중심성기도폐쇄를동반한폐암에서냉동치료의임상적유용성및부작용 1 고려대학교의과대학내과학교실, 2 고려대학교의료원구로병원정진용 1, 이승룡 1, 김대현 2, 이경주 1, 이은주 1, 강은해 1, 정기환 1, 김제형 1, 신철 1, 심재정 1, 인광호 1, 강경호 1, 유세화 1 Clinical Benefits and Complications of Cryotherapy in Advanced Lung Cancer with Central Airway Obstruction Jin Yong Jung, M.D. 1, Sung Yong Lee, M.D. 1, Dae Hyun Kim 2, Kyung Joo Lee, M.D. 1, Eun Joo Lee, M.D. 1, Eun Hae Kang, M.D. 1, Ki Hwan Jung, M.D. 1, Je Hyeong Kim, M.D. 1, Chol Shin, M.D. 1, Jae Jeong Shim, M.D. 1, Kwang Ho In, M.D. 1, Kyung Ho Kang, M.D. 1, Se Hwa Yoo, M.D. 1 1 Department of Internal Medicine, Korea University College of Medicine, 2 Guro Hospital, Korea University Medical Center, Seoul, Korea Background: The efficacy of the use of the interventional bronchoscope for palliation of patients with central airway obstruction has been established. In the palliative setting to alleviate central airway obstruction, the use of laser resection, electrocautery, argon plasma coagulation, photodynamic therapy and cryotherapy can provide relief of an airway obstruction. Cryotherapy is the therapeutic application of extreme cold for the local destruction of living tissue. Recently, this technique has been used for endoscopic management of central airway obstructions in Korea. We report the role and complications of the use of cryotherapy for airway obstructions in patients with advanced lung cancer. Methods: We used a flexible cryoprobe for cryotherapy using nitrous oxide as a cryogen. The cryoprobe was applied through the working channel of a flexible fiberoptic bronchoscope. The temperature of the tip was approximately 89 o C, and the icing time was 5 20 seconds. Results: Four patients with a central airway obstruction from advanced lung cancer were treated with cryotherapy. Three of the four patients were treated successfully and the airway obstruction was improved after the cryotherapy procedure. Dyspnea, hypoxia and atelectais were improved in three cases. Two patients experienced complications-one patient experienced pneumomediastinum and the other patient experienced massive hemoptysis during the cryotherapy procedure. However, these complications resolved and did not influence mortality. Conclusion: This technique is effective and relatively safe for palliation of inoperable advanced lung cancer with a central airway obstruction. (Tuberc Respir Dis 2008;64:272-277) Key Words: Cryotherapy, Central airway obstruction, Lung cancer 서 원발성폐암또는전이성폐암환자중중심성기도폐쇄를동반하는경우가있으며, 이러한환자들대부분이호흡곤란, 객혈등을호소하지만진행성폐암의경우가많으며특히수술적제거가곤란한경우가많다. 이러한 Address for correspondence: Sung Yong Lee, M.D., Ph.D. Department of Internal Medicine, Korea University College of Medicine, 80, Guro-dong, Guro-gu, Seoul 152-703, Korea Phone: 82-2-2626-3021, Fax: 82-2-865-6605 E-mail: pusarang@gmail.com Received: Feb. 4, 2008 Accepted: Mar. 24, 2008 론 중심성기도폐쇄를동반하는진행성폐암환자에서기도폐쇄를호전시키기위해다양한중재적시술방법들이시도되고있으며, 이러한시술방법들로는 Nd:YAG 레이저치료, 전기소작술 (electrocautery), 근접치료 (brachytherapy), 광역동치료 (photodynamic therapy) 및냉동치료 (cryotherapy) 등이있다. 이러한시술방법들은환자의상태에따라또는병변의위치에따라적절한시술방법을결정하여야하며필요에따라서는 2가지이상의방법을병행하여시술을시행할수있다. 최근냉동치료기계가한국식약청허가를받으면서냉동치료기계를이용한시술이국내에서도가능하게되었으며점차국내에서도이러한냉동치료를이용한치료가증가할것으로예상이된다. 냉동치료는다른치료방법들에비해기구가간단하 272
Tuberculosis and Respiratory Diseases Vol. 64. No. 4, Apr. 2008 Table 1. Basal characteristics of the patients Case Sex Age Pathology Stage Anatomic location Chief complain 1 Male 49 Squamous cell carcinoma IV Lt. main bronchus Dyspnea 2 Male 42 Squamous cell carcinoma IV Carina Dyspnea 3 Male 40 Squamous cell carcinoma IV Rt. main bronchus Dyspnea, hemoptysis 4 Male 64 Squamous cell carcinoma IIIB Lt. main bronchus Dyspnea, hemoptysis 며또한경제적으로도저렴하다는장점및부작용발생이적다는면에서점차시술례가증가할것으로기대되는치료방법으로, 저자들은중심성기도폐쇄를동반한진행성폐암환자에서냉동치료의시행성적및시술로인해발생한부작용경험을보고하는바이다. 대상및방법 1. 대상환자 2007년 1월부터조직학적으로폐암으로진단되고중심성기도폐쇄로인한무기폐또는폐렴등의소견으로호흡곤란을호소하는환자를대상으로하였으며이시술에대한동의서를작성한환자들에대해시술을시행하였다. 환자들의임상양상은 Table 1과같다. 2. 방법냉동치료기계는 cryomachine (ERBE, Tubingen, Germany) 과 flexible cryoprobe (length 80 cm, Diameter 2.2 mm, Length of Probe Tip 7 mm) 로구성이되며 flexible bronchoscopy의 working channel 를통해 cryoprobe를삽입한후기도폐쇄를유발하는악성종양의중심에 cryoprobe tip을위치시킨후약 5 20초간급속냉동을시행한다. 이때한제 (cryogen) 는 N2O ( 아산화질소 ) 가스가사용되었으며 cryoprobe tip 끝의냉각온도는약 89도 o C로냉각된다 1. 급속냉동후 cryoprobe tip에냉동되어부착되어있는종양을같이 pulling out하면서기도폐쇄를유발하는종양을제거하거나, 또는 cryoprobe 를이용하여종양에대하여 pulling out 과정없이단순히급속냉동및해동과정을 2 3회반복만시행하였다. 냉동치료후단순흉부 x-ray, 기관지내시경또는흉부 CT 를시행하여치료반응을확인하였다. 결과 1. 냉동치료의치료효과총 4명의환자가시술되었으며, 1명의환자를제외한 3명의환자에서성공적으로기도폐쇄를유발하는종양을제거하였다. 증례 1, 2에서냉동치료전에관찰된무기폐소견은냉동치료후안정시호흡곤란증상및무기폐소견이호전되었으며 (Figure 1), 증례 2의경우는급격히진행하는기도폐쇄로인해중환자실에서기계환기를실시했던환자로 2차례에걸친냉동치료후기계환기이탈을유도할수있었다. 증례 3에서는무기폐로인한호흡곤란보다는하부기관 (lower trachea) 에서내강으로성장하는악성종괴로인한환기장애로인한호흡곤란이있던환자로냉동치료후극적으로하부기관의악성종괴가소실되어호흡곤란이극적으로호전되었다 (Figure 2). 3명의증례에서환자들이안정시호흡곤란으로인해폐기능검사를실시할수없어객관적인기도폐쇄의호전을확인할수는없었으며, 또한 4명의환자를대상으로하였기때문에환자들의생명연장과같은사항은확인할수없었다. 2. 부작용증례 2에서냉동치료후 carina 에천공이발생하여종격동기종 (pneumomediastinum) 및피하기종 (subcutaneous emphysema) 이발생하였으나경험적항생제치료이후급성종격동염등의심각한부작용의발생없이경과가호전되었다 (Figure 1). 증례 4에서는좌측주기관지를폐쇄시키는종양으로인해간혈적으로객혈이발생하였으며이로인해우측하부폐에흡인성폐렴이발생한증례로 cryoprobe 를이용하여좌측주기관지에관찰되는종양을급속냉동시킨후 pulling out하여종양의일부를제거하였으나절제되고남은 stalk 부분에서종양내의혈관손상으로인한대량출혈이발생하였던증례로냉동치료시술을중단하고즉시기도삽관및기계환기시행후출혈이조절되어기도발관 (extubation) 을시행한후퇴원하였 273
JY Jung et al: Cryotherapy in advance lung cancer with central airway obstruction Figure 1. The chest PA and bronchoscopic finding before (A, C) and after (B, D) cryotherapy in case 2. The chest PA shows near completely obstructed left main bronchus and atelectasis of left lung. After cryotherapy, atelectasis of left lung was completely recovered, however pneumomediastinum and subcutaneous emphysema were developed (B, arrow). Bronchoscopic finding shows perforated carina after cryotherapy (D, arrow). 으나추적관찰되지않았다. 고찰진행성폐암환자중기관 (trachea) 이나주기관지 (main bronchus) 와같은중심성기도폐쇄를유발하는환자를종종임상에서경험을할수있다. 이러한중심성기도폐쇄를동반하는환자들은대부분호흡곤란, 객혈, 폐쇄성폐렴 (post obstructive pneumonia) 을동반하지만대부분진행성병기또는수술적절제가불가능한경우가많다. 하지만최근에여러중재적시술방법들의개발로점차 이러한병변을치료함으로써극적인증상완화및생존율향상을가져오고있다. 이러한환자들한테시술될수있는중재적시술방법들로는 external beam radiation therapy, carbon dioxide나 Nd:YAG 레이저치료법, 근접치료 (brachytherapy), 전기소작술 (electrocautery), 광역동치료 (photodynamic therapy) 및냉동치료 (cryotherapy) 등이있다 2. 현재국내에서는위에기술된대부분의중재적시술방법들이이용되고있으나냉동치료의경우는냉동치료기계가최근한국식약청허가를받으면서몇몇대학병원에서시행되고있다. 이러한냉동치료의역사는기원전부터염증이나전쟁 274
Tuberculosis and Respiratory Diseases Vol. 64. No. 4, Apr. 2008 Figure 2. The chest PA and bronchoscopic finding before (A, C) and after (B, D) cryotherapy in case 3. The right main bronchus was completely obstructed by the intraluminal ingrowing tumor lesion that was extending to the distal trachea and developed severe airway obstruction (A, C). The ingrowing tumor lesion was disappeared by cryotherapy and also some aeration was noted on right upper area in chest CT scan (B, D). 으로인한상처에치료했다는보고로거슬러올라가며, 또한히포크라테스도외상으로인해발생한부종과통증에대해냉동치료를시행했다는기록이있다 3. 실제로임상의사에의해종양에대해임상적으로적용된것은 1848 년 James Arnott 이총 30명의자궁암환자를치료한것으로, 치료결과완치를하지는못하였으나증상및조직학적변화 (histological regression of tumor) 를가져왔다는보고를하였다 4. 1960 년대에냉각매체로액체질소가사용되면서여러임상분야에서냉동치료가시도되었으나기관지내종양의경우에는해부학적인접근성이용이하지않아그동안다른냉각치료보다더발달이늦게진행이되었다. 실제로 1970년대말부터 Mayo Clinic의 Dr. Sanderson 그룹에서호흡기영역에서냉동치료가시도되어왔으나 5, 1980년대에 carbon dioxide laser 및 Nd:YAG laser 의개발로유럽지역에서만간간히명맥을유지해오다가늘고굴절이가능한 (flexible) 한 cryoprobe 가개발되면서다시각광을받게되었다 6. 이러한냉동치료로인한조직손상은냉동및해동의속도, 횟수그리고시간에의해결정이되며, 조직의종류에따라손상정도가다르다. 즉, 피부상피, 점막, 신경세포, 혈과내피세포들은쉽게손상을받지만신경막 (nerve sheaths), 섬유조직, 연골 (cartilage) 및지방조직같이세포구성이적은부위 (paucicellular lesions) 는대체로손상을잘받지않는다 1. 그리고 Rubinshy 등의연구결과에의하며정상세포에비해악성종양세포가냉동치료에쉽게손상을받는다고한다 7. 치료기전은급속냉동과정에세포내부및외부에냉동결정 (crystallization) 이발생하고이로인해직접적으로는기계적손상 (mechanical injury) 이발생하고, 간접적 275
JY Jung et al: Cryotherapy in advance lung cancer with central airway obstruction 으로는세포내 외부에 fluid shift 가발생하여세포손상이발생하게된다 8,9. 또한종양에대해냉동치료를시행하면종양조직이급속냉동과해동의과정을반복하게되면서종양내의혈관이수축및이완의과정이반복되고또한이로인해혈류속도의감소가유발되면서혈관내미세혈전 (microthrombi) 이생기게되어결국에는허혈성손상을유발하게되어종양의크기를감소시킬수있게된다 10. 냉동치료시술과 Nd:YAG 레이저치료그리고 Argon 등을이용한전기소작술치료를서로비교하였을때 Nd:YAG 레이저치료는 90% 이상의환자에서즉시치료효과를기대할수있으나 endobronchial fire 나대량출혈, 기도천공, 기흉, 종격동기종이발생할수있으며 11,12, 또한레이저치료시고가의기계장비가필요하다. 전기소작술인경우레이저치료기계에비해가격이저렴하며외래에서간단히환자를진정시킨상태에서굴곡성기관지내시경을이용하여쉽게시술할수있다는장점이있으며, 기도폐쇄를동반한환자에서시술시 55 75% 의증상완화효과가있어중심성기도폐쇄가있는경우많이이용되는시술이지만전기소작술또한레이저치료처럼천공, 기흉및종격동기종과같은부작용이발생할수있어시술시많은주의를요한다. 반면에냉동치료는 3 mm 직경의 cryoprobe 를사용하는경우 1 cm 직경의크기로 3 mm의깊이까지 cytotoxicity 를보이기때문에기도천공의가능성이높은 Nd:YAG 레이저치료나전기소작술과비교하였을때천공의위험성이낮으며 13, electrical accident로인한 endobronchial fire 등의위험성도없고, 레이저치료시시행하는 optical protection 을할필요도없다. 또한경기관지내시경에국한되지않고굴절성기관지내시경에서도쉽게적용이가능하다는장점이있으며, 시술방법및기계조작방법이간단하여시술자의 learning curve 가다른치료들과비교하여단기간에이루어질수있는장점이있다. Cryogen 으로사용되는 N2O 가스인경우가격이저렴하고 cryoprobe 는재사용이가능하여기구나유지비등이저렴하다. 하지만본증례에서와같이어느한부위를지속적으로치료하는경우나정상점막에대하여시술을시행하는경우기도천공이발생할수있으며, 급속냉동이후너무무리하게 stalk 을제거하는경우 stalk 내부의혈관손상으로인한대량출혈이발생할수있기때문에이러한부작용발생에대한주의를기울여야한다 14. 또한다른문헌에의하면냉동치료후괴사된조직덩어리 (necrotic slough) 가기침과정에서다른기도를넘어가서환기장애를유발할수있어 냉각치료 4 6일후기관지내시경을실시하여괴사된조직을제거할것을권고하고있다 6. 냉동치료는충분한효과가발생하는데는약 2 4주의시간이소요되기때문에빨리기도폐쇄증상을완화시켜야하는상황에서는다소부적절한시술방법이기는하지만급속냉동후 cryoprobe tip에냉각되어있는 stalk를 pulling하여제거하면바로기도폐쇄증상을완화를기대할수있다. 하지만증례 4와같이무리한 pulling시대량출혈이발생할수있으므로이러한부작용발생가능성을꼭염두에두고시술을시행하여야한다 14. 또한 Stalk을 pulling하여제거하지않고냉동과해동의과정만반복한시술인경우는수일이후에기관지내시경을다시시행하여괴사조직을제거하는것이좋다. 마지막으로중요한것은적절한환자의선택이다. 냉동치료의적응증은조직학적으로확인된기관또는기관지에발생한악성종양으로 1) 종양의위치가수술적치료가용이하지않은부위, 2) 폐기능장애로수술적치료가불가능한경우, 3) 악성종양으로인한기도폐쇄로호흡곤란이있거나반복적이거나대량객혈이있는경우, 4) 항암치료, 방사선치료또는수술치료후재발한경우로종양의위치가기도외부의압박으로인한병변이아니라기도내강에서발생하는악성종양의환자에서시도해볼수있으며 5) 기관또는기관지에서발생하는유두종 (papilloma), 카시노이드종양과같은양성종양에서시도해볼수있다. 특히레이저치료가천공의위험가능성이있어침윤성 (infiltrative) 병변에대해시술하기어려운반면냉동치료인경우에는외부압박에의한병변이아니라면침윤성병변에서도용이하게사용할수있는시술방법이다 13. 결론적으로냉동치료는중심성기도폐쇄로인한호흡곤란, 객혈및반복적인폐렴등의합병증이발생하는진행성악성종양환자에서있어서이러한증상및합병증들을호전시키기위한효과적인치료방법이며또한다른중재적시술방법들에비해부작용이적고, 시술과관련된부대비용이저렴하고시술시에복잡한기술을요하지않아냉동치료의시술적응증에해당되는환자들에게적극적으로시도해볼수있는시술방법이다. 요약연구배경 : 중심성기도폐쇄를동반하는진행성폐암환자에서기도폐쇄를호전시키기위해다양한중재적시술 276
Tuberculosis and Respiratory Diseases Vol. 64. No. 4, Apr. 2008 방법들이시도되고있으며, 이러한시술방법중최근굴절성 cryoprobe 를이용한냉동치료가국내에서도시도되고있다. 방법 : 냉동치료기계는 cryomachine 과 cryoprobe 로구성되며, 냉매로는아산화질소 (N2O) 를사용하였다. 굴곡경기관지내시경의 working channel 을통해굴절성 cryoprobe 를악성종양의중심에위치한후급속냉동 ( 89 o C) 하여악성종양조직을냉동시킨후 stalk 을 pulling 하여제거하거나급속냉동과해동과정을반복하였다. 결과 : 중심성기도폐쇄가발생한진행성폐암환자 4명에게냉동치료를시술하였다. 3명의환자에서성공적으로기도폐쇄를유발하는종양을제거하였으며, 그후호흡곤란및무기폐소견이호전되었다. 1명의환자에서기관지천공으로인한종격동기종이발생하였으며또다른환자에서냉동치료도중대량출혈이발생하였으나응급조치후다시회복되었다. 결론 : 진행성폐암환자에서중심성기도폐쇄로인하여호흡곤란, 객혈, 무기폐및반복적인폐렴등의합병증이발생하는경우에냉동치료는효과적인치료방법이다. 참고문헌 1. Maiwand MO, Homasson JP. Cryotherapy for tracheobronchial disorders. Clin Chest Med 1995;16:427-43. 2. Chetty KG, Moran EM, Sassoon CS, Viravathana T, Light RW. Effect of radiation therapy on bronchial obstruction due to bronchogenic carcinoma. Chest 1989; 95:582-4. 3. Sguazzi A, Bracco D. A historical account of the technical means used in cryotherapy. Minerva Med 1974;65: 3718-22. 4. Arnott J. On the present state of therapeutic enquiry. London: 1845. 5. Neel HB 3rd, Farrell KH, DeSanto LW, Payne WS, Sanderson DR. Cryosurgery of respiratory structures. I. Cryonecrosis of trachea and bronchus. Laryngoscope 1973;83:1062-71. 6. Homasson JP, Renault P, Angebault M, Bonniot JP, Bell NJ. Bronchoscopic cryotherapy for airway strictures caused by tumors. Chest 1986;90:159-64. 7. Rubinsky B, Ikeda M. A cryomicroscope using directional solidification for the controlled freezing of biological material. Cryobiology 1985;22:55-68. 8. Mazur P. Cryobiology: the freezing of biological systems. Science 1970;168:939-49. 9. Rubinsky B, Lee CY, Bastacky J, Onik G. The process of freezing and the mechanism of damage during hepatic cryosurgery. Cryobiology 1990;27:85-97. 10. Sheski FD, Mathur PN. Cryotherapy, electrocautery, and brachytherapy. Clin Chest Med 1999;20:123-38. 11. Kvale PA, Selecky PA, Prakash UB. Palliative care in lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007;132:368S-403S. 12. Cavaliere S, Venuta F, Foccoli P, Toninelli C, La Face B. Endoscopic treatment of malignant airway obstructions in 2,008 patients. Chest 1996;110:1536-42. 13. Vergnon JM, Huber RM, Moghissi K. Place of cryotherapy, brachytherapy and photodynamic therapy in therapeutic bronchoscopy of lung cancers. Eur Respir J 2006;28:200-18. 14. Chan AL, Yoneda KY, Allen RP, Albertson TE. Advances in the management of endobronchial lung malignancies. Curr Opin Pulm Med 2003;9:301-8. 277