폐암에서광역동치료술의효과 조선대학교의과대학내과학교실윤성호, 한경택, 김경남, 이승일 Effect of Photodynamic Therapy in Lung Cancer Sung Ho Yoon, M.D., Kyung Taek Han, M.D., Gyung Nam Kim, M.D., Seung Il Lee, M.D. Department of Internal Medicine, Chosun University, College of Medicine, Gwangju, Korea Background : Photodynamic therapy (PDT) involves the use of photosensitizing agents for treatment of malignant disease. PDT is approved by the U.S. Food and Drug Administration for the endobronchial microinvasive nonsmall cell lung cancer and for palliation in patients with obstructing tumors. We report our experience and results of PDT in lung cancer. Method : Ten patients with lung cancer who were diagnosed in Chosun university hospital by histologic confirm through bronchoscopy were included between August 2002 and May 2003. The photosensitizer (Photogem R, Lomonosov institute of Fine Chemical, Russia/ dose 2.0 mg/kg body weight) was injected 48 hours prior to the PDT session. For PDT with the photosensitizer (Photogem R ), Diode LASER system (Biolitec Inc., Germany, wavelength; 633nm) were used. PDTs were done at 48-72 hours after photogem injection. Follow up bronchoscopy and chest X-ray or thorax computerized tomography were done for evaluate PDT response. Results : 9 of 10 patients with endobronchial obstruction showed partial remission with bronchus opening after PDT. Direct reaction of the tumor to PDT was similar in despite of its localization. It was as follows; edema, hyperemia, in-situ bleeding, fibrin film occurrence. Any other complications such as sunburns of skin, inflammation within the PDT zone were not occurred by the end of the fourth week. Conclusion : In the advanced endobronchial disease, PDT has been shown to be useful in treating endobronchial tumors that are causing clinically significant dyspnea or are likely to progress and lead to further clinical complications, such as postobstructive pneumonia. (Tuberc Respir Dis 2004; 57:358-363) Key words : Lung cancer, Photodynamic therapy (PDT), Palliation. 서 광역동치료 (Photodynamic therapy; PDT) 는악성질환을치료하기위해정맥주사를통해종양내에잔류하는광과민물질을사용하며, 이물질은특수한파장의광선에노출되기전까지는불활성상태이나, 광노출에의해활성화되면독성의산소유리기를만들고, 그결과종양세포는괴사에이른다. 광역동치료는 1900 년대초반피부암을치료하기위 이논문은 2003 년도조선대학교학술연구비의지원을받아연구되었음. Address for correspondence : Seung Il Lee, M.D. Department of Internal Medicine, Chosun University, College of Medicine 375, Seosuk-dong, Dongu, Gwangju, Republic of Korea Phone : 062-220-3053 Fax : 062-234-9653 E-mail : drdbs@chosun.ac.kr Received : Mar. 26. 2004. Accepted : Aug. 24. 2004. 론 해사용되었으며, 여러광과민물질이만들어지고, 그중에서 hematoporphyrin이악성세포에선택적으로축적되고잔류하는것이알려지면서, 다양한 hemato porphyrin 유도체가연구되고, 이들이주로선암및편평상피암에서많이축적된다고밝혀졌다 1,2. 이러한물질들은이후유방암, 방광암및여러종류의암에서사용되었다. 이들연구 3,4 는광역동치료의기전에세포막손상, 산소의전달, 그리고, 면역및혈관계통의역할이관여한다고밝히고있다. 폐암에서 porfimer sodium (Photofin) 을이용한광역동치료는미세침습성비소세포폐암및기관지폐쇄를일으키는악성종양에대한기관지내치료를미국식품의약국 (FDA) 에서승인한상태이다 5. 국내에서는폐암세포주에대한보고 6 외에폐암에대한광역동치료연구가많지않아임상성적에대한보고가없어이에저자들은폐암에서시행된광역동치료에대한결과를문헌고찰과함께보고하고자한다. 358
Tuberculosis and Respiratory Diseases Vol. 57. No. 4, Oct, 2004 대상및방법 2002년 8월부터 2003년 5월까지조선대학교병원에서기관지내시경을통해조직학적으로진단된비소세포폐암환자중폐쇄성기관지폐렴을보인 10명을대상으로하였다. 대상환자는 10명모두남자이었으며, 연령은평균 63.8±8.8세이었다. 광과민제는 Photo frin 계열 (Photogem R, Lomonosov institute of Fine Chemical, Russia), 광원은 Diode LASER (Biolitec Inc., Germany, wavelength; 633nm) 을사용하였다. 광과민제 2.0 mg/kg 을정맥주사후 48시간, 72시간에기관지내시경을통한광역동치료를시행하였다. 기관지내시경은리도카인을이용한국소마취를시행한후경구로시행하였으며, 기관지내시경을통해원통형광섬유를병변부위에밀착시켜 Diode LASER를조사하였다. 폐암에서사용되는에너지조사량은 5 0~500 J/cm 2 를사용한다 7. 본연구에서는에너지조사량은 150 J/cm 2 을사용하였다. 추적기관지내시경은 1개월째에시행하였고, 이후에는흉부방사선촬영또는흉부전산화단층촬영을시행하였다. 광과민제에의한합병증중가장흔한일광화상을예방하기 위해광과민제를투여한후퇴원전까지는병실에서자연광에대한차폐를하였으며, 4주까지는외출을삼가고, 외출시는모자착용, 자외선차단용크림도포및선글라스를착용토록하였다. 광역동치료의효과판정을위해저자들은 Okunaka 등 8 이사용했던방법으로조직검사혹은세포진검사에서종양이관찰되지않는경우를완전관해로, 종양의용적이 50% 이상감소하였으나조직검사에서는암세포가지속되는경우를부분관해로정의하였다. 결과조직학적으로 10예모두비소세포폐암 ( 편평상피세포암 9예, 선암 1예 ) 이었으며, 병기는 IIIA가 3예, IIIB 가 4예, 그리고 IV는 3예이었다. 환자의평균추적기간은 7.6±3.9개월이었다. 추적과정중 4명이병의진행으로사망하였다. 10명의기관지폐쇄환자중 9예에서부분관해와함께기관지개통을보였으며, 1예에서는변화를보이지않았다 (Table 1). 광역동치료에대한부작용으로는광과민제의광독성으로일광화상이발생할수있으나모든환자에서 Table 1. Patients characteristics and PDT results Case Age Sex Histology Location Diffuser Energy dose (power, duration) F/U(Mo) Stage Current Status 1 62 M Squamous RUL 2cm 800mw, 500sec 15 IIIA Alive PR 2 64 M Squamous. 3 50 M Squamous Carina Rt. main Bronchus intermedius Result 4cm 1600mw, 500Sec 6 IIIB Died PR 2cm 1000mw, 400sec 4 IV Died PR 4 80 M Adeno Bronchus intermedius 4cm 400mw, 1000sec 12 IIIB Alive PR 5 61 M Squamous. RUL 2cm 800mw, 500sec 3 IV Died PR 6 62 M Squamous. LLL 2cm 1000mw, 400sec 5 IIIB Died PR 7 55 M Squamous Bronchus intermedius 4cm 400mw, 1000sec 11 IIIB Alive PR 8 60 M Squamous Lt. main 2cm 800mw, 500sec 8 IV Alive NR 9 73 M Squamous. Rt. main 3cm 1200mw, 500sec 6 IIIA Alive PR 10 71 M Squamous. LLL 2cm 800mw, 500sec 6 IIIA Alive PR Mean age : 63.8±8.8 years(mean±s.d), Mean follow up : 7.6±3.9 months(mean±s.d). Squamous : squamous cell carcinoma, Adeno : adenocarcinoma, Rt. : right, Lt. : left, RUL : Right upper lobe, LLL : Left lower lobe, PR : partial remission, NR : not respond. 359
SH Yoon, et al.: Effect of photodynamic therapy in lung cancer A B Figure 1. A case of bronchial obstruction with hypoxemia after PDT-Bronchoscopic changes after PDT. Before photodynamic therapy (A) ; endobronchial mass in right main bronchus and near complete obstruction of bronchus intermedius is seen. After photodynamic therapy (B) ; Necrotic tissue and more opened bronchus intermedius is seen. 관찰되지않았다. 광역동치료후추적검사로시행된내시경에서관찰되는종양의반응은부종, 발적, 광노출부위의출혈, 그리고, 괴사로인한섬유조직의증가를관찰할수있었다. 고찰광과민제의임상적사용은폐암의조기진단및위치확인, 상피내암종의치료, 기관지내진행성암종의치료에이용되고있다. 상피내암종의치료는광역동치료의중요한적용분야이며, 약간은비침습적이고, 선택적인종양에대한파괴능력, 폐기능을유지할수있고, 2차적인원발종양이발생할수있는환자군에서반복적으로검사를시행할수있다는점에서강점을보인다. 상피내암및 IA 병기에서치료결과로는 Edell 등 9 에의한보고에서는 7~49개월추적한상피내암종 77% 에서재발이없었고, Kato 등 10 은병변의장경이 1.0cm 이내에서는 94.2% 에서완전관해를보였고, 2.0cm 이상의병변에서는 37.5% 의완전관해율을보였으며, 5년생존율은 68.4% 에이른다고보고하였다. 상피내암종에비해보다많은빈도를보이는진행성기관지암의경우현재까지사용가능한치료방법에는 Nd-YAG LASER 절제가주로이용되고있으 며, 그외방법으로방사선치료, 근접방사선치료, 냉동요법및전기소작등이이용되고있다. 수술이불가능한기관지폐쇄를동반한 IIIA~IV기폐암환자 100명에서시행된전향연구에서광역동치료결과는기관지폐쇄기간, 폐기능및증상호전을현저히개선시켰다고보고하였다 11. McCaughan 등 12 의연구에서광역동치료전 84% 의환자에서기관지폐쇄가관찰되었고, 4주후이들중 18% 에서기관지폐쇄가호전됨을보고하였다. 이러한결과들에서광역동치료는진행성기관지폐쇄에서완화치료로써사용될수있다고판단된다. 광역동치료를다른치료방법과비교한연구는 Lam 등 13 은, 진행성기관지폐쇄를가진 41명의환자를대상으로방사선단독치료와방사선치료에광역동치료를병행했던군에서기관지개통이각각 10% 와 70% 로현저한개선을보고하였다. Moghissi 등 14 은광역동치료와 Nd-YAG LASER를비교하였던결과에서 III병기수술불가능환자 26명을대상으로전향연구를시행한결과 1개월후기관지폐쇄가 Nd- YAG LASER에서 39.1% 광역동치료술에서 17% 를보여광역동치료군에서더나은기관지폐쇄개선을보였다. 유럽과미국에서시행된다기관전향적무작위시험에서부분적인폐쇄를보이는폐암환자 211명을대상으로광역동치료와 Nd-YAG LASER를비교 360
Tuberculosis and Respiratory Diseases Vol. 57. No. 4, Oct, 2004 A B C Figure 2. Radiologic changes of patient after PDT. A; Chest PA on admission-right upper lobe atelectasis is seen. B; Chest AP after PDT 12 hours Right lung atelectasis and endobronchial intubation in situ is seen. C; Chest PA after PDT 48 hours Right lung atelectasis is improved. 한결과에서반응율이 1주에는차이가없었으나 1개월에는광역동치료군이 Nd-YAG 군보다나은결과를보였다 ( 유럽 61%; 36%, 미국 42%; 19%). 조직검사를통한완전관해를확인하였을때역시광역동치료군이 Nd-YAG 군보다나은결과를보였다 ( 유럽 12%; 3%, 미국 6%; 5%) 15. Diaze-Jimenez 등이시행한연구에서도광역동치료가 Nd-YAG LASER에비해증상의개선및생존기간에서이득이있다는보고를하였다,16. 이상의연구에서제한적인결과이지만광역동치료는 Nd-YAG와대등한효용성을가지고있으며, 방사선단독치료보다는우수한결과를보이고있다. 광역동치료는기관내종양에는효과적이나외부에서압박하거나점막하부의종양의경우는효과가떨어지며, Nd-YAG, 냉동요법및전기소작에서도같은결과를보여이러한경우에는스텐트가효과적이다. 광역 동치료의반응은 Nd-YAG에비해느리며, 심각한종양괴사와점액증가로기관지폐쇄를일으킬수있고, 심각한기관협착이있는경우에는기도폐쇄및호흡부전을초래할수있어 Nd-YAG LASER를먼저사용하고, 필요한경우광역동치료술이나방사선치료를추가하는것이도움이된다. 본연구에서 1예에서 PDT 후 12시간경과하여우측주기관지폐쇄로저산소혈증이발생하여기계호흡을시행하였으며, 광역동치료 48시간경과하여기관지내시경을통해괴사조직을제거한후기관지개통이이루어져기계호흡이탈을할수있었다 (Fig. 1, 2). 조기에발견된경우심폐기능이좋은환자에서는수술을우선적으로고려할수있으나다른병존질환특히만성폐쇄성폐질환을가진환자중 FEV 1 이 1L 이하에서는수술을시행하지못하는경우가있을수 361
SH Yoon, et al.: Effect of photodynamic therapy in lung cancer 있다 17. 이러한측면에서광역동치료가효과적인치료법으로고려될수있다. Cortese 등 18 은 21명 ( 병변수 23) 의편평상피암조기암환자에서광역동치료를시행하여 71.4% 에서완전관해를보였고, 광역동치료에추가적으로항암화학요법또는방사선치료혹은병합치료로평균 68개월동안무병생존할수있다고보고하였다. 본연구중 1예에서최초기관지내시경에서우측중간기관지의완전폐쇄를보였고, 광역동치료후 4주에시행한기관지내시경검사에서부분관해로판단하였고, Taxane 및 platinum 병용항암화학요법을 4회시행후흉부전산화단층촬영에서종괴의소실이확인되어기관지내시경검사를통해종괴는관찰되지않았고, 이전에종괴가위치했던곳에서시행한조직검사에서섬유화조직외에암세포는관찰되지않았다. 저자들이시행하였던 10예에서 1예가광역동치료후항암화학요법을추가하여기관지내시경및흉부전산화단층촬영을통해확인한결과완전관해를보였고, 기관지폐쇄를보였던모든환자중 9예에서기관지개통을보여기관지폐쇄로인한호흡곤란및기관지폐쇄와관련된폐렴을개선시켰다. 앞으로장기적인결과, 적절한치료적응증및조기폐암에서치료효과등에대한연구가필요할것으로생각된다. 요약연구배경 : 폐암에서광역동치료는미세침습성비소세포폐암및기관지폐쇄를일으키는악성종양에대한기관지내치료를미국식품의약국 (FDA) 에서승인한상태이다. 국내에서는폐암세포주에대한보고외에폐암에대한광역동치료연구가많지않아임상성적에대한보고가없어이에저자들은폐암에서시행된광역동치료에대한결과를문헌고찰과함께보고하고자한다. 방법 : 2002년 8월부터 2003년 5월까지조선대학교병원에서기관지내시경을통해조직학적으로진단된폐암환자중 10명을대상으로하여광역동치료 48시간전에광과민제 (Photogem R, Lomonosov institute of Fine Chemical, Russia) 를 2.0mg/Kg을정맥주사한후 48시간, 72시간에 Diode LASER system(biolitec Inc., Germany, wavelength; 633nm) 을사용하여광역동치료를시행하였다. 결과 : 10명중 9예에서부분관해와함께기관지개통을보였으며, 1예에서는변화를보이지않았다. 결론 : 저자들은광역동치료를통해기관지폐쇄로인한호흡곤란및기관지폐쇄와관련된폐렴이개선됨을확인하였으며, 합병증이적어안전한기관지내치료법으로생각된다. 앞으로광역동치료에대한장기적인결과및적절한치료적응증및조기폐암에서치료효과등에대한연구가필요할것으로생각된다. 참고문헌 1. Lipson RL, Baldes EJ, Gray MS. Hematoporphyrin derivative for detection and management of cancer. Cancer. 1967;20:2255-7. 2. Gregorie HG. Jr, Horger EO, Ward JL. Hematopor phyrin derivative fluorescence I Malignant neopla sms. Ann Surg 1968;167:820-8. 3. Kelly JF, Snell ME, Berenhaum MC. Photodynamic destruction of human bladder carcinoma. Br J Cancer 1975;31:237-44. 4. Dougherty TJ, Kaufman JE, Goldfarb A. Weishaupt KR, Bouleo, Mzfflewar A Photoradiationtherapy for the treatment of malignant tumors. Cancer Res 1978;38:2628-35. 5. Spiro SG, Porter JC. Porter, Lung Cancer-where are we today?: Current advances in staging and nonsu rgical treatment. Am J Respir Crit Care Med 2002; 166:1166-96 6. Kim YS, Park JS, Jee YK, Lee KY. Photodynamic therapy induced cell death using ALA and 632nm diode Laser in A549 lung cancer cells. Tuberculosis and Respiratory Disease. 2004;56:178-86 7. Marcus SL. Clinical photodynamic therapy: the con tinuing evolution. In: Henderson BW, Dougherty TJ, editors. Photodynamic therapy. New York: Marcel Dekker Inc., 1992.;219-68. 8. Okunaka T, Kato H, Tsutsui H, Ishizumi T, Ichinose S, Kuroiwa Y. Photodynamic therapy for peripheral lung cancer. Lung Cancer 2004;43:77-82. 9. Edell ES, Cortese DA. Photodynamic therapy in the 362
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