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1 = 증례보고 = 에를로티닙과라파티닙을사용한환자에서발생한표층점상각막병증 대한안과학회지 2014 년제 55 권제 2 호 J Korean Ophthalmol Soc 2014;55(2): pissn: eissn: 오은규 1,2 조동현 1,2 김미금 1,2 위원량 1,2 서울대학교의과대학안과학교실 1, 서울대학교병원의생명연구원인공안구센터안면역각막재생연구실 2 목적 : 항암치료로표피성장인자수용체억제제 ( 에를로티닙, 라파티닙 ) 를사용한환자에서표층점상각막병증 2 예를경험하여문헌고찰과함께보고하고자한다. 증례요약 : 증례 1 은에를로티닙을사용한후각막접촉이없는거대속눈썹증과미만성의표층점상각막병증이발생하였다. 각막병증은에를로티닙을중단한후호전되었고, 에를로티닙을다시사용한이후재발하였다. 증례 2 는라파티닙을사용한후속눈썹의변화없이미만성의표층점상각막병증이발생하였다. 두증례모두심각한시력저하는없었고, 무방부제인공누액과자가혈청안약을사용하고호전되었다. 결론 : 에를로티닙과라파티닙이미만성의표층점상각막병증을유발한것으로생각하고, 점안액사용으로호전되었다. < 대한안과학회지 2014;55(2): > 표피성장인자수용체억제제는비소세포폐암, 유방암, 췌장암, 대장직장암, 두경부편평세포암에널리쓰이는표적함암치료제이다. 1 지금까지미국식품의약국 (US Food and Drug Administration) 에승인을받은표피성장인자수용체억제제는세툭시맙 (Erbitux, ImClone Systems, Inc., Princeton, NY), 트라스투주맙 (Herceptin, F. Hoffmann-La Roche Ltd, Basel, Switzerland), 제페티닙 (Iressa, AstraZeneca Pharmaceuticals, Wilmington, DE), 에를로티닙 (Tarceva, Genetech, Inc., San Francisco, CA), 라파티닙 (Tykerb, Glaxo-Smith-Kline, Philadelphia, PA) 등모두다섯가지이다. 1,2 이중라파티닙을제외한약제에서거대속눈썹증, 안와주변발진, 각막미란, 흉터눈꺼풀겉말림등의안과적인합병증이발생했다는보고가있다 저자들은각각에를로티닙, 라파티닙을사용한두명의환자에서표층점상각막병증을경험하였고이를치료하였음을보고하고자한다. 표피성장인자수용체억제제치료중발생한안과적인합병증에대해서는외국의사례가몇차례보고된바있었지만, 국내에서는기보고된문헌이없어종양내과의와암환자를 Received: Revised: Accepted: Address reprint requests to Mee Kum Kim, MD, PhD Department of Ophthalmology, Seoul National University Hospital, #101 Daehak-ro, Jongno-gu, Seoul , Korea Tel: , Fax: kmk9@snu.ac.kr 진료하는안과의에게치료경험을공유하고자보고하는바이다. 증례보고 특별한안과병력이없는 42세남자환자 ( 증례 1) 가열흘전부터시작된우안의통증과우안이흐리게보이는증상을주소로내원하였다. 환자는기존에안구건조증상은없었다고하였다. 교정시력은양안각각 20/20 이었고, 양안의안압은골드만편평안압계로측정한결과, 각각 14 mmhg이었다. 세극등현미경검사에서양안각막의아래쪽에점상의각막미란이관찰되었다. 거대속눈썹증이있었지만, 속눈썹이각막에닿지는않았다. 환자는비소세포폐암으로제넥솔과카보플라틴을사용중이었고, 우측폐의상엽에새로생긴종괴로 4개월전부터에를로티닙을사용하기시작한병력이있었다. 두시간마다양쪽눈에점안하도록무방부제인공누액을처방하였다. 종양내과의와상의후에를로티닙도 2주간중단하였다. 이후각막미란은모두호전되었고, 이는각막미란이표피성장인자수용체억제제에의해발생하였음을시사하는소견이었다. 에를로티닙치료를재개하자, 각막미란은재발하였고에를로티닙에의해발생한표층점상각막병증으로확진하였다. 이후에를로티닙중단없이양쪽눈에 2시간마다무방부제인공누액과자가혈청안약을점안하였고, 한달후각막미란은호전되었고, 불편증상도해소되었다 (Fig. 1A-D)

2 - 대한안과학회지 2014년 제 55 권 제 2 호 - A B C D Figure 1. Case 1 using erlotinib showed punctate epithelial erosions on the inferior halves of the cornea in both eyes at initial examinations (A: right eye, C: left eye). W ith preservative-free artificial tears and autologous serum eye drops, erosions nearly all disappeared (B: right eye, D: left eye). A B C D Figure 2. Case 2 showed diffuse punctuate keratopathy in both eyes after taking lapatinib for 6 months (A: right eye, B: left eye). After 3 month treatment, the erosions decreased (C: right eye, D: left eye)

3 - 오은규외 : 항암치료중발생한표층점상각막병증 - 특별한안과병력이없는 56세여자환자 ( 증례 2) 가며칠전부터시작된양쪽눈의이물감을주소로내원하였다. 환자는우측유방의침윤성관세포암종으로우측변형근치유방절제술을시행받고, 파클리탁셀 / 트라스투주맙병합치료를받은병력이있었다. 이후종양의간전이가발견되어 6개월전부터는라파티닙을투약하고있었다. 라파티닙을사용하기이전에본원에서안과검진을받은적이있었는데, 당시에는각막미란이없었다. 우안시력은 20/20, 좌안시력은 20/25이었다. 골드만편평압압계로측정한안압은양안각각 16 mmhg 이었다. 세극등현미경검사에서양안각막에미만성점상의각막미란이관찰되었다. 무방부제인공누액과자가혈청안약을두시간마다 2개월동안양쪽눈에점안한결과, 양안의미만성각막미란은큰변화없이비슷한정도로유지되었다. 마침총 36주의라파티닙치료가완료되어라파티닙은중단하고 4주간무방부제인공누액과자가혈청안약치료를지속하였다. 4주후시행한세극등현미경검사에서양안각막미란은감소하였고, 환자의주관적인불편감도해소되었다 (Fig. 2A-D). 결론 표피성장인자수용체억제제는전이된대장직장암, 유방암, 폐선암종, 두경부편평세포암등다양한종류의종양에널리쓰이는치료제이다. 1,2 표피성장인자수용체억제제가등장한이후에세툭시맙 3 과제페티닙, 10 에를로티닙이 4,8,10 거대속눈썹증이나안와주변발진을유발할수있고, 세툭시맙, 5 에를로티닙, 6 제페티닙 7 이각막미란을유발할수있으며, 세툭시맙 9 과에를로티닙 11 이흉터눈꺼풀겉말림을유발할수있다는것이보고되었다. 오직라파티닙만이아직까지안과적합병증이보고되지않은유일한표피성장인자수용체억제제이다. 표피성장인자는눈물샘에서분비되는데, 표피성장인자수용체는각막의기저상피세포, 각막윤부, 모낭초등에분포한다. 표피성장인자와표피성장인자수용체의결합은각막상피손상의회복과각막의항상성을유지하는데영향을미친다고알려졌다. 12 표피성장인자와표피성장인자수용체와의결합이각막상피회복을촉진하는신호전달체계도보고된바있다. 13 Förster et al 14 은세툭시맙사용에의한각막미란환자에서표피성장인자를점안하는것이각막상피의회복에도움이될수있다는내용을보고하였다. 에를로티닙은 human epidermal growth factor receptor type 1/epidermal growth factor receptor (HER1/EGFR) tyrosine kinase에선택적인길항제이다. 라파티닙은 intracellular tyrosine kinase domains of both Epidermal Growth Factor Receptor (EGFR [ErbB1]) 와 Human Epidermal Receptor Type 2 (HER-2 [ErbB2]) receptor에선택적인길항제이다. ErbB1 과 ErbB2는특히각막표면에많이존재하는데특히 ErbB2는각막상피세포의이동에중요한역할을담당한다고알려졌다. 15 그러므로 ErbB1과 ErbB2 의억제는각막상피세포의유지에큰영향을미칠것이고, 이는증례 2의치료기간이증례 1보다길었던이유가될수있을것이다. 두증례에서각막병증과안구불편감은표피성장인자수용체억제제치료를시작하고나서평균 5개월이후에발생하였다. 기존의보고에따르면표피성장인자수용체억제제치료의안과적합병증은표피성장인자수용체억제제치료를시작하고 3주에서 6개월사이에발생하는것으로보고되었는데, 3-10 이는피부나폐와같은다른장기에합병증이발생하는데소요되는시간과비슷하다. 16,17 피부발진은표피성장인자수용체억제제치료의가장흔한부작용이며대부분의경우, 치료를중단하고한달이내에해소되는것으로알려졌다. 16 피부발진의발생여부와피부발진의중증도는체내표피성장인자억제제의활성도와연관이되어있다. 18 증례 2 환자에서경과관찰중피부발진이발생하였는데, 이는체내에서표피성장인자억제제가피부발진을유발할만큼충분히활성화되어있었다는간접적인증거이다. 표피성장인자수용체억제제치료가종료되고한달후에피부발진과각막미란이함께호전되었다는점도표피성장인자수용체억제제치료와각막미란사이의연관성을시사한다. 본증례에서는각막상피세포의증식과이동을촉진시키기위해무방부제인공누액과자가혈청안약을사용하였다. 자가혈청안약치료는안구건조증에의한표층점상각막병증의치료방법으로대한민국식품의약품안전청의승인을받은치료방법이다. 자가혈청안약은환자의사전동의후에 ml의혈액을채혈하여 2500 rpm에서 10분간원심분리후, 무균조작으로혈청만취하여생리식염수에 20% 농도로희석하여제조하였다. 19 사람의혈청에는표피성장인자, 전환성장인자-베타, 혈소판유래성장인자, 비타민 A, 섬유결합소, 알부민, P물질이나인슐린성장인자같은신경전달물질이함유되어있다. 20,21 하지만이번증례에서는자가혈청안약에포함된표피성장인자가전신적인표피성장인자수용체억제제의효과를감소시켰다고보기는어려운데, 그이유는에를로티닙과라파티닙은세툭시맙처럼세포표면의표피성장인자수용체에직접작용하는것이아니라, 세포내에침투하여세포내신호전달과정을방해하기때문이다. 6,16 오히려비타민 A나섬유결합소와같은다른혈청성분이각막상피회복에영향을미쳤을것으로 295

4 - 대한안과학회지 2014 년제 55 권제 2 호 - 생각한다. 증례 1의경우, 에를로티닙에의해각막병증이발생할수있다는기존의연구를지지하는국내첫사례이기때문에보고의가치가있다. 증례 2를고려할때, 라파티닙도각막상피의회복을저해하는후보약물이될수있다. 이에저자들은표피성장인자억제제치료중발생한표층각막병증환자에서무방부제인공누액과자가혈청안약으로성공적으로치료한경험을보고하는바이다. 향후충분한수의환자를대상으로전향적인연구를통해표피성장인자억제제치료와표층각막병증의연관관계를밝히는후속연구가필요할것이다. REFERENCES 1) Modjtahedi H, Essapen S. Epidermal growth factor receptor inhibitors in cancer treatment: advances, challenges and opportunities. Anticancer Drugs 2009;20: ) Flynn JF, Wong C, Wu JM. Anti-EGFR therapy: mechanism and advances in clinical efficacy in breast cancer. J Oncol 2009;2009: ) Bouché O, Brixi-Benmansour H, Bertin A, et al. Trichomegaly of the eyelashes following treatment with cetuximab. Ann Oncol 2005;16: ) Papadopoulos R, Chasapi V, Bachariou A. Trichomegaly induced by erlotinib. Orbit 2008;27: ) Foerster CG, Cursiefen C, Kruse FE. Persisting corneal erosion under cetuximab (Erbitux) treatment (epidermal growth factor receptor antibody). Cornea 2008;27: ) Johnson KS, Levin F, Chu DS. Persistent corneal epithelial defect associated with erlotinib treatment. Cornea 2009;28: ) Tullo AB, Esmaeli B, Murray PI, et al. Ocular findings in patients with solid tumours treated with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) in Phase I and II clinical trials. Eye (Lond) 2005;19: ) Methvin AB, Gausas RE. Newly recognized ocular side effects of erlotinib. Ophthal Plast Reconstr Surg 2007;23: ) Garibaldi DC, Adler RA. Cicatricial ectropion associated with treatment of metastatic colorectal cancer with cetuximab. Ophthal Plast Reconstr Surg 2007;23: ) Zhang G, Basti S, Jampol LM. Acquired trichomegaly and symptomatic external ocular changes in patients receiving epidermal growth factor receptor inhibitors: case reports and a review of literature. Cornea 2007;26: ) Frankfort BJ, Garibaldi DC. Periocular cutaneous toxicity and cicatricial ectropion: a potential class effect of antineoplastic agents that inhibit EGFR signaling. Ophthal Plast Reconstr Surg 2007; 23: ) Nakamura Y, Sotozono C, Kinoshita S. The epidermal growth factor receptor (EGFR): role in corneal wound healing and homeostasis. Exp Eye Res 2001;72: ) Lyu J, Lee KS, Joo CK. Transactivation of EGFR mediates insulin-stimulated ERK1/2 activation and enhanced cell migration in human corneal epithelial cells. Mol Vis 2006;12: ) Förster CG, Cursiefen C, Kruse FE. [Topical application of EGF for the therapy of persisting corneal erosion under cetuximab treatment]. Ophthalmologe 2008;105: ) Xu KP, Riggs A, Ding Y, Yu FS. Role of ErbB2 in corneal epithelial wound healing. Invest Ophthalmol Vis Sci 2004;45: ) Li T, Perez-Soler R. Skin toxicities associated with epidermal growth factor receptor inhibitors. Target Oncol 2009;4: ) Ricciardi S, Tomao S, de Marinis F. Toxicity of targeted therapy in non-small-cell lung cancer management. Clin Lung Cancer 2009; 10: ) Peréz-Soler R, Saltz L. Cutaneous adverse effects with HER1/ EGFR-targeted agents: is there a silver lining? J Clin Oncol 2005;23: ) Tsubota K, Goto E, Fujita H, et al. Treatment of dry eye by autologous serum application in Sjögren's syndrome. Br J Ophthalmol 1999;83: ) Matsumoto Y, Dogru M, Goto E, et al. Autologous serum application in the treatment of neurotrophic keratopathy. Ophthalmology 2004;111: ) Kojima T, Higuchi A, Goto E, et al. Autologous serum eye drops for the treatment of dry eye diseases. Cornea 2008;27 Suppl 1: S

5 - 오은규외 : 항암치료중발생한표층점상각막병증 - =ABSTRACT= Superficial Punctate Keratoepitheliopathy Under Treatment with Erlotinib and Lapatinib Eun Kyu Oh, MD 1,2, Dong Hyun Jo, MD 1,2, Mee Kum Kim, MD, PhD 1,2, Won Ryang Wee, MD, PhD 1,2 Department of Ophthalmology, Seoul National University College of Medicine 1, Seoul, Korea Seoul Artificial Eye Center, Seoul National University Hospital Clinical Research Institute 2, Seoul, Korea Purpose: To report the corneal superficial punctate keratoepitheliopathy in 2 patients taking the epidermal growth factor receptor (EGFR) inhibitors, erlotinib and lapatinib, respectively. Case summary: Case 1, who received erlotinib, showed trichomegaly without touching the cornea and diffuse punctate keratoepitheliopathy. Corneal epitheliopathy and the corresponding symptoms resolved after discontinuation of the drug then recurred with reapplication. Case 2 presented diffuse corneal punctate epithelial erosions that developed without any cilia involvement after the patient was administered lapatinib. The visual acuity of both patients was not severely diminished and keratoepitheliopathy was mostly resolved with the treatment of preservative-free artificial tears and autologous serum eye drops. Conclusions: Erlotinib and lapatinib are both likely to cause visually tolerable corneal punctate keratoepitheliopathy which can be resolved with appropriate topical treatment. J Korean Ophthalmol Soc 2014;55(2): Key Words: Cancer treatment, Corneal erosion, Epidermal growth factor Address reprint requests to Mee Kum Kim, MD, PhD Department of Ophthalmology, Seoul National University Hospital #101 Daehak-ro, Jongno-gu, Seoul , Korea Tel: , Fax: , kmk9@snu.ac.kr 297

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<31382D30312D303628BCDBC1BEBCAE2DB3AAB0C7C8C E687770> 대한안과학회지 2014 년제 55 권제 6 호 J Korean Ophthalmol Soc 2014;55(6):908-912 pissn: 0378-6471 eissn: 2092-9374 http://dx.doi.org/10.3341/jkos.2014.55.6.908 Case Report 항암치료를위해사용된표피성장인자수용체억제제로유발된긴속눈썹증 2 예 Paradoxical