Case Report Ewha Med J 2013;36(S):S17-S21 http://dx.doi.org/10.12771/emj.2013.36.s.s17 pissn 2234-3180 eissn 2234-2591 Gefitinib 에의해유발된방사선회귀피부염 강버들, 임아영, 김영재, 황의동, 윤유정, 김선욱, 김효송 연세대학교의과대학내과학교실 Beodeul Kang, Ah Young Leem, Young Jae Kim, Eudong Hwang, Yujung Yun, Sun Wook Kim, Hyo Song Kim Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea Radiation recall dermatitis refers to an acute inflammatory reaction in a previously irradiated field triggered by the administration of certain drugs days to years after the exposure to radiation. Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor and is an effective treatment for patients with advanced stage of non small cell lung cancer (NSCLC). Here, we report a rare case of gefitinib induced radiation recall dermatitis. A 52-year-old woman with a metastatic NSCLC had received a palliative radiation therapy of 20 cgy on spine metastasis area (C6-T6). After 24 days of receiving radiation therapy, she had started to take gefitinib. Eight months after taking drug, pain, swelling and erythema of skin were occurred on previously irradiated field. These symptoms were resolved after the cessation of gefitinib for 6 days and the topical use of steroid. (Ewha Med J 2013;36(Suppl):S17-S21) Received August 5, 2013 Accepted August 26, 2013 Corresponding author Hyo Song Kim Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, 50, Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea Tel: 82-2-2228-6661, Fax: 82-2-2227-7870 E-mail: hyosong77@yuhs.ac Key Words Gefitinib; Lung cancer; Radiation recall dermatitis; Radiation therapy 서론방사선회귀피부염 (radiation recall dermatitis, RRD) 은특정약물을투여하면서발생하는피부의염증반응의일종으로이러한반응이이전에방사선조사를받은부위에국한되어나타나는현상을의미한다. RRD 는현재까지정확한발생률이알려져있지않으며, 주로정맥으로투여되는항암제, 예를들어 actinomycin-d [1], adriamycin [2,3], paclitaxel [4,5], docetaxel [6], vincristine [7], bleomycin [8], gemcitabine [9] 등에의해발생된증례가보고되었고, 이외에경구약으로 simvastatin [10], tamoxifen [11], 항결핵제 [12] 등도유발시킬수있다고알려져있다. 최근종양학분야에서기존의세포독성항암제뿐만아니라표 적치료제의사용이증가하고있으며, 표적치료제의적응증및사용기간이늘어나면서이와관련된합병증에대한연구가다양하게진행되고있다. Gefitinib 은종양세포의표피성장인자수용체 (epidermal growth factor receptor, EGFR) 의티로신키나아제억제제 (tyrosine kinase inhibitor, TKI) 로현재 EGFR 돌연변이가있는진행성비소세포폐암의 1차치료및 EGFR 돌연변이가없는진행성, 전이성비소세포폐암의 2차및 3차치료제로사용되고있는약제이다. EGFR TKI 는종양세포뿐만아니라정상피부에도작용하여구진, 농포성발진, 피부건조증, 조갑주위염등이상반응을일으키는것으로알려져있다 [13-15]. 저자들은 gefitinib 복용중일반적인피부이상반응이아닌국내외적으로보고가드문방사선치료후 gefitinib 복용중기존에방사선조사를받았던부위에발생한 RRD 증례를경험하여문헌고 S17
Kang B, et al 찰과함께보고한다. 증례 52 세여자가내원 3주전부터의흉벽, 등, 둔부통증으로타병원에서시행한전신뼈스캔 (whole body bone scan) 에서이상소견보여본원전원되었다. 과거력에서특이질환은없었으며사회력상흡연, 음주력은없었다. 입원당시활력징후는안정적이었고신체검사에서양측경부림프절 IV 번위치에압통을동반하지않은림프절종대가있었다. 종양표지자는 CEA 6,686.5 ng/ml, CYFRA 21-1 104.8 ng/ml, squamous cell carcinoma antigen 0.7 ng/ml 이었다. 양전자방출전산화단층촬영 (positron emission tomography-computed tomograpy) 상좌하엽에 1.1 cm 크기의 fluorodeoxyglucose 섭취를보이는종괴가발견되었고, 왼쪽종격동, 기관분기부하부, 흉부대동맥주위, 양측하부기관옆림프절, 기관앞림프절, 양측경부 IV 번림프절, 왼쪽위, 온간동맥주위, 대동정맥및왼쪽대동맥옆림프절전이소견보였으며, 경추, 흉추, 요추, 천골, 양측흉곽, 흉골, 양측견갑골, 골반뼈, 대퇴골의뼈전이소견보였다. 다발성골수종을배제하기위해시행한골수검사에서골수를침범한전이성샘암진단되었으며면역화학염색결과 thyroid transcription factor-1 양성소견보였다. 또한왼쪽경부림프절흡인검사상에서도전이성샘암소견보였다. 비소세포폐암, 샘암, ct4n3m1b, 4기진단후통증조절을위해요추 4번-천골, 오른쪽장골과대퇴골에 4회에걸쳐총 19 Gy 의방사선치료 (2012.1.17~1.20) 시행받았으며이후 2012 년 1월 20 일부터 3주간격으로 2차례완화적요법의 paclitaxel (175 mg/ BSA)/carboplatin (AUC5) 항암치료시행하였다. 이후골반부위통증지속및골용해성병변으로인한골절가능성높아 2012 년 3월 2일양측예방적내부고정및골수내고정술 (internal fixation with intramedullary nailing) 시행받았다. 이후 3~6차 paclitaxel/carboplatin 항암치료 (2012.3.17~6.7) 시행후갑자기발생한경추부위통증있어시행한전신척추 magnetic resonance imaging (MRI) 상뼈전이악화소견보여 C6~T6까지 5회에걸쳐총 20 Gy 방사선치료 (2012.7.24~7.30) 시행받았다. 이후갑작스런하지무력감, 보행장애악화소견보여시행한 MRI 상압박골절진행소견보여 2012 년 8월 2일응급으로감압후궁절제술 C7-T1-T2, 척추경나사고정술 C7-T2-T3-T4-T5 시행하였다. 이후증상호전되어 2번째완화적전신화학요법으로 gefitinib (250 mg, daily, 2012.8.17~) 복용시작하였다. 약제복용하며외래경과관찰중 2012.9 월초부터두경부및흉부의여드름양발진 (acneiform eruption) 으로불편감호소하여피부과외래서국소도포스테로이드연고및항히스타민제복용하고증상호전되었다. Gefitinib 복용후폐암병변부위악화소견없이안정적인상태유지되어약제유지중 2013 년 4월초부터방사선치료받았던부위의발적, 열감, 통증증상있어봉와직염감별위해입원하였다. 병변부위자외선노출력은없었으며신체검진에서하부경추부터상부흉추까지열감과동통을동반한홍반성부종소견을보였으며 (Fig. 1), 다른피부부위의이상반응은없었다. 당시혈압 110/70 mmhg, 맥박 84 회, 체온 36.8 o C 측정되었으며말초혈액검사상혈색소 11.4 g/dl, 백혈구 7,150/mm 3, 혈소판 197,000/ mm 3, ESR 10 mm/hr, CRP 7.0 mg/l 였다. 병변부위의감염여부확인위해 whole spine MRI 검사시행하였다. MRI 상에서는하 Fig. 1. (A) Erythema on upper back area (previously irradiated area). (B) Magnification of upper back area. S18
Fig. 2. Skin thickening and localized edema of lower cervical and upper thoracic area. There are no definite evidence of cellulitis (gadolinium enhanced T1 weighted sagittal magnetic resonance imaging). 부경추와상부흉추의국소적인피부부종은있으나봉와직염소 견은보이지않았다 (Fig. 2). 혈액검사및 MRI 검사상 RRD 가의 심되어 gefitinib 중단및국소도포스테로이드연고사용후발적, 열감, 통증증상호전되어약제중단 6 일후다시 gefitinib 복용시 작하였고, 복용후 RRD 재발소견없이현재까지약제유지하며 외래경과관찰중이다. 고찰 RRD 를일으키는기전은명확하게밝혀지지않았지만다음과 같은다양한가설이제시되고있다. 첫번째로방사선치료의영 향으로피부의국소적인혈관투과성및증식성의변화가발생하 여그로인해특정약제의약동학적변화로 RRD 가유발된다는 가설이다 [11]. 두번째로방사선을받았던부위의표피줄기세포 (epithelial stem cell) 의감소및증식능력이저하된상태에서약 물주입시발생하는추가적인손상을극복할수없어 RRD 가발생 한다는가설이다 [16,17]. 또한방사선조사부위의표피줄기세포 의 DNA 염기서열돌연변이발생으로특정약제민감성이증가하 여발생할수있다는의견도제시되고있다 [18]. 세번째로약제에 처음노출시발생하며반응속도를고려하였을때비면역학적염 증반응으로인한약제과민반응으로 RRD 가발생한다는주장이 있다 [19,20]. 이는방사선치료로인해 cytokine 이지속적으로분 비되는상태에서원인약제에의해 cytokine 분비가증폭되어발 생된다는가설이다 [21]. RRD 의임상양상은발적, 가려움증, 건성표피박리, 통증, 부 종, 두드러기양병변, 수포, 괴사, 궤양, 출혈등다양한양상으로나타난다. Camidge 와 Price [22] 의중증도분류를이용하여경중도를나누면이증례의경우통증과부종을동반한발적이나타나는 2단계의병변이관찰되었다. 방사선조사와약물복용후 RRD 발생까지의간격은증례마다다양하게보고되고있으며방사선치료종료수일후부터가장간격이긴경우는 15 년뒤에 RRD 가발생한경우가있었다 [23]. RRD 가발생할수있는방사선조사량은 10 Gy 에서 61.2 Gy 까지보고되었으며 [22], 방사선조사량과 RRD 증상의중증도와는의미있는상관관계는밝혀지지않았다. 본증례에서는 2차례방사선치료가시행되었다. Gefitinib 복용 7개월전에 19 Gy 의방사선조사를받았던부위에는영향이없었으나 gefitinib 복용 24 일전에 20 Gy 의방사선조사를받았던부위에서 RRD 가발생하였다. 기존의 Fontana [24] 의증례와유사하게누적방사선조사량보다는방사선조사로부터 RRD 유발약제투여시점이증상발생에유의한영향이있을수있음을예측할수있었다. 약물복용후 RRD 증상이발생하는시간은정맥주사제제는투여후수분에서 14 일까지 ( 평균 3일 ), 경구제제는정맥주사제제보다늦게발생하며보통투여후 3일에서 2달까지 ( 평균 8일 ) 나타나는것으로보고되어있다 [22]. 본증례에서는 gefitinib 투여시작후 8개월후에방사선조사부위에 RRD 가발생한경우로기존에보고된발생시점보다늦게발생하였다. 이에대한원인으로는 gefitinib 복용초기두경부및흉부의여드름양발진으로인해투여했던국소스테로이드연고와항히스타민제에의해증상이두드러지게나타나지않았다가피부증상이호전되어약제복용을중단하면서악화되었을가능성및아직명확하게밝혀지지않은 EGFR TKI 의약물대사와관련되었을가능성도고려할수있다. RRD 반응이늦게나타났던원인에대해서는향후더많은 gefitinib 에의한 RRD 또는 EGFR TKI 에의한 RRD 증례고찰을통해규명해야할것으로생각된다. 현재까지국내외적으로 gefitinib 복용후발생한 RRD 는보고된바는없지만, 유사한기전을가진 EGFR TKI 인 erlotinib 복용후 RRD 가발생한예는 2009 년 Dauendorffer 와 Dupuy [25] 가보고했던유방암방사선치료후 9년뒤 Erlotinib 복용후발생한 1 예가있었으며, 국내에서는 2010 년 Kim 등 [26] 이보고했던폐암으로방사선치료후 1년 3개월뒤 erlotinib 복용후발생한 1 예가있었다. RRD 의치료는유발약제중단및증상에따라국소혹은전신스테로이드제사용과항히스타민제로소양증조절이필요하다. 자연치유가가능하지만중증도가심할경우수포, 괴사, 궤양까지발생가능하므로이차적인감염이발생하지않도록주의가필요하다. Camidge 와 Price [22] 의논문에따르면 RRD 를유발했던약물 S19
Kang B, et al 을재투약했었던 15 증례에서 5 증례는 RRD 가재발하지않았고, 10 증례가증상재발을경험하였으나미약한정도로나타났다. 이 렇게재투여후증상재발이발생하지않거나미약한원인으로는 방사선조사로민감해진표피줄기세포가파괴되어 RRD 를일으 키게되고다시약물투여시약제에민감했던표피줄기세포가파 괴되었거나수가감소하여반응이미약하거나일어나지않는다는 의견이제시되고있다 [27]. 본증례의경우기존의 erlotinib 에의 한 RRD 증례 [25,26] 와유사하게증상호전후 gefitinib 을재투 여하였을때증상재발은발생하지않았다. 폐암의경우원발병변뿐만아니라전이부위에방사선치료가 동반되는경우가많으며, 다양한적응증으로 gefitinib 을치료약 제로사용하는빈도가높다. Gefitinib 사용시발생하는피부이 상반응은외국의경우 68~75% 로보고되었으며 [13], 국내에서 도 56~65% 로보고되었다 [15]. Gefitinib 에의한피부부작용정 도와치료효과가연관됨이보고되어피부부작용을간과하는경 우가있으나피부부작용이조절되지않을경우이로인한치료 순응도가저하되어생존율에영향을끼친다는보고가있다 [28]. Gefitinib 으로인한 RRD 역시치료순응도를저하시킬수있는심 각한증상을유발할수있으므로기존의방사선치료부위에나타 나는가역적피부반응이며증상호전후약물재투여시증상재발 이경미하거나없을수있음을인지시키고순응도를높일수있도 록하는노력이필요하다. 또한외국의경우 erlotinib 에의한치명 적인방사선회귀폐렴 (radiation recall pneumonitis) 증례가수회 보고된바있으며 [29-31], gefitinib 역시일본에서방사선회귀폐 렴 1 예보고된바있으므로 [32] 방사선치료후 EGFR TKI 를사 용한경우에는더욱주의깊은관찰이필요하다. 본증례는방사선치료후 gefitinib 복용중발생한 RRD 에대한 국내첫보고이며, 최근폐암치료에사용이증가되고있는 EGFR TKI 약제사용시주의가필요한증상으로생각하여기존문헌고 찰과함께보고하는바이다. 참고문헌 1. D'angio GJ. Clinical and biologic studies of actinomycin D and roentgen irradiation. Am J Roentgenol Radium Ther Nucl Med 1962;87:106-109. 2. Donaldson SS, Glick JM, Wilbur JR. Letter: adriamycin activating a recall phenomenon after radiation therapy. Ann Intern Med 1974;81:407-408. 3. Etcubanas E, Wilbur JR. Letter: uncommon side effects of adriamycin (NSC-123127). Cancer Chemother Rep 1974;58:757-758. 4. Schweitzer VG, Juillard GJ, Bajada CL, Parker RG. Radiation recall dermatitis and pneumonitis in a patient treated with paclitaxel. Cancer 1995;76:1069-1072. 5. Raghavan VT, Bloomer WD, Merkel DE. Taxol and radiation recall dermatitis. Lancet 1993;341:1354. 6. Camidge DR, Kunkler IH. Docetaxel-induced radiation recall dermatitis and successful rechallenge without recurrence. Clin Oncol (R Coll Radiol) 2000;12:272-273. 7. Nemechek PM, Corder MC. Radiation recall associated with vinblastine in a patient treated for Kaposi sarcoma related to acquired immune deficiency syndrome. Cancer 1992;70:1605-1606. 8. Stelzer KJ, Griffin TW, Koh WJ. Radiation recall skin toxicity with bleomycin in a patient with Kaposi sarcoma related to acquired immune deficiency syndrome. Cancer 1993;71:1322-1325. 9. Castellano D, Hitt R, Cortes-Funes H, Romero A, Rodriguez- Peralto JL. Side effects of chemotherapy. Case 2. Radiation recall reaction induced by gemcitabine. J Clin Oncol 2000;18:695-696. 10. Abadir R, Liebmann J. Radiation reaction recall following simvastatin therapy: a new observation. Clin Oncol (R Coll Radiol) 1995;7:325-326. 11. Bostrom A, Sjolin-Forsberg G, Wilking N, Bergh J. Radiation recall--another call with tamoxifen. Acta Oncol 1999;38:955-959. 12. Extermann M, Vogt N, Forni M, Dayer P. Radiation recall in a patient with breast cancer treated for tuberculosis. Eur J Clin Pharmacol 1995;48:77-78. 13. Kris MG, Natale RB, Herbst RS, Lynch TJ Jr, Prager D, Belani CP, 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. 14. Park JH, Oh JJ, Choi YL, Kim WS, Lee JH, Lee ES. Cutaneous adverse effects associated with Iressa(R)(Gefitinib) medication. Korean J Dermatol 2005;43:92-95. 15. Jang YH, Choi JH, Lim HY, Lee ES. Study of clinical features of cutaneous side effects associated with ZD 1839. Korean J Dermatol 2005;43:22-28. 16. Hellman S, Botnick LE. Stem cell depletion: an explanation of the late effects of cytotoxins. Int J Radiat Oncol Biol Phys 1977;2:181-184. 17. Seymour CB, Mothersill C, Alper T. High yields of lethal mutations in somatic mammalian cells that survive ionizing radiation. Int J Radiat Biol Relat Stud Phys Chem Med 1986;50:167-179. 18. Phillips TL, Fu KK. Quantification of combined radiation therapy and chemotherapy effects on critical normal tissues. Cancer 1976;37(2 Suppl):1186-1200. 19. Wintroub BU, Stern R. Cutaneous drug reactions: pathogenesis and clinical classification. J Am Acad Dermatol 1985;13(2 Pt 1):167-179. 20. Vozenin-Brotons MC, Gault N, Sivan V, Tricaud Y, Dubray B, Clough K, et al. Histopathological and cellular studies of a case of cutaneous radiation syndrome after accidental chronic exposure to a cesium source. Radiat Res 1999;152:332-337. 21. Johnston CJ, Piedboeuf B, Rubin P, Williams JP, Baggs R, Finkelstein JN. Early and persistent alterations in the expression of interleukin-1 alpha, interleukin-1 beta and tumor necrosis factor S20
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