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1 고위험군신경모세포종에서진단시나이에따른임상양상의차이 성균관대학교의과대학삼성서울병원소아과학교실 현혜선ㆍ성세인ㆍ최희원ㆍ이수현ㆍ유건희ㆍ성기웅ㆍ구홍회ㆍ김주연ㆍ조은주 Clinical Characteristic of High-risk Neuroblastoma Patients with Respect to Age at Diagnosis Hye Sun Hyun, M.D., Se In Sung, M.D., Heewon Chueh, M.D., Soo Hyun Lee, M.D., Keon Hee Yoo, M.D., Ki Woong Sung, M.D., Hong Hoe Koo, M.D., Ju Youn Kim, R.N. and Eun Joo Cho, R.N. Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Purpose: The purpose of this study was to evaluate the clinical characteristics and outcome of patients with high-risk neuroblastoma with respect to age at diagnosis. Methods: From January 1997 to December 2008, 76 patients were newly diagnosed with stage 4 neuroblastoma over 1 year of age at diagnosis. Patients were divided into two groups according to age at diagnosis; less than 18 months vs. over 18 months, less than 24 months vs. over 24 months and less than 36 months over 36 months. The clinical characteristics and outcome of patients were investigated with respect to the age. Results: Difference in the 5-year relapse-free survival rate was biggest when the patients were divided into less than 24 month group (n=17) and over 24 month group (n=59) (91.7±15.6% vs. 61.3±14.5%, P=0.049). While there was no difference in the toxic death rate between the two groups (11.8% vs. 11.9%), relapse was more frequent in over 24 month group (5.9% vs. 23.7%, P<0.001). There were no differences in sex, stage, histology, lactate dehydrogenase, ferritin, and neuron-specific enolase between the two groups. However, N-myc amplified tumor ( 3 copies) was more frequent in less than 24 month group (75.0% vs. 39.7%, P=0.012). In the multivariate analysis, age less than 24 months was a favorable factor for relapse-free survival with borderline significance (HR 0.16, 95% CI P=0.078). Conclusion: Relapse-free survival rate was higher in less than 24 month group than in over 24 month group despite a higher frequency of N-myc amplified tumor in less than 24 month group. Therefore, revision of treatment protocol might be needed to reduce treatment-related toxicity without jeopardizing survival rate in high-risk neuroblastoma patients less than 24 months of age at diagnosis. (Clin Pediatr Hematol Oncol 2010;17:36 42) Key Words: Stage 4 Neuroblastoma, Age, Prognosis 책임저자 : 성기웅, 서울시강남구일원동 50 성균관대학교의과대학삼성서울병원소아청소년과, Tel: , Fax: kwsped@skku.edu 서론신경모세포종은영유아기에가장흔한악성종양의하나로전체소아암의약 7% 를차지하며매 임상소아혈액종양제 17 권제 1 호

2 고위험군신경모세포종에서나이에따른임상양상 37 년 100만명중 10명에서발생한다. 환자의약 90% 가 5세이전에발생하며약 40% 가고위험군이다 1). 예후인자로는진단시나이, 전이여부, N-myc 유전자의증폭여부, Shimada 병리형, 종양세포 DNA의고배수성여부및 1번염색체단완및 11번염색체장완의결실여부, 종양의발생부위등이있다. 나이가중요한예후인자중하나로서 12개월이상은 12개월이하에비해상대적으로예후가불량하여 Maris 2) 의보고에따르면진단시 12개월이하인경우생존율이 83% 이나 12개월이상에서는 45% 로나이에따라큰차이가있다. 그러나, 최근일부연구들은 18개월이예후인자의기준으로서더합당하다고제시하고있다 2-5). 고위험신경모세포종에서도나이에따른임상양상의차이가있을것으로추정되나아직잘연구되어있지않다. 이러한배경에서본연구는같은원칙으로치료하였던진단시 12개월이상, 4병기인신경모세포종환자에서나이에따른임상적특징을비교하였다. 대상및방법 1) 대상 1997년 1월부터 2008년 12월까지삼성서울병원소아청소년과에서새로진단된신경모세포종환자중진단시나이가 12개월이상이면서 4병기인환자를연구대상으로하였다. 타원에서치료를하던중혹은재발후전원된환자들은대상에서제외하였다. 2) 진단시평가원발종양및전이부위의조직학적검사로신경모세포종을진단하였다. 종양의전이정도를파악하기위하여전산화단층촬영, technetium-99 뼈스캔, 양쪽골반의골수생검, 그리고 I 혹은 I 123 -metaiodobenzylguanidine scan을시행하였다. N-myc 유전자의증폭수는 Southern blot analysis 나정량역전사중합효소연쇄반응 (quantitative reverse transcriptase-polymerase chain reaction) 을통해서평가하였다. 병기분류는국제분류법 (Internatinal Neuroblastoma Staging System; INSS) 을사용하였다. 병리학적소견은 Shimada 분류법을사용하였다. 진단시혈청 lactate dehydrogenase (LDH), ferritin, neuron-specific enolase (NSE) 그리고 24시간소변의 vanillylmandelic acid (VMA) 를측정하였다. 3) 치료대상환자들에게수술전화학요법, 수술, 수술후화학요법을시행한후 2회의고용량화학요법및자가조혈모세포이식을시행하였다. 2003년까지는수술후잔존종양이있는경우만원발부위에국소방사선치료를시행하였으며 2004년이후에는모든고위험군환자들에게고용량화학요법및자가조혈모세포이식후에국소방사선치료를시행하였다. 고용량화학요법및자가조혈모세포이식후분화요법으로 125 mg/m 2 의 13-cisretinoic acid를 2주간사용후 2주간휴식하는방법으로총 10회사용하였다. 또한이식후혈소판이수혈없이 /L에이르면 interleukin-2를 U/m 2 /day 용량으로매 4주마다 5일동안연속하여피하주사하는방법으로면역요법을시작하였다. 13-cis-retinoic acid의첫투여일은 interleukin-2의첫투여일과같게하였다. 4) 통계대상환자들을 18개월이하 / 이상, 24개월이하 / 이상, 36개월이하 / 이상으로분류하여이들집단사이의임상적, 생물학적특징및생존율을비교하였다. 생존율은 Kaplan-Meier 방법을이용하여구하였으며생존율의비교는 log-rank test를이용하였다. 사건은재발과독성사망으로정의하였다. 생존율에영향을주는위험인자에대한다변

3 38 현혜선ㆍ성세인ㆍ최희원등 Table 1. The Probability of 5-year Event-free Survival (EFS) Rates with Respect to the Clinical and Biological Characteristics No. 5-year EFS (95% CI) P value Sex Female ±20.5 Male ± N-myc Nonamplified (<3 copies) ±17.5 Amplified (3 copies) ± Shimada pathology Favorable ±26.1 Unfavorable ± Bone metastasis Negative ±29.8 Positive ± Bone marrow metastasis Negative ±23.6 Positive ± LDH <Median (<2,145 U/L) ±19.6 Median ( 2,145 U/L) ± Ferritin <Median (<195 ng/ml) ±18.1 Median ( 195 ng/ml) ± NSE <Median (<178.2 ng/ml) ±17.9 Median ( ng/ml) ± hour urine VMA <Median (<6.8 mg/day) ±16.1 Median ( 6.8 mg/day) ± Event-free survival <18 m ± m ± <24 m ± m ± <36 m ± m ± Relapse-free survival <18 m ± m ± <24 m ± m ± <36 m ± m ± Abbreviaions: LDH, lactate dehydrogenase; NSE, neuron-specific enolase; VMA, vanillylmandelic acid

4 고위험군신경모세포종에서나이에따른임상양상 39 수분석은 Cox-regression analysis를이용하였다. 두집단간위험인자의분포는 Chi-square test를이용하였다. P값이 0.05미만일때의미있는것으로간주하였다. 결과진단시나이가 12개월이상이며 4병기인 76명의환자들에서성별, 병리소견, 뼈전이, 골수전이에따른 5년무사건생존율의차이는없었다. N-myc 증폭과 LDH, NSE, urine VMA 값의고저에따른 5년무사건생존율도차이가없었으나 ferritin 값의고저에따라서는생존율의차이가있었 다 (Table 1). 환자들의진단시나이에따라 18개월이하 (n= 8)/ 이상 (n=68), 24개월이하 (n=17)/ 이상 (n=59), 36개월이하 (n=32)/ 이상 (n=44) 로각각나누어 5년무사건생존율을비교하였을때세군모두나이가어릴수록무사건생존율이높았으며 24개월이하 / 이상에서가장큰무사건생존율의차이가있었다 (80.9±19.7% vs. 51.4±14.2%, P=0.091) (Fig. 1). 24 개월이하 / 이상에서독성사망은각각 2명 (11.8%), 7명 (11.9%) 으로차이가없었으나재발은각각 1명 (5.9%), 14명 (23.7%) 로 24개월이상군에서많았으며 (P<0.001), 양군간 5년무재발생존율에서도유의한차이가있었다 (91.7±15.6% vs. 61.3±14.5%, Fig. 1. Results of Kaplan-Meier analysis for eventfree survival (EFS) with respect to age at diagnosis. (A) The 5-year EFS (±95% CI) for less than 18 month and over 18 month group were 70.0±35.7% and 56.6±13.1%, respectively (P=0.577). (B) The 5-year EFS (±95% CI) for less than 24 month and over 24 month group were 80.9±19.7% and 51.4±14.2%, respectively (P=0.091). (C) The 5-year EFS (±95% CI) for less than 36 month and over 36 month group were 65.8±17.5% and 51.3±16.8%, respectively (P=0.300).

5 40 현혜선ㆍ성세인ㆍ최희원등 Table 2. Clinical and Biologic Characteristics with Respect to Age <24 m (n=17) 24 m (n=59) P value Sex Female 5 (29.4%) 21 (35.6%) Male 12 (70.6%) 38 (64.4%) N-myc Nonamplified (<3 copies) 4 (25.0%) 35 (60.3%) Amplified ( 3 copies) 12 (75.0%) 23 (39.7%) Shimada pathology Favorable 4 (28.6%) 12 (24.1%) Unfavorable 10 (71.4%) 41 (75.9%) Bone metastasis Negative 3 (17.6%) 4 (6.8%) Positive 14 (82.4%) 55 (93.2%) Bone marrow metastasis Negative 4 (23.5%) 14 (23.7%) Positive 13 (76.5%) 45 (76.3%) LDH (U/L) 2,145 (176 15,720) 1,981 (505 9,944) Ferritin (ng/ml) 195 (74 670) 367 (51 6,690) NSE (ng/ml) 178 (14 1,507) 168 (14 1,080) Abbreviaions: LDH, lactate dehydrogenase; NSE, neuron-specific enolase P=0.049). 무재발생존율에대한다변수분석을시행하였을때 24개월이상나이와 N-myc 증폭의 hazard ratio는각각 6.30 (95% CI , P=0.078) 및 1.43 (95% CI , P=0.443) 였다. 진단시나이 24개월을기준으로임상양상을비교하였을때성별, 병리형, 뼈전이, 골수전이, LDH, ferritin, NSE 등에서차이가없었으나 N-myc 이증폭된 (3 copy 이상 ) 경우는 24개월이하에서더많았다 (75.0% vs. 39.7%, P=0.012) (Table 2). 고찰신경모세포종의예후는다양한임상적, 생물학적특징에의해영향받는다. 진단시나이 5), 병기 6,7), N-myc 증폭여부 8,9), Shimada 병리소견 10,11) 그리고종양세포 DNA의고배수성 12) 등을근거로해서위험군을분류하고있으며 6,13) 임상적, 생물학적다양성에따라분류된위험군들에적정치 료를함으로써예후의향상이지난수십년간에걸쳐이루어졌다 14,15). 진단시나이에관한여러연구들에서나이의기준으로 12개월이중요하다고보고하고있는데 16-18), Schmidt 등 13) 의보고에의하면 12개월이하의환아들은 3년무병생존율이 93% 이나, Matthay 등 19,20) 의보고에의하면 12개월이상의신경모세포종환자들은고용량화학요법후에도약 1/3만이생존하여나이에따른예후의차이가큼을알수있다. 그러나최근연구에서 4병기신경모세포종에서도 N-myc 유전자의증폭이없으면 12 18개월에서예후가양호하다고보고하고있으며나이의기준으로 12개월이적정함에대해의문점을제시하고있다 3,21). 이러한배경에서본연구에서는고위험군신경모세포종에서도나이에따른예후의차이가있는지알아보고자하였다. 연구결과, 진단시 12개월이상, 4병기신경모세포종인환자에서나이에따른 5년무사건생존율을비교하였을때나이가

6 고위험군신경모세포종에서나이에따른임상양상 41 어릴수록생존율이높았고 24개월기준으로비교하였을때생존율의차이가가장컸다. 24개월을기준으로비교하였을때, 양군간독성사망의차이는없었으나재발은 24개월이상군에서많았다. 5년무재발생존율에서도 24개월이하에서유의하게양호하였다. 진단시 24개월을기준으로환자의임상양상을비교하였을때성별, 병리형, LDH, ferritin, NSE 등에서차이가없었으나 N-myc 이증폭된 (3 copy 이상 ) 경우는오히려 24개월이하에서많았다. 즉, 24개월이하에서는 N- myc이증폭된경우가더많았음에도무재발생존율이유의하게높음을알수있었다. 적정한치료는치료로인한독성을최소화하면서치료로인한생존율의향상을이루어야한다. 이런측면에서본연구에서 24개월이하인군에서재발은 1명뿐이었으나 2명이이식중독성으로사망한것으로보아치료의강도가필요이상으로높았을지도모른다. 더구나나이가어릴수록치료의후기독성이더많은것을감안한다면 24개월이하환자에서는재발이증가되지않는범위내에서장단기치료독성을줄이기위한새로운치료적접근이필요하다고사료된다. 치료독성을줄이기위해서는항암화학요법기간의단축, 항암제용량의감량및 12 24개월군에서 N-myc 증폭음성군과 N-myc 증폭양성군을분류하여치료방법을달리적용하는방법등을고려할수있다. 반면, 24개월이상인군에서는재발이주된치료실패의원인이므로재발을줄이기위한좀더적극적인치료가필요한것으로사료되며이에대해서는지속적인연구가필요할것이다. 요약목적 : 고위험군신경모세포종환자에서나이에따른임상적특징을비교하고자하였다. 방법 : 1997년 1월부터 2008년 12월까지삼성서울병원에서새로진단되고치료를시작한신경모세포종환자중진단시나이가 12개월이상, 4병 기인환자들을나이에따른임상양상을분석하였다. 18개월이하 / 이상, 24개월이하 / 이상, 36개월이하 / 이상으로환자들을두군으로각각나누어임상적특징을비교하였다. 결과 : 5년무재발생존율의차이는 24개월이하 (n=17)/ 이상 (n=59) 으로나누어비교하였을때가장컸다 (91.7±15.6% vs. 61.3±14.5%, P=0.049). 두군에서독성사망의차이는없었으나 (11.8% vs. 11.9%) 재발은 24개월이상인군에서많았다 (5.9% vs. 23.7%, P<0.001). 진단시나이 24개월을기준으로임상양상을비교하였을때성별, 병리형, LDH, ferritin, NSE 등에서차이가없었으나 N-myc이증폭된 (3 copy 이상 ) 경우는 24개월이하에서많았다 (75.0% vs. 39.7%, P=0.012). 무재발생존율에대한다변수분석을시행하였을때 24개월이하의나이는예후양호인자였다 (HR 0.16, 95% CI P=0.078). 결론 : 24개월이하인환자들은 N-myc이증폭된경우가더많았음에도무재발생존율이유의하게높았다. 그러므로진단시 12개월이상 24개월이하인환자에서는양호한생존율을유지하면서장단기치료독성을줄이기위해새로운치료적접근이필요할것으로사료된다. 참고문헌 1. Park JR, Eggert A, Caron H. Neuroblastoma: biology, prognosis, and treatment. Pediatr Clin North Am 2008;55: Maris JM. The biologic basis for neuroblastoma heterogeneity and risk stratification. Curr Opin Pediatr 2005;17: London WB, Castleberry RP, Matthay KK, Look AT, Seeger RC, Shimada H, et al. Evidence for an age cutoff greater than 365 days for neroblastoma risk group stratification in the Children's Oncology Group. J Clin Oncol 2005;23: Evans AE. Staging and treatment of neuroblastoma. Cancer 1980;45: Breslow N, McCann B. Statistical estimation of prognosis for children with neuroblastoma. Cancer Res 1971;31:

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( )Jkstro011.hwp 비인강암의방사선치료결과및생존율에관한예후인자분석 2005 2 1 2005 3 28. :, Tel: 053)250-7665, Fax: 053)250-7984 E-mail: jhkim@dsmc.or.kr 정영연외 2 인 : 비인강암의예후인자분석 정영연외 2 인 : 비인강암의예후인자분석 Carcinoma of the nasopharynx treated by radiotherapy