http://dx.doi.org/10.4046/trd.2011.71.4.266 ISSN: 1738-3536(Print)/2005-6184(Online) Tuberc Respir Dis 2011;71:266-270 CopyrightC2011. The Korean Academy of Tuberculosis and Respiratory Diseases. All rights reserved. 조기폐암환자에서광역동치료의효과 1 울산대학교의과대학서울아산병원호흡기내과학교실, 2 한림대학교의과대학한림대성심병원호흡기내과학교실 이영석 1, 오연목 1, 심태선 1, 김우성 1, 안정선 2, 최창민 1, 장승훈 2 Original Article The Clinical Outcomes of Photodynamic Therapy in Early Lung Cancer Patients Young Seok Lee, M.D. 1, Yeon-Mok Oh, M.D., Ph.D. 1, Tae Sun Shim, M.D., Ph.D. 1, Woo Sung Kim, M.D., Ph.D. 1, Jung Sun An, M.D. 2, Chang-Min Choi, M.D., Ph.D. 1, Seung Hun Jang, M.D., Ph.D. 2 1 Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 2 Division of Pulmonary, Allergy and Critical Care Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Korea Background: Photodynamic therapy (PDT) is effective in managing small superficial early lung cancer patients who were deemed nonsurgical candidates. However, we do not have any previous report on the usefulness of PDT in early lung cancer in South Korea. Thus we report here our experience of PDT in early lung cancer patients. Methods: 10 patients who underwent PDT for managing early lung cancer between June 2006 and July 2010 were analyzed. PDT was carried out 48 hours after photosensitizer injection. Re-bronchoscopy was carried out 48 hours after PDT in order to remove a necrotic tissue from the PDT site. For evaluation of PDT response, bronchoscopy and chest computed tomography (CT) were performed after 3 months. Results: The median age of patients was 69 (49 77) and all patients were male. The smoking history of patients was 48 (20 75) pack-year and the median follow up of patients was 25 (11 52) months. Complete remission was observed in 10 patients and the recurrence of lung cancer was observed in 3 patients. Out of 10 patients, 3 patients died (one case of lung cancer progression and two cases of pneumonia). Conclusion: The PDT is a safe and effective treatment in early lung cancer patients who are not suitable for surgical resection. The PDT in clinical practice is an attractive option in the treatment of early lung cancer. Key Words: Lung Neoplasm; Photochemotherapy; Therapeutics 서 론 Address for correspondence: Seung Hun Jang, M.D., Ph.D. Division of Pulmonary, Allergy and Critical Care Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, 896, Pyeongan-dong, Dongan-gu, Anyang 431-796, Korea Phone: 82-31-380-3718, Fax: 82-31-380-3973 E-mail: chestor@hallym.or.kr Co-correspondence: Chang-Min Choi, M.D., Ph.D. Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, 86, Asanbyeongwon-gil, Songpa-gu, Seoul 138-736, Korea Phone: 82-2-3010-5902, Fax: 82-2-3010-6968 E-mail: ccm@amc.seoul.kr Received: Jul. 19, 2011 Accepted: Sep. 1, 2011 폐암은전세계적으로암사망의주요한원인중의하나이고, 다른고형암과는달리치료성적의개선이매우더디다 1. 폐암의가장좋은치료법은수술이지만, 수술을고려할만큼조기에발견되는경우가많지않고, 조기폐암이라할지라도심폐기능의저하로인해수술을시행하지못하거나환자가수술을원치않거나동시다발성기관지병변 (synchronous multiple bronchial lesion) 인경우차선책이필요한데, 이때광역동치료 (photodynamic therapy, PDT) 를고려해볼수있다 2,3. PDT 는정상조직에비하여암조직에선택적으로축적되는광과민제를투여한후, 광과민제의흡수도와일치하는파장의레이저를조사 266
Tuberculosis and Respiratory Diseases Vol. 71. No. 4, Oct. 2011 하면자유라디칼 (free radical) 이생성되어암세포자체의광손상과암세포에영양을공급하는혈관의파괴, 면역반응으로인해항암효과를나타내는치료법이다 4-6. 1970년대 PDT 의유용성이알려진이후 PDT 는여러연구를통해수술을할수없는조기폐암환자에서유용하고안전한치료법으로인정받았다 2,4,7. 국내에서 PDT에관련된연구는폐암으로인한기관지폐쇄환자의완화요법에대한것으로조기폐암에대한근치적치료성적보고는거의없다 8. 이에저자들은수술을할수없는조기폐암환자에서의 PDT치료성적을문헌고찰과함께보고하고자한다. 대상및방법 본연구는 2006년 6월부터 2010년 7월까지서울아산병원과한림대학교성심병원에서조직학적으로진단된비소세포암환자중 PDT시술을받은 10명을대상으로임상지표와치료성적을후향적으로조사하였다. 대상자들은모두심폐기능이나쁜경우, 환자가수술을거부한경우, 동시다발성기관지병변인경우등으로수술을못하는조기폐암환자들이었다. PDT 는각병원의시행방법에따라, 4명의환자는광과민제로 Photogem R (Photogem, Moscow, Russia) 을체중에관계없이 200 mg 정주하였고, 나머지 6명은 Photofrin R 을 2 mg/kg 로정주하였으며, 모두 Ceralas PDT diode laser system (630 nm 파장 ) 을이용하여시행하였다. 광과민제정주 48시간후에광섬유 (Optiguide TM DCYL 220; diffuser length 2 cm, cylindrical type 800 mw) 를통해 diffuser 1 cm당 100 200 J의레이저를병변에조사하였고, PDT 시행 48시간후기관지내시경으로병변관찰후추가로 PDT 를시행할지를결정하였다. 광과민제의부작용인일광화상을예방하기위하여퇴원전까지자연광에대한차폐를시행하였고, 퇴원후 4주까지는외출을삼가고, 외출시에는모자착용등빛에노출되지않아야함을환자에게교육하였다. 시술 1개월후기관지내시경으로추적관찰하였고, 이후로는흉부전산화단층촬영과기관지내시경으로 3개월마다추적관찰하였다. 치료효과는완전관해 (complete remission, CR), 3년무진행생존율 (disease free survival rate) 과 3년전체생존율 (overall survival rate) 로기술하였다. 완전관해는최소 4주이상 PDT 시행병소의조직검사나세포진검사에서암세포가발견되지않고, 국소및원격전이가발견되지않은경우로정의하였다. 무진행생존기간은 PDT 시행일로부터최초로재발이발견된시점까지, 전체생존기간 은 PDT시행일로부터모든원인에의한사망시점까지로계산하였다 9,10. 연속변수는중앙값으로표시하였다. 결과 1. 환자의특성환자의나이는 69세 ( 범위, 49 77 세 ) 였고, 모두남자였으며, 흡연력은 48갑년 ( 범위, 20 75 갑년 ) 이었다. 환자의 FEV 1 은 2.2 L ( 범위, 1.4 3.9 L) 였고, 상피내암종 (carcinoma in situ) 이 70% (7/10), 1 cm 이하두께의기관지돌출병변이 30% (3/10) 였다. 이들의추적관찰기간은 25 개월 ( 범위, 11 52개월 ) 이었고, 조직형은모두편평상피암 (squamous cell carcinoma) 이었다. PDT시행이유를보면, 주병소와다른부위에부병소가있어주병소는수술적치료를하고부병소는 PDT 를시행한동시다발성기관지병변환자가 40% (4/10) 이고, 이들중 50% (2/4) 는 PDT를시행한부위외다른부위암에대해서수술을시행하였으며, 나머지 50% (2/4) 는수술과보조항암치료를병행하였다. 또한내과적제한점때문에 PDT를시행한환자가 60% (6/10) 인데, 이들중좌측주기관지병변이있고폐기능이충분하지못하여근치적절제가불가능했던경우가 33.3% (2/6), 환자가수술을거부한경우가 33.3% (2/6), 예전에폐암으로수술하고재발했는데이전수술로인해재수술이불가능했던경우가 16.7% (1/6), 협심증과폐결핵으로수술이불가능했던경우가 16.7% (1/6) 였다. 광과민제로는 40% (4/10) 가 Photogem R 을사용하였고, 60% (6/10) 가 Photofrin R 을사용하였다 (Table 1). 2. 치료효과동시다발성기관지병변환자 4명에서 PDT를시행한부위의치료성과는, 모두 CR이었으며치료부위의재발은없었지만, 25% (1/4) 에서 PDT 치료 6개월만에종격동임파선전이형태로재발하여항암치료도중폐렴과폐암의진행으로사망하였다 (Table 2). 내과적제한점때문에수술을시행하지못했던환자 6명에서도 PDT를시행한부위의치료성과는, 모두 CR이었으나, 33.3% (2/6) 에서 PDT를시행한지각각 3개월과 7개월에 PDT시행부위에서재발하였고, 재발한병변에대해서는모두방사선치료를시행하였다. 그외다른부위의재발은발견되지않았다. 이환자들중 33.3% (2/6) 가폐렴으로사망하였다 (Table 2). PDT 를시행한 10명중에 PDT 부작용이발생한환자는없었고, 모든환자가 CR이었으며 20% (2/10) 는 267
YS Lee et al: The efficacy of photodynamic therapy Table 1. Clinical characteristics of patients Case No. Age (yr) Sex Smoking (PY) Histology TNM Site FEV 1 (L) Cause site treatment histology Photo sensitizer 1 72 M 75 Sqcc TisN0M0 LUL 2.17 Double* RLL OP+CTX Adeno Photogem carcinoma 2 70 M 40 Sqcc TisN0M0 RUL 2.28 Double LLL OP+CTX Sqcc Photogem 3 69 M 50 Sqcc TisN0M0 LLL 2.12 Double RLL OP Sqcc Photogem 4 58 M 30 Sqcc T1aN0M0 LUL 3.03 Double RLL OP Sqcc Photofrin 5 77 M 50 Sqcc TisN0M0 RLL 1.97 Refuse N N N Photogem 6 49 M 60 Sqcc TisN0M0 Lt. main 3.98 Lt. main N N N Photofrin 7 56 M 45 Sqcc T1aN0M0 LLL 1.43 Postop. N N N Photofrin 8 69 M 46 Sqcc TisN0M0 RML 2.4 Refuse N N N Photofrin 9 69 M 50 Sqcc TisN0M0 LLL 2.29 CRI N N N Photofrin 10 65 M 20 Sqcc T1aN0M0 Lt. main 1.95 Lt. main N N N Photofrin *Synchronous multiple bronchial lesion, Operation refuse, Cancer on Lt. main bronchus, Cancer after previous lung cancer operation (pneumonectomy). PY: pack-year; TNM: the TNM Classification of Malignant tumors; FEV 1: forced expiratory volume in one second; sqcc: squamous cell carcinoma; CRI: cardiorespiratory insufficiency; LUL: left upper lobe; RUL: right upper lobe; RLL: right lower lobe; LLL: left lower lobe; N: no other site cancer; OP+CTX: operation and chemotherapy. Table 2. The outcome in PDT patients Case No. F/U (mo) PDT result Local recur in PDT site Months from PDT to local recurrence Treatment of local recurrence Recur in other site Prognosis 1 52 CR None None None None Alive 2 31 CR None None None None Alive 3 23 CR None None None LN Death* 4 20 CR None None None None Alive 5 36 CR Recur 3 Radiotherapy None Death 6 21 CR None None None None Alive 7 16 CR None None None None Death 8 31 CR None None None None Alive 9 27 CR None None None None Alive 10 11 CR Recur 7 Radiotherapy None Alive *Death due to lung cancer progression, Death due to pneumonia. F/U: follow-up period; PDT: photodynamic therapy; CR: complete remission; LN: cancer recurrence in mediastinal lymph node; mo: month. PDT 를시행한부위에서재발이있었고, 10% (1/10) 는종격동임파선전이의형태로재발하였으며, 10% (1/10) 는암의재발후진행으로항암치료를시행하였으나사망하였고, 20% (2/10) 는단순폐렴으로사망하였다. 우리환자에서 3년무진행생존율은 70% 였고, 3년전체생존율은 75% 였다 (Figure 1). 고찰광역동치료는 1 cm 이하의다른부위에전이가없는중심부조기폐암환자에서전신상태나다른이유로인해수술이불가능할때유용한치료이다 2. 본연구의환자들도수술이불가능한동시다발성병변을가지고있거나수술을거부하는등조기폐암임에도불구하고수술을시행하지못하는환자들을대상으로하였다. 기존의연구보고와마찬가지로모두편평상피암이었고, 남자였으며, 흡 268
Tuberculosis and Respiratory Diseases Vol. 71. No. 4, Oct. 2011 Figure 1. Progression-free survival and overall survival in the PDT patients. Kaplan-Meier curves for progression-free survival (A) and overall survival (B) in PDT patients are shown. In (A) and (B), tick marks indicate patients for whom data were censored at the data cutoff point. The median of progression-free survival is N.R. (not reached) and the median of overall survival is 36 months. PDT: photodynamic therapy. 연자였다. 조기폐암에서 PDT의효과는여러논문에서증명되었다 2,4,11-15. 대부분의환자들은수술의적응증이안되는조기폐암환자들을대상으로하였고, 완전관해는 64 86%, 재발 13 39%, 5년생존율은 43.4 68.4% 로다양하였지만, 평균적으로완전관해는 75%, 재발은 30% 정도였다 13. 폐암의침윤정도에따라치료효과가결정되기때문에침윤정도는중요한데 16, 최근초음파기관지내시경검사 (endobronchial ultrasonography, EBUS) 의이용이증가하면서 PDT 의적용이늘어나고있다. 중심부초기폐암의진단에있어서 EBUS 가유용하다는보고가있었고, 이연구에서는일반적인기관지내시경과고해상도흉부전산화단층촬영보다 EBUS 에서폐암의침윤정도를정확히파악할수있으므로 PDT치료에서중요한검사법이라고보고하였다 17. 조기폐암환자에서생존율을가장증가시킬수있는치료법은수술이지만, 비용대비효과 (cost-effectiveness) 면에서수술과 PDT를비교하였을때 PDT가더우월하다는연구도있었다 18. 폐암에서동시다발성기관지병변인경우는 0.2 20% 정도된다고알려져있고 19-21, 이경우에도수술을하는것이생존율을높일수있는방법인데, 수술에관련된사망률이나이와동반질환에따라 1.1 11% 까지다양하여수술적치료를선택할때는나이와동반질환에대한고려가필요하다 22. 폐암환자군이고령인점을감안하면 23 수술적치료가힘든경우가많고, 수술을시행했다고하더라도재발하는경우가많아 24,25, 적절한적응증만된다면 PDT는효과적인치료법이될수있다. 동시다발성기관지병변환자에서 PDT 의효용성에대한보고는있지만 26,27, 아직까지명확하지는않다. 향후이부분에대해서많은연구가필요할것이라생각된다. 조기폐암에서 PDT 의효용성에관한국내보고는거의없다. 본연구가대상자가적고, 여러병원이참여한연구가아니라결론을내기힘든것이사실이나앞에서본바와같이적절한적응증의환자만선택된다면, PDT 는효과적인치료법이며, 조기폐암환자에게치료법의일환으로제시할수있을것이라생각된다. 결론적으로 PDT는수술적응증이되지않는중심부조기폐암환자를대상으로하고있고, 재발할수있으나환자들이편안하게시술받을수있으며, 한번시술후에도여러차례다시시술할수있다는등의장점을가진치료법이다. 아직우리나라에서는경험이적어그적용에제한이있으나적절한적응증인환자를선택할수있고, 적절한방법으로시술한다면조기폐암환자에서효과적인치료법이될수있을것이라생각된다. 참고문헌 1. Welch HG, Schwartz LM, Woloshin S. Are increasing 5-year survival rates evidence of success against cancer? JAMA 2000;283:2975-8. 2. Kennedy TC, McWilliams A, Edell E, Sutedja T, Downie G, Yung R, et al. Bronchial intraepithelial neoplasia/ 269
YS Lee et al: The efficacy of photodynamic therapy early central airways lung cancer: ACCP evidencebased clinical practice guidelines (2nd edition). Chest 2007;132(3 Suppl):221S-233S. 3. Moghissi K. Role of bronchoscopic photodynamic therapy in lung cancer management. Curr Opin Pulm Med 2004;10:256-60. 4. Maziak DE, Markman BR, MacKay JA, Evans WK; Cancer Care Ontario Practice Guidelines Initiative Lung Cancer Disease Site Group. Photodynamic therapy in nonsmall cell lung cancer: a systematic review. Ann Thorac Surg 2004;77:1484-91. 5. Nowis D, Makowski M, Stokƚosa T, Legat M, Issat T, Goƚab J. Direct tumor damage mechanisms of photodynamic therapy. Acta Biochim Pol 2005;52:339-52. 6. Kim JO, Jung MK, Jung SS. Photodynamic therapy (PDT) in lung cancer. Tuberc Respir Dis 2007;62: 175-83. 7. Moghissi K, Dixon K. Is bronchoscopic photodynamic therapy a therapeutic option in lung cancer? Eur Respir J 2003;22:535-41. 8. Yoon SH, Han KT, Kim GN, Lee SI. Effect of photodynamic therapy in lung cancer. Tuberc Respir Dis 2004;57:358-63. 9. Endo C, Miyamoto A, Sakurada A, Aikawa H, Sagawa M, Sato M, et al. Results of long-term follow-up of photodynamic therapy for roentgenographically occult bronchogenic squamous cell carcinoma. Chest 2009; 136:369-75. 10. Okunaka T, Kato H, Tsutsui H, Ishizumi T, Ichinose S, Kuroiwa Y. Photodynamic therapy for peripheral lung cancer. Lung Cancer 2004;43:77-82. 11. Corti L, Toniolo L, Boso C, Colaut F, Fiore D, Muzzio PC, et al. Long-term survival of patients treated with photodynamic therapy for carcinoma in situ and early non-small-cell lung carcinoma. Lasers Surg Med 2007; 39:394-402. 12. Furukawa K, Kato H, Konaka C, Okunaka T, Usuda J, Ebihara Y. Locally recurrent central-type early stage lung cancer <1.0 cm in diameter after complete remission by photodynamic therapy. Chest 2005;128: 3269-75. 13. Mathur PN, Edell E, Sutedja T, Vergnon JM; American College of Chest Physicians. Treatment of early stage non-small cell lung cancer. Chest 2003;123(1 Suppl): 176S-180S. 14. Moghissi K, Dixon K, Thorpe JA, Stringer M, Oxtoby C. Photodynamic therapy (PDT) in early central lung cancer: a treatment option for patients ineligible for surgical resection. Thorax 2007;62:391-5. 15. Usuda J, Kato H, Okunaka T, Furukawa K, Tsutsui H, Yamada K, et al. Photodynamic therapy (PDT) for lung cancers. J Thorac Oncol 2006;1:489-93. 16. Nakamura H, Kawasaki N, Hagiwara M, Ogata A, Kato H. Endoscopic evaluation of centrally located early squamous cell carcinoma of the lung. Cancer 2001;91: 1142-7. 17. Miyazu Y, Miyazawa T, Kurimoto N, Iwamoto Y, Kanoh K, Kohno N. Endobronchial ultrasonography in the assessment of centrally located early-stage lung cancer before photodynamic therapy. Am J Respir Crit Care Med 2002;165:832-7. 18. Kato H, Okunaka T, Tsuchida T, Shibuya H, Fujino S, Ogawa K. Analysis of the cost-effectiveness of photodynamic therapy in early stage lung cancer. Diagn Ther Endosc 1999;6:9-16. 19. Carey FA, Donnelly SC, Walker WS, Cameron EW, Lamb D. Synchronous primary lung cancers: prevalence in surgical material and clinical implications. Thorax 1993;48:344-6. 20. Ferguson MK, DeMeester TR, DesLauriers J, Little AG, Piraux M, Golomb H. Diagnosis and management of synchronous lung cancers. J Thorac Cardiovasc Surg 1985;89:378-85. 21. Wu SC, Lin ZQ, Xu CW, Koo KS, Huang OL, Xie DQ. Multiple primary lung cancers. Chest 1987;92:892-6. 22. Jung EJ, Lee JH, Jeon K, Koh WJ, Suh GY, Chung MP, et al. Treatment outcomes for patients with synchronous multiple primary non-small cell lung cancer. Lung Cancer 2011;73:237-42. 23. National Cancer Information Center (NCIC). Cancer incidence rate 2008. Goyang: ICIC; c2010 [cited 2011 Sep 30]. Available from: http://www.cancer.go.kr/ncic/cics_f/ 01/011/index.html. 24. Johnson BE. Second lung cancers in patients after treatment for an initial lung cancer. J Natl Cancer Inst 1998;90:1335-45. 25. Johnson BE, Cortazar P, Chute JP. Second lung cancers in patients successfully treated for lung cancer. Semin Oncol 1997;24:492-9. 26. Moghissi K, Dixon K. Photodynamic therapy for synchronous occult bronchial cancer 17 years after pneumonectomy. Interact Cardiovasc Thorac Surg 2005;4:327-8. 27. Usuda J, Ichinose S, Ishizumi T, Hayashi H, Ohtani K, Maehara S, et al. Management of multiple primary lung cancer in patients with centrally located early cancer lesions. J Thorac Oncol 2010;5:62-8. 270