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1 DOI: /trd ISSN: (Print)/ (Online) Tuberc Respir Dis 2009;67: CopyrightC2009. The Korean Academy of Tuberculosis and Respiratory Diseases. All rights reserved. 진행성비소세포폐암환자에서 Pemetrexed 의효과와안전성 Original Article 고신대학교의과대학내과학교실 이규진, 정만홍, 장태원, 옥철호, 정현주 Efficacy and Safety of Pemetrexed in Advanced Non-Small Cell Lung Carcinoma Gyu Jin Lee, M.D., Mann Hong Jung, M.D., Tae Won Jang, M.D., Chul Ho Ok, M.D., Hyun Joo Jung, M.D. Department of Internal Medicine, Kosin University College of Medicine, Busan, Korea Background: Pemetrexed has been prescribed newly as a second line chemotherapy in advanced non-small cell lung carcinoma (NSCLC). The aim of study was to determine the efficacy and toxicity of pemetrexed in advanced NSCLC. Methods: Patients with histologically or cytologically confirmed NSCLC were evaluated from June 2006 to December The patients had relapsed or progressed after prior chemotherapy treatment. They were treated with intravenous pemetrexed 500 mg/m 2 for 10 min on Day 1 of each 21-day cycle. Results: A total of 89 patients were eligible for analysis. The response rate and disease control rate were 11% and 66%. Non-squamous cell carcinoma histology was significantly associated with a superior response rate (p= 0.035) and disease control rate (p=0.009) than squamous cell carcinoma histology. The median survival time was 13 months and the median progression free survival time was 2.3 months. The median survival time of patients with ECOG PS 0 1 was 13.2 months, whereas median survival time was 11.6 months for patients with PS 2 (p=0.002). The median progression free survival time of patients with PS 0 1 were 3.8 months, but 2.1 months for patients with PS 2 (p=0.016). The median progression free survival time of smokers with non-squamous cell carcinoma was 3.4 months, which was significant (p=0.014). Grade 3 4 neutropenia were seen in 7.9% patients. Conclusion: Pemetrexed has efficacy in patients who had prior chemotherapy with advanced NSCLC and less hematologic toxicity. Key Words: Pemetrexed, Non-small-cell lung carcinoma, Drug therapy 서 폐암은가장흔한악성종양이며그발생률또한증가하고있다. 2005년미국에서남녀사망률 1위 1 를보였으며, 한국에서도 2000년이후암사망률 1위 2 를기록하고있다. 폐암은크게소세포암 ( 약 15%) 과비소세포암 ( 약 Address for correspondence: Tae Won Jang, M.D. Department of Internal Medicine, College of Medicine, Kosin University, 34, Amnam-dong, Seo-gu, Busan , Korea Phone: , Fax: jangtw@ns.kosinmed.or.kr Received: Jun. 20, 2009 Accepted: Aug. 11, 2009 론 85%) 으로나눌수있다 3. Platinum 을근간으로하는 1차항암요법은비소세포폐암환자들에게최선의지지요법보다증상완화에따른삶의질개선뿐만아니라생존율도향상시켰다 4. 그럼에도불구하고대다수의비소세포폐암은재발하거나진행하여 3개월에서 6개월의관해지속중앙값을가졌으며, 1차항암치료를받은비소세포폐암환자의 40 50% 가 2차항암치료를받았다 5. 2차항암치료약제로 docetaxel, pemetrexed, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) 인 erlotinib, gefitinib이있다. 이중 pemetrexed 는항엽산제제로세포핵복제과정에서엽산의존적효소를억제함으로써항암효과를나타내고 6, 비소세포폐암뿐만아니라중피종, 유방암, 대장암, 췌장암, 방광암, 121

2 GJ Lee et al: Efficacy and safety of pemetrexed in advanced non-small-cell lung carcinoma 두경부암및자궁경부암에도효과가있는것으로보고되고있다 7-9. 이에저자들은이전의항암치료를받고재발하거나진행한비소세포폐암환자에서 pemetrexed 의치료효과와부작용에대하여후향적분석을시행하였다. 대상및방법 1. 대상환자 2006년 6월부터 2008년 12월까지고신대학교복음병원에서진행성비소세포폐암으로 pemetrexed 를투여받은환자를대상으로하였다. 모든환자는정상적인장, 간, 신장및골수기능을가졌으며 pemetrexed 투여에동의하였다. 치료시작전단순흉부촬영, 흉부컴퓨터단층촬영, 골주사또는양전자방출단층촬영 (PET-CT) 등을시행하여 TNM 국제병기법에의해병기판정을받았다. 매투여시혈액학적검사및흉부단순촬영을시행하였으며, 흉부단순촬영상명확한크기증가가없다면 2회또는 3회항암치료시마다흉부컴퓨터단층촬영을시행하였다. 또한두통, 오심, 구토및신경학적증상이있어뇌전이가의심되는경우뇌자기공명영상법을, 뼈전이로의심되는통증을호소할경우골주사를시행하였다. 2. 치료방법치료는매 3주마다 pemetrexed 500 mg/m 2 을 10분동안정주하였다. 첫 pemetrexed 투여 1주일에서 2주일전부터엽산을매일경구복용하였고, pemetrexed 투약중단후 3주까지복용시켰다. Vitamin B12는 1,000 μg 을첫 pemetrexed 투여 1주일전에근주하여매 9주마다근주하였고 pemetrexed 치료중단시 3주까지근주하였다. 덱사메사손 (dexamethasone) 은금기사항일경우를제외하고항암치료전날과당일, 그다음날하루두번주었다. 병의진행이진단되거나심각한부작용이발생하거나환자가더이상의치료를거부하는경우에 pemetrexed 투여를중단하였다. 필요시진통제, 항생제, 수액등을사용하여지지요법을시행하였다. 3. 치료효과및독성판정반응은 Response Evaluation Criteria in Solid Tumors (RECIST) criteria 10 에근거하여판단하였고부작용의판정은 WHO 기준에따라그정도를평가하였다. 4. 통계학적분석 통계분석은 SPSS 17.0 (SPSS Inc., Chicago, IL, USA) 통계프로그램을이용하여분석하였다. 생존기간은첫 pemetrexed 를투여한날부터사망하거나추적이종료되었던날까지의기간으로하였고, 관해지속기간은첫 pemetrexed 를투여한날부터진행으로평가된날까지의기간으로하였다. 흡연력은한번도흡연한과거력이없는환자를비흡연자로정했고 1년이상금연한환자를과거흡연자로정했다. 생존기간분석은 Kaplan-Meier 법을사용하였고, p값은 Log-Rank 에근거를두었다. 환자군의각각의특징들에대한치료반응률과질병조절률비교는 chi-square test 를사용하였다. 생존에영향을미치는인자분석에는로지스틱회귀모형을이용하였다. 통계적유의성은 p<0.05로정했다. 1. 환자군특성 결 치료반응평가가능한환자는총 89명이었다. 남자가 59명 (66%), 여자가 30명 (34%) 이었다. 연령분포는 34 81세 ( 중앙값 63세 ) 였다. 수행상태는 Eastern Cooperative Oncology Group performance status (ECOG PS) 0 1이 44예 (59%), 2가 45예 (41%) 이었다. 조직학적으로선암 Table 1. Patients characteristics (n=89) Characteristics No. of patients (%) Age (years) Median 63 Range Gender Male 59 (66) Female 30 (34) Smoking Current 51 (57) Never 26 (29) Former 12 (13) ECOG PS 0~1 44 (59) 2 45 (41) Histology Adenocarcinoma 52 (58) Squamous cell ca. 31 (35) Others 6 (7) No. of prior CTx 2nd 29 (33) 3rd or further 60 (67) Stage IIIB 17 (19) IV 72 (81) No: number; ECOG PS: eastern cooperative oncology group performance status; ca: carcinoma; CTx: chemotherapy. 과 122

3 Tuberculosis and Respiratory Diseases Vol. 67. No. 2, Aug Table 2. Response after 3 cycles of pemetrexed in NSCLC Response No. of patients (%) Complete response (CR) 0 Partial response (PR) 10 (11) Stable disease (SD) 49 (55) Progressive disease (PD) 30 (34) Overall response (CR+PR) 10 (11) NSCLC: non-small cell lung carcinoma; No: number. (adenocarcinoma) 이 52예 (58%), 편평상피암 (squamous cell carcinoma) 이 31예 (35%), 그밖의조직형태가 6예 (7%) 이었다. Pemetrexed 가 2차항암치료인환자가 29명 (33%), 3차이상의항암치료인환자가 60명 (67%) 이었다. 병기별로는 IIIB가 17예 (19%), IV가 72예 (81%) 이었다. 현재흡연자는 51명 (57%), 비흡연자는 26명 (29%), 과거흡연자는 12명 (13%) 이었다 (Table 1). 평균항암치료횟수는 3.8회였다. 2. 반응률및생존율 89예중완전관해는없었으며부분관해 10예 (11%), 불변 49예 (55%), 진행성병변 30예 (34%) 로치료반응률은 11% 였고질병조절률은 66% 였다 (Table 2, Figure 1). 생존중앙값은 13개월이었고, 관해지속중앙값은 2.3개월이었다 (Figure 2). 3. 각환자군특성에따른반응률및생존율비교 Figure 1. Waterfall plot of response on pemetrexed in advanced NSCLC. Waterfall plot illustrates patients' response to pemetrexed. Bars represent measurement for Response Evaluation Criteria for Solid Tumor-designated target lesions. Bars below the dotted line represent patients with confirmed partial response. 비편평상피암군이 7예 (12%) 로편평상피암군 3예 (9.7%) 에비해치료반응률이유의하게높았으며 (p=0.035), 질병조절률또한비편평상피암군이 44예 (75.9%) 로편평상피암군 15예 (48.4%) 에비해유의하게높았다 (p=0.009). 병기 (IIIB/IV), 흡연여부, PS (0 1/2), 성별그리고항암치료차수 (2차/3차이상항암치료 ) 는치료반응률및질병조절률에서통계적으로유의성이없었다. PS 0 1군과 2 군의생존중앙값이각각 13.2개월과 11.6개월로 PS 0 1 군이 2군보다통계적으로유의하게길었다 (p=0.002). 관해지속중앙값은 PS 0 1 군이 3.8 개월로 2군 2.1 개월보다 Figure 2. Median survival and median progression free survival (PFS) curve of patients with pemetrexed chemotherapy. The median survival time was 13 months and the median progression free survival time was 2.3 months. 123

4 GJ Lee et al: Efficacy and safety of pemetrexed in advanced non-small-cell lung carcinoma Table 3. Univariate and multivariate analyses for progression-free survival Characteristics PFS (months) Univariate analysis p-value Multivariate analysis Odds ratio (95% CI) Smoking Current+Former Never 3.23 ( ) Histology Squamous cell ca Non-squamous cell ca ( ) No. of prior CTx. 2nd line rd or further 3.54 ( ) Stage IIIB IV 3.54 ( ) ECOG PS ( ) Gender Male Female 4.03 ( ) PFS: progression-free survival; CI: confidence interval; No: number; CTx: chemotherapy; Ca: carcinoma; ECOG PS: eastern cooperative oncology group performance status. Table 4. Toxicities* of pemetrexed chemotherapy Gr 1 Gr 2 Gr 3 Gr 4 n (%) n (%) n (%) n (%) Hematologic toxicity Neutropenia 4 (4.5) 5 (5.6) 5 (5.6) 1 (1.1) Anemia 2 (2.2) 6 (6.7) Thrombocytopenia 1 (1.1) Non-hematologic toxicity Diarrhea 1 (1.1) Rash 2 (2.2) Gr: grade. *Toxicities were evaluated according WHO toxicity criteria. Figure 3. Progression free survival (PFS) curve of patients divided according to smoking and histology subtype. The median progression free survival time of smokers with non-squamous cell carcinoma was 3.4 months, which was significant. 통계적으로유의하게길었다 (p=0.016). 병리조직 (nonsquamous cell ca./squmous cell ca.), 병기, 흡연여부, 성별그리고항암치료차수에따른생존중앙값및관해지속중앙값은통계적유의성이없었다. 다변량분석시관해지속중앙값에영향을미칠것으로예상되는병리 조직, 병기, 흡연여부, PS, 성별그리고항암치료차수중유의한독립변수는없었다 (Table 3). 흡연자이면서비편평상피암조직형을가진환자군의관해지속중앙값은 3.4개월이었다. 이는흡연자이면서편평상피암군, 비흡연자이면서비편평상피암군, 그리고비흡연자이면서편평상피암군과비교시통계적으로유의하였다 (Figure 3). 4. 독성치료도중혈액학적독성이 24예 (27%), 소화기독성 1 예, 피부독성 2예이었다. 혈액학적독성은 3 4도가 7예 (7.9%) 이었고, 소화기독성및피부독성은각각 1도이었다 (Table 4). 124

5 Tuberculosis and Respiratory Diseases Vol. 67. No. 2, Aug 고찰현재진행성비소세포폐암의 1차항암치료는 platinum 을근간으로하는복합항암요법이다 11. 1차항암요법후재발또는진행한비소세포폐암의경우 2차항암치료제로 doxetaxel, pemetrexed, EGFR-TKI (erlotinib, gefitinib) 가있다. Doxetaxel 은 2차항암치료제중제일먼저제 3상임상시험이행해졌는데, 중앙생존값이최선의지지요법보다유의하게긴것으로밝혀져생존의이득이있음이증명되었다 12. EGFR TKI인 erlotinib 또한 1차항암치료에실패한비소세포폐암환자에서최선의지지요법보다중앙생존값이유의하게더길게나옴으로써그효과가증명되었다 13. 제3상임상시험에서 pemetrexed 는 docetaxel 3주요법과비교시비슷한중앙생존값을보임으로써그효과를인정받았으며부작용면에서는더안전함을보였다 14,15. 본연구에서는 pemetrexed 를비소세포폐암에서 2차이상의항암치료로사용하였다. 치료반응률은 11% 였으며질병조절률은 66% 였다. 생존중앙값은 13개월, 관해지속중앙값은 2.3개월이었다. 비편평상피암군이편평상피암군에비해통계적으로유의하게치료반응률과질병조절률이높게나왔다. 생존중앙값과관해지속중앙값은 PS 0 1군이 2군보다통계적으로유의하게길었다. 흡연자이면서비편평상피암군이관해지속중앙값이유의하게다른군들보다길었다. 하지만생존에대한독립인자는없었다. 혈액학적독성 3 4도는 7.9% 로독성은미미하였다. 이는치료반응률 9.1%, 질병조절률 54.9%, 생존중앙값 8.3개월, 관해지속중앙값 2.9개월, 혈액학적독성 3 4도 5.3% 를보이는 doxetaxel 과 pemetrexed 의효능및안전성을비교한제3상임상시험과비슷한결과를보였다 14,15. 본연구에서는생존에영향을미치는독립인자는없었지만 doxetaxel 과 pemetrexed 의효능및안전성을비교한제 3상임상시험에서예후인자는 PS 0 1군, III기그리고마지막항암치료후 3개월이상의시간경과였다 14,15. Bearz 등 16 과 Weiss 등 17 의연구에서는여성, PS 0 1군, III기, 비편평상피암군및이전 1차항암치료에대한반응이좋을수록생존에이득이있는것으로보고되고있다. 한국의다른연구결과들과비교하여보면 Lee 등 18 의연구는본연구와비슷한방법으로진행되었다. 진행성비소세포폐암에서 2차항암치료로 pemetrexed 단독요법을시행하였다. 치료반응률은 5.1%, 질병조절률은 46.2% 였 다. 생존중앙값은 7.8개월, 관해지속중앙값은 3.1개월이었다. 치료반응률에영향을미치는변수는없었으며, 질병조절률에영향을미치는독립인자로는비흡연자와선암군이있었다. PS와선암군이생존에영향을미치는독립인자이었다. 혈액학적독성및비혈액학적독성은 10% 미만으로본연구와비슷했다. 본연구보다질병조절률이낮은이유는환자구성면에서선암군은본연구환자비율과비슷하지만비흡연자가 74.1% 로본연구 29% 보다많기때문인것으로생각된다. Sun 등 19 의연구는연구방법및 pemetrexed 투여환자군을 2차및 3차이상의항암치료군두군으로나누었으며, 그비율이각각 30% 와 70% 로저자들의연구와비슷하였다. 치료반응률은 12%, 질병조절률은 55% 였다. 생존중앙값은 12.8개월, 관해지속중앙값은 3.03개월이었다. 2차항암치료와 3차이상의항암치료의관해지속기간을비교시통계적유의성은없었다. 생존이득의독립인자는 PS였다. 혈액학적독성 3 4도는 2% 였다. 이는본연구의결과와유사하였다. Sun 등 19 의연구가더나은관해지속중앙값을가지는것은 PS 0 1군이 79% 로본연구 59% 보다비율이더높기때문인것으로생각된다. 따라서위의제시된연구들및본연구에서 pemetrexed는이전항암치료에실패한비소세포폐암환자의경우 2차이상의항암치료제로효과가있으며, 독성은미미하였다. 참고문헌 1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer statistics, CA Cancer J Clin 2008;58: Korea National Statistical Office. Annual report on the cause of death statistics, Daejeon: Korea National Statistical Office; Herbst RS, Heymach JV, Lippman SM. Lung Cancer. N Engl J Med 2008;359: Socinski MA, Morris DE, Masters GA, Lilenbaum R. Chemotherapeutic management of stage IV non-small cell lung cancer. Chest 2003;123:226S-43S. 5. Socinski MA, Schell MJ, Peterman A, Bakri K, Yates S, Gitten R, et al. Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV nonsmall-cell lung cancer. J Clin Oncol 2002;20: Thödtmann R, Depenbrock H, Dumez H, Blatter J, Johnson RD, van Oosterom A, et al. Clinical and phar- 125

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기관고유연구사업결과보고 작성요령 2001 ~ 2004 2005 ~ 2007 2008 ~ 2010 2001 ~ 2004 2005 ~ 2007 2008 ~ 2010 1 2/3 2 1 0 2 3 52 0 31 83 12 6 3 21 593 404 304 1,301 4 3 1 8 159 191 116 466 6 11 (`1: (1: 16 33 44 106