has been reported to be about 20 days.8,10 The folliculitis can resolve with continuation of or within a few days of stopping the EGFR inhibitor.11,12 Variable and, at times, only partial success for treatment of the folliculitis while remaining on an EGFR inhibitor has been reported.4,5,7,11,13,14 EGFR slows cell growth of multiple cell types within the hair follicle, and some investigations have noted keratin plugs and dilated infundibula with micro-organisms as the predominant histopathologic finding of EGFR inhibition.15 EGFR also has a central role in controlling the inflammatory response in the skin. EGFR blockade increases expression of the proinflammatory chemokines CCL2, CCL5, and CXCL10 after stimulation with tumor necrosis factorealpha and interferon gamma.16 Conceivably, the getifinib-induced folliculitis could result from a combination of these effects on the hair follicle. The severe folliculitis associated with getifinib created psychologic distress for our patients. In addition, all patients had significant pruritus. Treatment of this eruption should improve quality of life for individuals who experience this complication. Although treatment did not result in complete resolution for all the patients, improvement was achieved. In addition, two patients who developed xerosis and eczematous eruptions were treated successfully with topical triamcinolone compounded with Eucerin. With expanding clinical use of EGFR inhibitors, increasing numbers of patients are likely to present with associated cutaneous side effects. Moreover, development of a suppurative folliculitis may correlate with higher EGFR treatment responses.2,3 Establishing reliable treatment options for these eruptions is necessary for patients to maintain satisfactory quality of life during the course and complete their treatment regimens. In addition, protocols for treatment of EGFR inhibitor—associated cutaneous eruptions should be specified in future clinical trials.
REFERENCES 1. National Cancer Institute. Common toxicity criteria. Version 2.0. Available at: http://ctep.cancer.gov/reporting/ctc_archive. html. Published April 1999. 2. Busam KJ, Capodieci P, Motzer R, Kiehn T, Phelan D, Halpern AC. Cutaneous side effects in cancer patients treated with the antiepidermal growth factor receptor antibody C225. Br J Dermatol 2001;144:1169-76. 3. Needle MN. Safety experience with IMC-C225, an antiepidermal growth factor receptor antibody. Semin Oncol 2002; 29(Suppl):55-60. 4. Perez-Soler R. Phase II clinical trial data with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib (OSI-774) in non-small-cell lung cancer. Clin Lung Cancer 2004;6(suppl 1):S20-3. 5. Physicians’ desk reference, 59 ed. Montvale, NJ: Medical Economics Production Company; 2005. p. 657. 6. Nanney LB, Magrid M, Stoscheck CM, King LE Jr. Comparison of epidermal growth factor binding and receptor distribution in normal human epidermis and epidermal appendages. J Invest Dermatol 1984;83:385-93. 7. Herbst RS, LoRusso PM, Purdom M, Ward D. Dermatologic side effects associated with gefitnib therapy: clinical experience and management. Clin Lung Cancer 2003;6:366-9. 8. Lee MW, Seo CW, Kim SW, Yang HJ, Lee HW, Choi JH, et al. Cutaneous side effects in non-small cell lung cancer patients treated with Iressa (ZD1839), an inhibitor of epidermal growth factor. Acta Derm Venereol 2004;84:23-6. 9. Baselga J, Rischin D, Ranson M, Calvert H, Raymond E, Kieback DG, et al. Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol 2002;20:4292-302. 10. Segaert S, van Custem E. Clinical signs, pathophysiology, and management of skin toxicity during therapy with epidermal growth factor inhibitors. Ann Oncol 2005;16:1425-33. 11. Fernandez-Galar M, Espana A, Lopez-Picazo JM. Acneiform lesions secondary to ZD1839, an inhibitor of the epidermal growth factor receptor. Clin Exp Dermatol 2004;29:138-40. 12. Herbst RS, Maddox AM, Rothenberg ML, Small EJ, Rubin EH, Baselga J, et al. Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD 1839 is generally welltolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a phase one trial. J Clin Oncol 2002;20:3815-25. 13. Jacot W, Bessis D, Jorda E, Ychou M, Fabbro M, Pujol JL, et al. Acneiform eruption induced by epidermal growth factor receptor inhibitors in patients with solid tumors. Br J Dermatol 2004;151:238-41. 14. Van Doorn R, Kirtschig G, Scheffer E, Stoof TJ, Giaccone G. Follicular and epidermal alterations in patients treated with ZD 1839 (Iressa), an inhibitor of the epidermal growth factor receptor. Br J Dermatol 2002;147:598-601. 15. Albanell J, Rojo F, Averbuch S, Feyereislova A, Mascaro JM, Herbst R, et al. Pharmacodynamic studies of the epidermal growth factor inhibitor ZD1839 in skin from cancer patients: histopathologic and molecular consequences of receptor inhibition. J Clin Oncol 2001;20:110-24. 16. Mascia F, Mariani V, Girolomoni G, Pastore S. Blockade of the EGF receptor induces a deranged chemokine expression in keratinocytes leading to enhanced skin inflammation. Am J Pathol 2003;163:303-12.