Clinical Pediatric Hematology-Oncology Volume 23 ㆍ Number 1 ㆍ April 2016 REVIEW ARTICLE 중추신경계생식세포종양의최근치료경향 한정우 1,2 ㆍ고경남 3 ㆍ김지윤 4 ㆍ백희조 5 ㆍ이지원 6 ㆍ심규원 7 ㆍ조재호 8 ㆍ김동석 7 1 연세대학교의과대학소아과학교실, 2 연세암병원소아청소년암센터소아혈액종양과, 3 울산대학교의과대학소아과학교실, 4 경북대학교의과대학경북대학교병원소아과학교실, 5 전남대학교의과대학소아과학교실, 6 성균관대학교의과대학소아과학교실, 7 연세대학교의과대학신경외과학교실, 8 연세대학교의과대학방사선종양학교실 Current Trends in Management for Central Nervous System Germ Cell Tumor Jung Woo Han, M.D. 1,2, Kyung-Nam Koh, M.D. 3, Ji Yoon Kim, M.D. 4, Hee Jo Baek, M.D. 5, Ji Won Lee, M.D. 6, Kyu-Won Shim, M.D. 7, Jaeho Cho, M.D. 8 and Dong-Seok Kim, M.D., Ph.D. 7 1 Division of Pediatric Hemato-Oncology, Department of Pediatrics, Yonsei University College of Medicine, Yonsei University Health System, 2 Department of Pediatric Hemato-Oncology, Yonsei Cancer Center, Yonsei University Health System, 3 Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Ulsan College of Medicine & Asan Medical Center, Seoul, 4 Department of Pediatrics, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, 5 Department of Pediatrics, Chonnam National University Medical School, Chonnam National University Hwasun Hospital, Gwangju, 6 Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 7 Department of Pediatric Neurosurgery, Severance Hospital, Yonsei University Health System, 8 Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University Health System, Seoul, Korea Central nervous system germ cell tumor is a rare but important tumor in childhood brain tumors. It requires a multidisciplinary approach to increase survival and promote quality of life, and all three treatment modalities including surgery, radiotherapy and chemotherapy has its own distinct role for germ cell tumor. For germinoma, radiotherapy alone can cure the disease but, the effort to limit the long term toxicity and the proper combination of chemotherapy and radiotherapy are under investigation. Craniospinal irradiation is reserved only for the disseminated germinoma or nongerminomatous germ cell tumor (NGGCT). For germinoma, craniospinal irradiation of 20 to 24 Gy is sufficient to control microscopic disease in the spinal axis. Chemotherapy and radiotherapy composed of 30 to 40 Gy of local field radiotherapy and 20 to 24 Gy of whole ventricular irradiation are required for localized germinoma, but the proper combination of two modalities has yet to be defined. For NGGCT, both the chemotherapy and radiotherapy should be performed, and survival rate is substantially increasing with modern treatment protocols. The omission of craniospinal irradiation is being tried for the localized NGGCT in international cooperative group trials. Surgery has its role for the resection of residual disease after the treatment, and the extent of resection in NGGCT has the prognostic implication. Bifocal germ cell tumors and basal ganglia germ cell tumor have distinctive clinical course and mandate special attention. To advance clinical and biological perspectives in central nervous germ cell tumor, the cooperation and communication of the multidisciplinary specialists are essential. Key Words: Neoplasms, Germ cell and embryonal, Brain neoplasms, Germinoma, Neoplasms pissn 2233-5250 / eissn 2233-4580 http://dx.doi.org/10.15264/cpho.2016.23.1.17 Clin Pediatr Hematol Oncol 2016;23:17 27 Received on March 30, 2016 Revised on April 11, 2016 Accepted on April 21, 2016 Corresponding Author: Dong-Seok Kim Department of Pediatric, Neurosurgery in Severance Children s Hospital, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Yonsei University Health System, CPO Box 8044, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea Tel: +82-2-2228-2160 Fax: +82-2-393-9979 E-mail: dskim33@yuhs.ac 17
Jung Woo Han, et al 서론중추신경계생식세포종양은전체뇌종양중약 1-2% 를차지하는종양이다. 여타중추신경계종양과달리, 생식세포종양에는수술, 방사선, 항암화학요법의다양한역할이공존하고, 이들의적절한조합으로생존율의향상과삶의질제고에기여할수있다. 이에, 각치료방침의이해와, 다학제간협력이무엇보다중요한종양이라고할수있다 [1,2]. 본종설에서는중추신경계생식세포종양의임상양상과다양한치료방법의역할에대해고찰하고자한다. 본론 1) 중추신경계생식세포종양 (germ cell tumor) 의기원중추신경계생식세포종양 (germ cell tumor, GCT) 는드문신경계종양으로, 원인에대해두가지학설이있다. 첫째는원시생식세포 (primordial germ cell) 가잘못이주 (migration) 하여생식기능선 (genital ridge) 대신배아의중추신경계 (embryonic central nervous system) 에정착하였다는것이고, 둘째는다능성줄기세포 (pluripotent stem cell) 가중추신경계내에존재하다가생식세포종으로변화한다는것이다 [3]. 2) 역학빈도는전통적으로서양에서 0.4-3.4%, 일본과대만에서 2.1-9.4% 를차지하는것으로알려져있었다 [4]. 미국의등록사업보고에따르면 0-19세신경종양중 3.9% 를차지하고 10만명당 0.1명이발생한다. 남녀의성비는 2.1:1로남성에서더흔한것으로알려져있다. 발생중앙연령은 16.0세이다. 또한백인에서 1.5배정도로흑인보다많다. 0-19세에 0.22명으로가장높고, 20-34세에 0.10명, 이후연령대에서는 0.02-0.05명으로매우드물게발생한다. 매년미국에서는약 290명이발생하는것으로알려져있다 [5]. 일본에서는구마모토 (Kumamoto) 현에서 1989-1998년까지 10만명당 0.20명이발생하고, 남 : 녀 2.58이라고하여서양보다높다고알려졌다. 특히 15세미만에서 0.55명으로높고, 10-19세에빈발하였다. 조직확인비율은 65.8% 였다 [6]. 같은지역에서 1989-2008년까지최근보고에의하면발생률은 0.22, 성비는 3.36이었고전체중추신경계종양중 1.2% 를차지하였다. 특히 2005-2008년에는발생률 0.10, 성비 1.62로보고되어서양과차이가없었다 [7]. 미국과일본의등록사업을통합한연구에서일본에서는송과샘 (pineal gland) 에 40.2%, 안장위 (suprasellar) 에 41.8% 가 발생하였고미국에서는송과샘 46.4%, 안장위 65.6% 가발생하였다 [8]. 여성에서는 75% 가안장위에나타나고, 남성에서는 67% 가송과샘에발생된다고하는데, 일본남성의 57.7% 와미국남성의 86.6% 에서송과샘에, 일본여성의 82.3% 와미국여성의 66.1% 에서안장위에위치하였다 [4,8]. 송과샘종양의남녀비는 11.7-14.4였고, 안장위종양의남녀비는 1.8-1.1이었다. 미국와일본에서전체종양중 77.5-82.0% 가뇌종자세포종 ( 뇌종자종, intracranial germinoma) 였다. 전연령대에서비슷한뇌종자종분포를보였으나 0-9세에서는 42.9-51.1% 만이뇌종자종이었다. 뇌종자종과전체생식세포종양의절대발생수는미국과일본모두 10-14세에가장많았다 [8]. 3) 분류 WHO (World Health Organization) 분류에서생식세포종양은뇌종자종과비종자종성생식세포종양 (non germinomatous germ cell tumor, NGGCT) 으로분류된다 (Table 1) [9]. 뇌종자종은일반적으로종양표지자를표현하지않지만, 융합영양세포 (syncytiotrophoblast) 가포함되어있는경우베타- 인간융모막성선자극호르몬 (beta-human chorionic gonadotrophin ( hcg, hcg)) 가상승할수있다. 상승범위에대해서는이견이있으나 50 miu/ml까지는뇌종자종의범주로간주하는것이추세이고, 연구자에따라서는 50-100 miu/ml까지도뇌종자종으로간주할때도역시치료성적이유사하다고하고있다 [10]. 미국에서도 100 miu/ml까지는뇌종자종으로간주하여치료하여도예후에차이가없었으나그이상인경우는주의가필요하다고의견이있다 [11]. 일부에서는 200 miu/ml 또는그이상인경우에도예후에차이가없다고주장하기도한다 [12]. 이를종합하여유럽에서는 hcg>50 miu/ml 그리고 / 또는 AFP (Alpha fetoprotein)>25 ng/ml 또는기관의참 Table 1. Classification of germ cell tumors Germ cell tumors Morphology code Germinomas 9064/3 Nongermionmatous germ cell tumors Embryonal carcinoma 9070/3 Yolk sac tumor 9071/3 Choriocarcinoma 9100/3 Teratoma 9080/1 Immature teratoma 9080/3 Mature teratoma 9084/0 Teratoma with malignant transformation 9084/3 Mixed germ cell tumors 9085/3 18 Vol. 23, No. 1, April 2016
Management of Central Nervous System Germ Cell Tumor 고치이상을분비성생식세포종양 (secreting germ cell tumor) 로정의하고있고 [13,14], 미국에서는조직학적진단이없는경우 AFP 10 ng/ml 또는기관의참고치이하, hcg 50 miu/ml를뇌종자종으로, 조직학적진단이있는경우 hcg 100 miu/ml까지로정의하고있다 [15]. 난황낭종양 (york sac tumor, YST) 이나융모막암종 (choriocarcinoma) 은각각 AFP와 hcg를특이적으로분비하며, 예후가나쁘다 [2]. 일본에서는생식세포종양을불량예후군 (Poor prognosis group), 중간예후군 (intermediate), 양호예후군 (good) 으로분류하고있다 (Table 2). 마츠타니등은도쿄대학교에서 153명의조직학적으로확인된생식세포종양을분석하였다 [16]. 비종자종성생식세포종양에대해 Japanese Intracranial Germ Cell Tumor Study Group의항암화학요법과방사선치료를하였고, 뇌종자종 50예에대해 43명은방사선치료를, 7 명은항암치료와방사선치료를하였다 [16]. 뇌종자종과성숙기형종은 10년 92.7-92.9% 의생존율을보였으나, 순수악성생식세포종양 (pure malignant germ cell tumor (N=11); 융모망암종, 배아암종또는난환낭종양 ) 또는조직에순수생식세포종양이포함된혼합생식세포종양 (mixed germ cell tumor, N=12) 에서는 5년생존율이 9.3-27.3% 에불과하였다. 이를바탕으로 3가지단계의분류가제안되었다 [16]. 중간예후군의예후는시스플라틴기반의항암화학요법과방사선치료로 5년생존율 92-97% 정도를보이며, 이는방사선치료단독군의 62% 에비해높다 [17]. 불량예후군의예후는과거 10-20% 에머물렀으나현재는최소 60% 를상회한다 [16,18]. Table 2. Japanese classification of germ cell tumors Good prognosis group Pure germinoma Mature teratoma Intermediate prognosis group Germinoma with STGC (Syncytiotrophoblastic giant cells) Immature teratoma Mixed GTC consisted of germinoma with either mature or immature teratoma Teratoma with malignant transformation Poor prognostic group Embryonal carcinoma Yolk sac tumor Choriocarcinoma Mixed germ cell tumors including a component of embyonal carcinoma, yolk sac tumor, choriocarcinoma or other malignant neoplasm 4) 임상증상임상증상은환자의연령, 종양의위치, 종류, 분비물질, 크기에따라다양하게나타난다 [19]. 송과샘위치종괴는폐쇄성수두증을발생하여뇌압이상승하는경우가많아, 뇌실복강단락술 (ventriculoperitoneal shunt) 를시행하거나제3뇌실창냄술 (ventriculostomy) 을시행할수있으며, 이중현실적으로가능하다면제3뇌실창냄술이추천된다 [20]. 또한파리노증후군 (Parinaud s syndrome, dorsal midbrain syndrome; 상향주시력마비, pseudo-argyll robertson 동공, 눈꺼풀뒤당김, 일몰징후 (setting sun sign), 폭주후퇴안진등의증상복합증후군 ), 사시, 복시를포함한안구증상등이나타날수있다. 내분비계이상이나이차성징발달이상은안장위종양에비해적다 [21]. 안장위종양에서는내분비이상특히중추성요붕증이흔히종양의첫증상으로발생한다 [22]. hcg 상승으로 LH (luteinizing hormone), FSH (follicular stimulating hormone) 상승과성조숙증이발생한다 [2,22]. 그외에뇌하수체기능저하증, 성선기능저하, 사춘기성숙지연, 갑상선기능저하, 성장장애등내분비증상이나타난다 [3,19]. 5) 진단정확한진단은치료의결정에반드시필요하다 [2]. 임상증상, 종양표지자및영상검사, 뇌척수액검사등으로진단및병기를결정한다. 가능한한생검으로조직학적확진이필요하다. 종양표지자로는 AFP, hcg와 PLAP (placental alkaline phosphatase) 이있으며, 혈액및뇌척수액에서시행한다. 종양때문만아니라정상에서도, 혈청보다뇌척수액에서종양표지자가더높게측정되는경향이있어주의를요한다 [3,20,23]. 종양표지자는진단시뿐만아니라치료반응을관찰할수있으므로정기적으로추적되어야하며, 진단시음성이라하여도추적검사를주기적으로행해야한다 [20]. 뇌척수액세포학적검사는양성결과를치료결정에반영하는국가나기관에서는반드시시행하는것을추천하며, 뇌실보다는요추천자로시행하여야한다 [20]. 영상검사에는뇌및척수자기공명영상이추천된다 [20]. 기저체 (basal ganglia) 에발생한종양은초기에조영증강이잘되지않고구분이어려운경우가많으므로진단과추적에주의를요한다 [24]. 병기는생식세포종양에특화된체계는없으며, 수모세포종 (medulloblastoma) 의병기체계를따라 M0-M4까지분류하여적용한다 [2,25]. 뇌척수전이는뇌종자종에서약 7-12% 에서나타나며난황낭종양에서는 23% 까지보고된다 [4,26]. 드물지만 Clin Pediatr Hematol Oncol 19
Jung Woo Han, et al 3% 에서폐, 뼈등으로전신전이를하는경우가있고, 뇌실복강단락술을받은경우 10% 까지복강내전이가발생하기도하며, 매우드물지만동시에고환또는난소에종괴가있는경우도배제할수없으므로, 복부, 가슴, 뼈및고환부위의영상검사도필요시고려하여시행하기도한다 [3,4]. 6) 생식세포종양의치료-뇌종자종 (germinoma) (1) 방사선치료단독연구-두개척추방사선조사 (craniospinal irradiation, CSRT) 두개척추방사선조사 (craniospinal irradiation, CSRT) 는뇌종자종치료에충분한효과를갖는다. MAKEI (the maligue keimzelltumoren) 83/86 연구 (N=60) 에서는, 두개척추방사선조사 36 Gy 및원발부위추가치료 (primary tumor boost, PTB) 14 Gy를, MAKEI 89연구에서두개척추방사선조사 30 Gy 및원발부위추가치료 15 Gy를조사하여 5년무재발생존율 (Relapse Free Survival, RFS) 은 91%±3.9%, 5년전체생존율 (overall survival, OS) 는 93.7±3.6% 으로, 두개척추방사선조사 30-36 Gy, 국소부위방사선치료 (local field radiotherapy, LFRT) 45-50 Gy는뇌종자종을완치시킬수있었다 [27]. 두개척추방사선조사로완치가가능함이알려지면서용량을낮추는시도가이루어졌다. Shibamato 등은 50 Gy 이상을시작으로점차감량하여뇌척수전이예방용량으로두개척추방사선조사 20-24 Gy 정도가충분한것으로생각되었다 [28]. Children s Hospital of Philiadelphia (CHOP, Pennsylvania) 에서최소 30.6 Gy 이상의두개척추방사선조사를조사를시작으로감량하여 23.4-27 Gy (89년까지) 및그이후 19-19.8 Gy까지조사량을낮추었으며전이가없는환자에서는 18-19.8 Gy의두개척추방사선조사를받아도높은생존율을보였다 [29]. 허등은국소부위방사선치료 54 (40-56.1) Gy, 전뇌방사선치료 (whole brain radiotherapy, WBRT) 36 (19.8-44) Gy, 척추축 (spinal axis) 24 (13.1-36) Gy를투여하여 5년및 10년전체생존율 96.9% 였다 [30]. 따라서뇌종자종에서필요한두개척추방사선조사는최소 20-24 Gy 정도로생각된다. Cho 등은최근에이를수록원발부위용량 59에서 39.3 Gy, 두개척추방사선조사 34.2에서 19.2 Gy로낮추어치료하였으며, 두개척추방사선조사를진행한 60예중 51예 (85%) 가두개척추방사선조사 25 Gy 미만을, 22예 (36.7%) 가 20 Gy 미만 ( 중앙값 19.5 Gy) 를받아, 두개척추방사선조사 19.5 Gy 정도로완전한조절을이룰것으로기대되었다 [31]. 따라서뇌종자종에서전이가있다하더라도일반적으로두개척추방사선조사 20-24 Gy 가충분하다고보여진다 [32]. (2) 방사선치료단독연구-제한된영역의방사선조사원발부위 40-50 Gy의방사선치료는재발을일으키지않으며두개척추방사선조사는뇌종자종치료에명확한효과를갖는다 [28,33]. 그러나치료효과를얻으며장기후유증을예방하기위해, 방사선치료의용량과범위에많은연구가진행되었다. 파종성전이여부는예후에관계가있으나두개척추방사선조사여부는예후에관계가없어, 완전한뇌척수전이평가가이루어진다면, 비전이성뇌종자종에서두개척추방사선조사는필요없다 [34]. 비전이성뇌종자종에서두개척추방사선치료대신국소부위방사선치료하는경우질환을조절하는데일정부분효과가있다 [35]. 그러나, 국소부위방사선치료만으로는비전이성뇌종자종치료시척수나두개내, 뇌실부위재발이많았으므로최소한뇌실을방사선치료에포함할필요성이있다 [36]. 특히 40 Gy미만의조사를한경우국소부위방사선치료는두개내재발확률이높아불충분하였다 [37]. 40 Gy 정도의치료는조사부위내부에서는재발을방지하였지만뇌실이포함되지않은국소부위방사선치료는재발위험성이있으며, 범위를넓힌전뇌방사선치료는뇌종자종치료에충분한조절효과를발휘하였다 [38]. 결과적으로전뇌실방사선치료 (whole ventricle irradiation, WVI) 이상의치료가뇌종자종치료에필요하다 [39]. 전뇌실방사선치료및원발부위추가치료포함원발부위 40 Gy 이상정확한 CT 시뮬레이션으로투여한환자에서는재발이없었다 [40]. 전뇌실방사선치료를점차감소시켜 20-40 Gy 수준까지낮추고, 원발부위추가치료도총 30-50 Gy까지낮추어시행하여도재발없이잘치료되었다 [41,42]. 또한항암화학요법의반응성에따라, 반응이좋은환자에서는방사선치료의범위가축소될수있는가능성도제시되었다 [43]. 현재전뇌실방사선치료 20-24 Gy, 원발부위최소 30-40 Gy 정도가뇌종자종치료에충분한용량으로생각된다. (3) 항암화학요법및방사선치료항암치료의병합은방사선치료의용량과범위를낮출것으로예상되어연구되어왔다 [20]. Allen 등은전보조 (neoadjuvant) 항암화학요법으로방사선치료의용량을원발부위 55 Gy에서 33.1 (30-45) Gy, 두개척추방사선조사를 36 Gy에서 26.2 (20.0-30.0) Gy로낮추었다고보고하였다 [44]. POG 9530 에서는 4회의항암화학요법후국한성뇌종자종인경우국소부위방사선치료 30.6-50.4 Gy 시행하고 91.7% (11/12) 가중앙추적기간 66개월에무진행생존하여항암화학요법병합시국소부위방사선치료만으로관해를유지할수있음을보여주었다 [45]. 20 Vol. 23, No. 1, April 2016
Management of Central Nervous System Germ Cell Tumor 하지만국소부위방사선치료는항암치료병합에도불충분하다는의견이많다. SFOP에서항암화학요법을병합하였으나비전이성뇌종자종에대해국소부위방사선치료 40 Gy를조사하고, 두개내재발이다수발생하여국소부위방사선치료만으로는질병조절에부족하였다 [46]. SIOP CNS 96 뇌종자종연구에서는항암화학요법후비전이성뇌종자종에국소부위방사선치료 40 Gy를사용하여, 뇌실막하재발을경험하였다 [13]. 반면항암화학요법병용시에도국소부위방사선치료보다는뇌실이상에방사선치료한경우재발이없었다. Aoyama 등은그들의경험에서최종적으로뇌종자종에서 WV 24 Gy+ 원발부위추가치료 6-16 Gy로치료하는것을권고하였다 [47]. Children s Hospital LA (CHLA) 에서도역시항암화학요법에전뇌실방사선치료 21.6-25.5 Gy 및원발부위추가치료추가, 총 30.0-30.6 Gy가사용되어투여하여 3년무사건생존율 89.5%, 전체생존율 100% 로질환이조절됨을보고하였다 [11]. 비전이성뇌종자종의치료시국소부위방사선치료는뇌실막하국소재발뿐만아니라척수재발역시높으며대신, 전뇌실방사선치료는척수재발률에서두개척추방사선치료와비슷하였다 [48]. 따라서항암화학요법병합시에도전뇌실방사선치료이상이추천된다. (4) 전이성뇌종자종전이성뇌종자종에는두개척추방사선치료가필요하며잘조절된다 [31,45,49]. 항암화학요법을병합할때두개척추방사선치료를줄일수있는지에대해서는아직명확하지않지만, 대부분의기관에서항암화학요법을병용한다 [45,49]. 최근에는선량을낮추어 19.5-25 Gy 미만의저용량두개척추방사선조사로도질환이잘조절됨이알려져있다 [31,50]. (5) 항암화학요법단독치료생식세포종양은일반적으로항암화학요법반응성이좋으며, 따라서중추신경계생식세포종양에서도항암화학요법단 독치료법이연구되었다. 항암화학요법단독으로는질환을조절하기어렵다 [51]. 첫번째국제임상시험으로서진행된연구에서, 항암화학요법은높은완전관해율 (77.4%) 을얻었지만, 2 년전체생존율은뇌종자종 84%, 비종자종성생식세포종양 62% 으로기대보다낮았다. 하지만, 54명의생존환자중 22명 (40.7%) 은방사선치료없이생존하였으므로항암치료단독으로생존할수있는환자들도소수이지만있었다는것이알려졌다 [52]. 3번째국제 CNS GCT 연구에서는항암화학요법만으로 11/25 (44%) 에서재발하였고, 7/11은뇌종자종, 4/14명은비종자종성생식세포종양이었으며이와같이항암화학요법단독으로는치료가불가능하나, 완전관해율은높았고소수의환자들은항암화학요법단독으로충분한기간생존하였다 [53]. (6) KSPNO 뇌종자종임상시험대한소아뇌종양학회에서는 G051/081 임상시험을진행하였다 (Table 3, 4). KSPNO G051임상시험에서방사선단독치료군과항암화학요법 / 방사선치료병용군으로나뉘어진행되었으나, 2008년이후 G081/G082로통합되어방사선단독치료군은제외되었다. G051 방사선치료단독군 30명과 G081 치료결과 122명이등록되었다. 조직학적진단은 115명 (94.2%) 에서이루어졌고, 임상적으로 5예가진단되었다. 항암화학요법후 75% 에서완전관해또는 VGPR (very good partial response) 이관찰되었고 1명의질환관련사망이있었다. 완전관해환자중 5명이최종재발하였고 PD는 1명에서관찰되었고, 알수없는이유로뇌출혈이발생한 1명, 총 7명에서질환관련사건 (event) 이발생하였다. 재발한환자 1명과, 뇌출혈로 1명이사망하였으며, 항암화학요법중에도 PD를보였던 1명이최종적으로사망하여전체사망환자는 3명이었다. 5년무사건생존율 93%, 전체생존율 97% 였다. Table 3. Pre-radiotherapy chemotherapy regimen for KSPNO clinical trial (A/B/A/B, total 4 courses every 3 weeks, alternating) Germinoma NGGCT Course A Carboplatin 450 mg/m 2 D1 450 mg/m 2 D1-2 Etoposide 150 mg/m 2 D1-3 150 mg/m 2 D1-3 Bleomycin - 15 mg/m 2 D3 Course B Cyclophosphamide 1,000 mg/m 2 D1-2 2,000 mg/m 2 D1-2 Etoposide 150 mg/m 2 D1-3 150 mg/m 2 D1-3 Bleomycin - 15 mg/m 2 D3 NGGCT, nongerminomatous germ cell tumor. Clin Pediatr Hematol Oncol 21
Jung Woo Han, et al Table 4. Radiotherapy plan for KSPNO G081 and G082 Classification Response to chemotherapy CSRT (Gy) LFRT (Gy) Total (Gy) KSPNO G081 Solitary CR 0 30.6 30.6 <CR 19.5 19.8 39.3 Multiple or disseminated CR 19.5 10.8 30.3 <CR 24 16.2 40.2 KSPNO G082 Localized 36 18-23.4 54-59.4 Disseminated 39 14.4-19.8 53.4-58.8 CR, complete remission; CSRT, craniospinal irradiation; LFRT, local field irradiation. 7) 비종자종성생식세포종양 (nongerminomatoud germ cell tumor, NGGCT) (1) 비종자종성생식세포종양의치료전통적으로비종자종성생식세포종양의예후는매우좋지않아전통적으로마츠타니분류의불량예후군은 5년생존율 9.3-27.3% 에불과하였다 [16]. 또한 1990년대이전의생식세포종양 5년생존율은뇌종자종약 45-64%, 비종자종성생식세포종양 25.7% 였다 [4,54]. 현재비종자종성생식세포종양의치료에는항암화학요법과두개척추방사선조사가모두필요하다 [20,47,55-57]. 항암화학요법과병용하여방사선치료를하는경우에도, 두개척추방사선조사를하지않으면척수재발이흔하였다 [58]. 두개척추방사선조사를한환자들의재발율은낮았다 [18,59]. MAKEI 89 분석에서는 cisplatin 400 mg/m 2 이상사용되었을때생존율이높았고 (18/22 vs. 2/8), 두개척추방사선조사 30 Gy, 원발부위추가치료 15-20 Gy를받은환자에서가장생존율이높았다 [60]. 항암화학요법으로는 cisplatin, carboplatin, etoposide, ifoafamide, bleomycin, vinblastine 등이사용된다 [20,45,47,57]. POG 9530 고위험군치료에서항암화학요법 (etoposide, cisplatin, vincristine, cyclophosphamide) 과방사선요법으로 78.6% (11/14) 가 58개월에무진행생존하여생존율향상을보여주었다 [45]. COG-ACNS0122 연구에서는비종자종성생식세포종양에대해 CE (carboplatin 600 mg/m 2 D1, etoposide 90 mg/m 2 /d D1-3) 또는 IE (ifosfamide 1,800 mg/m 2 D1-5, etoposide 90 mg/m 2 D1-5) 를총 6회치료하고완전관해인경우방사선치료, 완전관해이하인경우잔존종양수술을진행하여완전관해또는부분관해인경우방사선치료, SD 또는부분관해이면서종양표지자양성인때고용량항암화학요법및조혈모세포이식을진행한후방사선를하였다. 두개척추방사선조 사 36 Gy, 국소부위방사선치료 54 Gy를투여하였고척수의육안적전이종괴에대해 45 Gy의부스트를하였다. 5년무사건생존율 84%, 전체생존율 93% 를나타내었다. 항암화학요법후잔존종양수술은 15명에서시행되었고, 단 2명 (13%) 만비종자종성생식세포종양의잔존세포가있었다. 치료중진행한 5명중 4명은기형종이었다. 치료중단 2명만이식의대상이되었고두명다생존하였다. 비종자종성생식세포종양의종류에따라생존율차이가없었으며항암화학요법후완전관해또는부분관해를얻은환자의생존율이 3년무사건생존율 92%, 전체생존율 98% 에이르렀다 [61]. 대부분의재발은 18개월이내에일어나지만 5년이후에발생되는경우도있어장기간의추적을요한다 [4,16,55]. 종합하면비종자종성생식세포종양의방사선치료는원발부위총 50 Gy, 두개척추방사선조사는 30-36 Gy 정도로적용된다. 또한비종자종성생식세포종양의치료에는수술, 방사선치료, 항암화학요법등이모두쓰인다. 최근진행되는임상시험인 COG-ACNS 1123에서는국한성비종자종성생식세포종양에서 SIOP CNS 96의예비결과와첫번째국제임상시험에서완전관해를이룬 15/21명이살아있고, 두번째국제임상시험에서완전관해를이룬환자가부분관해보다오래생존하며, 완전관해를이루지못한 5명모두사망한결과등을근거로, 항암화학요법에반응이있는환자에대해서두개척추방사선조사대신침범부위방사선치료 (involved filed RT) 를시행하고있다 [15]. (2) KSPNO 비종자종성생식세포종양임상시험대한소아뇌종양학회에서는 G052/082 임상시험을진행하였다 (Table 3, 4). 조직검사에서비종자종성생식세포종양으로확진되거나혈청, 뇌척수액종양표지자검사에서 hcg가 50 miu/ml 이상, AFP이 10 ng/dl 이상인경우비종자종성 22 Vol. 23, No. 1, April 2016
Management of Central Nervous System Germ Cell Tumor 생식세포종양으로진단하였다. 조직학적으로뇌종자종이었으나종양표지자양성이었던 22예와, 임상적또는조직학적으로확진된비종자종성생식세포종양 46예를포함하여총 99예가등록되었다. 사망은 8예였고, 질환관련 6예, 독성사망 2예있었다. 항암화학요법에의해 49.5% 가완전관해또는매우양호한부분관해 (very good partial remission) 을보였고, PD는 11예 (11.1%) 에서있었다. 5년무사건생존율은 74%, 전체생존율 89% 였다. 8) 최근의국제임상시험동향 COG-ACNS1123은국소성중추신경계생식세포종양의치료를연구하고있다. AFP>10 ng/ml와함께조직검사로확인된경우 hcg 100 miu/ml까지를, 조직검사로확인하지않는경우 hcg 50 miu/ml를뇌종자종으로한다. 항암화학요법후반응에따라방사선치료또는이차수술을계획한다. 항암화학요법에완전관해인경우전뇌실방사선치료를 18 Gy까지낮추어치료한다. 국한성비종자종성생식세포종양인경우두개척추방사선조사를제외하고전뇌실방사선치료 30.6 Gy, 국소부위방사선치료 23.4 Gy를사용하였다. 전이성비종자종성생식세포종양인경우 COG-ACNS0122 프로토콜에따른다. SIOP CNS GCT II 연구에서는그동안잘알려지지않았던기형종 (teratoma) 에대한치료방침을설정하고자노력하고있다. 또한 AFP가 1,000 ng/ml으로극히높은군을고위험군으로지정하고조혈모세포구제술을응용한중등용량항암화학요법을사용한다. 특히뇌종자종에서도항암화학요법후기형종이남아있는경우, 완전절제가되지않으면재발위험이있다는 SIOP CNS 96연구의하위분석결과에따라, 기형종이있는경우절제가완전하지않다면 54.4 Gy까지국소방사선용량을높일것을주장하고있다. 비전이성뇌종자종에는전뇌실방사선치료 24.0 Gy를투여하고, 항암요법에완전관해미만인경우국소부위방사선치료 14.0 Gy를추가한다. 비전이성비종자종성생식세포종양에는두개척추방사선조사없이 54 Gy의국소부위방사선치료만을사용하며, 전이성비종자종성생식세포종양에두개척추방사선조사 30 Gy, 국소부위방사선치료 24 Gy를투여한다. 9) 기타관련된이슈들 (1) 중추신경계생식세포종양에서의수술의역할종양표지자가정상인경우, 조직검사없이치료하여높은성적을보고하기도한다 [62]. 그러나대개, 정상일경우라도, 영상소견에상관없이진단을위한수술적조직검사가행해져야한다 [20]. 근치적절제술 (radical surgery) 은뇌종자종에서 무재발생존율이나전체생존율에영향을주지않으며조직검사단독으로도최종진단은대개정확하다 [63]. 이와같이영상검사가발달하고, 정위조직검사의기술이좋아져진단에어려움이없으며, 특히시상하부, 뇌하수체등에종괴가위치할때는합병증을초래할위험이많으므로, 뇌종자종의근치적절제는피하는것이좋다. 또한 SIOP CNS GCT 96 연구를보면잔존종양이남은 67명의환자들은다른환자들에비해무사건생존율과무진행생존율이차이가없었다 (0.95 vs. 0.93, P=0.54; 0.97 vs. 0.94 P=0.41) [13]. 다만방사선치료없이항암화학치료만단독으로시행하는경우에는, 근치적절제술을받은환자들이결과적으로생존하였으므로, 수술의역할이있을것으로예상할수있다 [52]. 비종자종성생식세포종양은종양표지자가상승되어진단에적합한경우조직검사를하지않을수있다 [20]. 다만, 항암화학요법후에도잔존종양이남는경우가많고종양표지자가지속적으로상승되어있는등잔존종양에대해수술하는것은추천된다 [20]. 기형종, 괴사, 섬유화된조직일경우가많으며, 수술로써치료가종료된다 [19]. 비종자종성생식세포종양인경우절제범위에따른생존율차이를보인다 [59,64]. 수술은합병증과사망을초래할수있으므로, 증상이없다면 1 차적절제는피하고잔존종양이남을때수술하는지연접근법을추천한다 [65,66]. SIOP CNS 96 연구에따르면수술적절제를하지않는것보다는, 항암치료후지연수술을받거나, 부분절제후지연수술을받는경우가장결과가좋았다고하였다 [67]. 결과적으로비종자종성생식세포종양에서절제범위는생존에영향을줄수있으며, 북미에서는지연수술을권고한다. (2) 기형종증식증후군 (growing teratoma syndrome, GTS) 종양표지자가정상화되면서항암화학요법중간또는그후크기가커지며, 병리학적으로비종자종성생식세포종양의잔존종양이없을때기형종증식증후군이라고부른다 [68,69]. 빈도는 2-7% 로알려져있다 [69,70]. 1997-2008년의 170명의환자분석중 11명 (6.5%) 에서 GTS가발생하였고모두비종자종성생식세포종양이었다. 9명은전절제, 2명은부분절제로치료되었다. 잔존 GTS의재발과진행이 2명의환자에서사망을초래하였다 [69]. 따라서비종자종성생식세포종양치료중증상, 의식, 신경학적징후의악화소견이있다면영상학적검사확인및수술이필요하다. (3) hcg의상승과뇌종자종 Shibamato 등은방사선단독치료으로뇌종자종과 hcg 분 Clin Pediatr Hematol Oncol 23
Jung Woo Han, et al 비종자종사이에 10년전체생존율및무재발생존율은각각 89% 와 100% 로두군간에차이가없었다고하였다 [12]. 반면 Sawamura는 hcg 분비뇌종자종 (5-200 mui/ml) 과순수뇌종자종간에는질환특이무진행생존율 (cause specific progression) 에차이가있다고하였다 (P<0.001) [65]. Fujikami 등은뇌종자종과 hcg 분비뇌종자종사이에재발률 12.4% 와 12.8%, 5년전체생존율 98.3% 와 100% 로차이가없었다고하였으나, 방사선치료는 27.8 Gy 대 36.9 Gy (P<0.01) 로, 항암화학요법의횟수도 3.1회 vs. 5.3회 (P<0.01) 로 hcg 분비뇌종자종에서더많이사용되어치료강도가달랐음을유념할필요가있다 [71]. Ogino 등도생존율차이가없었다고하였으나, hcg 분비뇌종자종환자들은두개척추방사선조사를더많이받았다 [72]. Ogawa 등은뇌종자종과 hcg 분비뇌종자종사이에 hcg의상승여부가예후에차이가없었다고 ( 각각 94%, P=0.95) 하였지만, 이연구역시방사선치료단독연구이다 [38]. CHLA의연구에서도 hcg 100 miu/ml을넘은환자가 1명재발하였음에유의할필요가있다 [11]. Lim 등도그들의분석에서 hcg가 5명에서는 200 이상, 4명은 500 miu/ml 이상을나타내었으나모두생존하여, hcg의수치는예후에크게상관이없었으나, 두개척추방사선조사가모두투여되었기때문에 hcg 효과가상쇄되었을가능성이있다 [73]. 따라서항암치료및방사선치료병용으로방사선치료의용량이적어질경우 hcg 분비종양의예후는나빠질가능성을고려해야한다. 현재북미임상시험 ACNS 1123에서는뇌종자종의진단기준으로서, 조직학적으로확진되는경우혈청및뇌척수액 hcg 100 miu/ml까지로하였다 [15]. (4) 양초점생식세포종양 (bifocal germ cell tumor) 송과샘과안장위에동시에침범하나연뇌막파종의증거가없을때중추신경계생식세포종양을양초점생식세포종양 (bifocal germ cell tumor, BFG) 이라고부른다 [2,4]. 약 6-10% 를차지하며진단중간연령은 12.9세였다 [2,4]. 예후에관하여이견이존재하며, 반응이좋아국한성으로볼수있다는견해와, 연수막전이를하므로전이성질환으로봐야한다는견해가있다 [74]. Phi 등은전체생식세포종양환자중 23예 (12.7%) 의양초점생식세포종양을확인하였고이중뇌종자종은 18예였으며동시발생보다는전이성일가능성이많을것이라고주장하였다. 또한양초점생식세포종양은방사선치료범위가더넓은경향이었음에도무사건생존율 62.8% 로낮았다 (P< 0.01) [75]. 두개척추방사선치료대신항암화학요법후전뇌실방사선치료 2,400-4,000 cgy와원발부위추가치료 (1,600 cgy) 만으로도질환이잘조절된다 [76]. 또한 Weksberg 등도항암화학요법을진행한다면두개척추방사선조사를제외한방사선요법이가능할것이라고하였다. 반면전이가있는경우에는두개척추방사선조사의여부가생존율에큰영향 (100% vs. 69%. P=0.013) 을나타내므로양초점생식세포종양이발견될경우철저한전이여부확인이반드시필요하며, 전이가없을때두개척추방사선조사를제외한다면항암화학요법을추가하는것이좋을것으로분석된다 [77]. 임상시험으로서현재북미에서는전이성질환으로, 유럽에서는국한성질환으로보고치료한다 [48,74]. (5) 기저체생식세포종양 (basal ganglia germ cell tumor) 기저체생식세포종양은약 10% 에서발생한다고알려져있으며종양의경계가불분명하고기저체침범범위를정확히확인하기어렵기때문에보다확장된국소 (extended local) 또는전뇌방사선치료가필요하다 [78,79]. 영상검사상발견이어려워진단이지연되거나, 침범범위를잘못설정하여국소부위방사선치료만으로치료를종료하는경우가있어뇌실막하전파를막지못하여생존율이낮아지므로, 최소한뇌실을포함한방사선치료가필요하다 [24]. 일부에서는두개척추방사선조사를하기도한다 [78]. 이렇듯기저체생식세포종양에서는방사선치료범위의확장이필요하다. 결론뇌종자종은현재의치료방식으로충분히완치를이룰수있으며, 방사선용량과범위도많이축소하여왔다. 방사선및항암화학요법의각각의부작용과장기후유증, 항암화학요법과의병용의필요성과그역할에대한많은의견들이있지만, 뇌종자종의치료방침에끊임없는천착으로각치료방식의가장적절한능력과조합방식, 그한계에대한결론을도출하기위해다학제간의소통과연구가필요하다. 비종자종성생식세포종양은과거와달리병리및영상학적발달, 방사선치료와항암화학요법의병용, 적절한수술적조치등으로생존율의지대한향상을보여왔다. 그러나생식세포종양은태생적으로중추신경계종양으로서의특성, 통계적으로충분치않은환자수, 다양한임상양상, 임상시험의난점등으로연구자에게는깔끔한결론을도출하는데걸림돌이많다. 다양한, 그리고알려져있지않은생식세포종양의모습과이요약에다루지않은생물학적특징, 재발성중추신경계생식세포종양, 더욱다양해질암종의분자병리학적분류와각치료방식에가장잘반응할환자들을찾는예측인자 (predictive mark- 24 Vol. 23, No. 1, April 2016
Management of Central Nervous System Germ Cell Tumor er) 등에대해, 연구자들의더많은관심이필요하다. References 1. Kyritsis AP. Management of primary intracranial germ cell tumors. J Neurooncol 2010;96:143-9. 2. Thakkar JP, Chew L, Villano JL. Primary CNS germ cell tumors: current epidemiology and update on treatment. Med Oncol 2013;30:496. 3. Bromberg JE, Baumert BG, de Vos F, et al. Primary intracranial germ-cell tumors in adults: a practical review. J Neurooncol 2013;113:175-83. 4. Jennings MT, Gelman R, Hochberg F. Intracranial germ-cell tumors: natural history and pathogenesis. J Neurosurg 1985;63:155-67. 5. Ostrom QT, Gittleman H, Fulop J, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008-2012. Neuro Oncol 2015;17 Suppl 4:iv1-62. 6. Kuratsu J, Takeshima H, Ushio Y. Trends in the incidence of primary intracranial tumors in Kumamoto, Japan. Int J Clin Oncol 2001;6:183-91. 7. Nakamura H, Makino K, Yano S, Kuratsu J; Kumamoto Brain Tumor Research Group. Epidemiological study of primary intracranial tumors: a regional survey in Kumamoto prefecture in southern Japan--20-year study. Int J Clin Oncol 2011;16: 314-21. 8. McCarthy BJ, Shibui S, Kayama T, et al. Primary CNS germ cell tumors in Japan and the United States: an analysis of 4 tumor registries. Neuro Oncol 2012;14:1194-200. 9. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. WHO Classification of tumours of the central nervous system. 4th ed. Geneva: World Health Organization, 2007;197-204. 10. Finlay J, da Silva NS, Lavey R, et al. The management of patients with primary central nervous system (CNS) germinoma: current controversies requiring resolution. Pediatr Blood Cancer 2008;51:313-6. 11. Khatua S, Dhall G, O'Neil S, et al. Treatment of primary CNS germinomatous germ cell tumors with chemotherapy prior to reduced dose whole ventricular and local boost irradiation. Pediatr Blood Cancer 2010;55:42-6. 12. Shibamoto Y, Takahashi M, Sasai K. Prognosis of intracranial germinoma with syncytiotrophoblastic giant cells treated by radiation therapy. Int J Radiat Oncol Biol Phys 1997;37:505-10. 13. Calaminus G, Kortmann R, Worch J, et al. SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease. Neuro Oncol 2013;15:788-96. 14. Calaminus G, Andreussi L, Garre ML, Kortmann RD, Schober R, Gobel U. Secreting germ cell tumors of the central nervous system (CNS). First results of the cooperative German/Italian pilot study (CNS sgct). Klin Padiatr 1997;209:222-7. 15. Bartels U, Dhall G. Chemotherapy followed by radiation therapy in treating younger patients with newly diagnosed localized central nervous system germ cell tumors.. Children's Oncology Group. (Accessed March 1, 2016, at https:// clinicaltrials.gov/ct2/show/nct01602666) 16. Matsutani M, Sano K, Takakura K, et al. Primary intracranial germ cell tumors: a clinical analysis of 153 histologically verified cases. J Neurosurg 1997;86:446-55. 17. Matsutani M. Combined chemotherapy and radiation therapy for CNS germ cell tumors--the Japanese experience. J Neurooncol 2001;54:311-6. 18. Kim JW, Kim WC, Cho JH, et al. A multimodal approach including craniospinal irradiation improves the treatment outcome of high-risk intracranial nongerminomatous germ cell tumors. Int J Radiat Oncol Biol Phys 2012;84:625-31. 19. Echevarria ME, Fangusaro J, Goldman S. Pediatric central nervous system germ cell tumors: a review. Oncologist 2008;13:690-9. 20. Murray MJ, Bartels U, Nishikawa R, Fangusaro J, Matsutani M, Nicholson JC. Consensus on the management of intracranial germ-cell tumours. Lancet Oncol 2015;16:e470-7. 21. Crawford JR, Santi MR, Vezina G, et al. CNS germ cell tumor (CNSGCT) of childhood: presentation and delayed diagnosis. Neurology 2007;68:1668-73. 22. Jorsal T, Rorth M. Intracranial germ cell tumours. A review with special reference to endocrine manifestations. Acta Oncol 2012;51:3-9. 23. Tian C, Shi Q, Xiao G, et al. CSF and serum hcg in patients without gestational and neoplastic hcg-secretion. Scand J Clin Lab Invest 2011;71:264-8. 24. Phi JH, Cho BK, Kim SK, et al. Germinomas in the basal ganglia: magnetic resonance imaging classification and the prognosis. J Neurooncol 2010;99:227-36. 25. Packer RJ, Cohen BH, Cooney K. Intracranial germ cell tumors. Oncologist 2000;5:312-20. 26. Brada M, Rajan B. Spinal seeding in cranial germinoma. Br J Cancer 1990;61:339-40. 27. Bamberg M, Kortmann RD, Calaminus G, et al. Radiation therapy for intracranial germinoma: results of the German cooperative prospective trials MAKEI 83/86/89. J Clin Oncol 1999; 17:2585-92. 28. Shibamoto Y, Takahashi M, Abe M. Reduction of the radiation dose for intracranial germinoma: a prospective study. Br J Cancer 1994;70:984-9. 29. Maity A, Shu HK, Janss A, et al. Craniospinal radiation in the treatment of biopsy-proven intracranial germinomas: twenty-five years' experience in a single center. Int J Radiat Oncol Biol Phys 2004;58:1165-70. 30. Huh SJ, Shin KH, Kim IH, Ahn YC, Ha SW, Park CI. Clin Pediatr Hematol Oncol 25
Jung Woo Han, et al Radiotherapy of intracranial germinomas. Radiother Oncol 1996;38:19-23. 31. Cho J, Choi JU, Kim DS, Suh CO. Low-dose craniospinal irradiation as a definitive treatment for intracranial germinoma. Radiother Oncol 2009;91:75-9. 32. Shibamoto Y, Oda Y, Yamashita J, Takahashi M, Kikuchi H, Abe M. The role of cerebrospinal fluid cytology in radiotherapy planning for intracranial germinoma. Int J Radiat Oncol Biol Phys 1994;29:1089-94. 33. Fields JN, Fulling KH, Thomas PR, Marks JE. Suprasellar germinoma: radiation therapy. Radiology 1987;164:247-9. 34. Shikama N, Ogawa K, Tanaka S, et al. Lack of benefit of spinal irradiation in the primary treatment of intracranial germinoma: a multiinstitutional, retrospective review of 180 patients. Cancer 2005;104:126-34. 35. Buckner JC, Peethambaram PP, Smithson WA, et al. Phase II trial of primary chemotherapy followed by reduced-dose radiation for CNS germ cell tumors. J Clin Oncol 1999;17:933-40. 36. Alapetite C, Brisse H, Patte C, et al. Pattern of relapse and outcome of non-metastatic germinoma patients treated with chemotherapy and limited field radiation: the SFOP experience. Neuro Oncol 2010;12:1318-25. 37. Haddock MG, Schild SE, Scheithauer BW, Schomberg PJ. Radiation therapy for histologically confirmed primary central nervous system germinoma. Int J Radiat Oncol Biol Phys 1997;38:915-23. 38. Ogawa K, Shikama N, Toita T, et al. Long-term results of radiotherapy for intracranial germinoma: a multi-institutional retrospective review of 126 patients. Int J Radiat Oncol Biol Phys 2004;58:705-13. 39. Yen SH, Chen YW, Huang PI, et al. Optimal treatment for intracranial germinoma: can we lower radiation dose without chemotherapy? Int J Radiat Oncol Biol Phys 2010;77:980-7. 40. Shirato H, Nishio M, Sawamura Y, et al. Analysis of long-term treatment of intracranial germinoma. Int J Radiat Oncol Biol Phys 1997;37:511-5. 41. Haas-Kogan DA, Missett BT, Wara WM, et al. Radiation therapy for intracranial germ cell tumors. Int J Radiat Oncol Biol Phys 2003;56:511-8. 42. Kawabata Y, Takahashi JA, Arakawa Y, Shirahata M, Hashimoto N. Long term outcomes in patients with intracranial germinomas: a single institution experience of irradiation with or without chemotherapy. J Neurooncol 2008;88: 161-7. 43. Joo JH, Park JH, Ra YS, et al. Treatment outcome of radiation therapy for intracranial germinoma: adaptive radiation field in relation to response to chemotherapy. Anticancer Res 2014;34: 5715-21. 44. Allen JC, Kim JH, Packer RJ. Neoadjuvant chemotherapy for newly diagnosed germ-cell tumors of the central nervous system. J Neurosurg 1987;67:65-70. 45. Kretschmar C, Kleinberg L, Greenberg M, Burger P, Holmes E, Wharam M. Pre-radiation chemotherapy with responsebased radiation therapy in children with central nervous system germ cell tumors: a report from the Children's Oncology Group. Pediatr Blood Cancer 2007;48:285-91. 46. Bouffet E, Baranzelli MC, Patte C, et al. Combined treatment modality for intracranial germinomas: results of a multicentre SFOP experience. Société Française d'oncologie Pédiatrique. Br J Cancer 1999;79:1199-204. 47. Aoyama H, Shirato H, Ikeda J, Fujieda K, Miyasaka K, Sawamura Y. Induction chemotherapy followed by low-dose involved-field radiotherapy for intracranial germ cell tumors. J Clin Oncol 2002;20:857-65. 48. Rogers SJ, Mosleh-Shirazi MA, Saran FH. Radiotherapy of localised intracranial germinoma: time to sever historical ties? Lancet Oncol 2005;6:509-19. 49. Chen YW, Huang PI, Hu YW, et al. Treatment strategies for initially disseminated intracranial germinomas: experiences at a single institute. Childs Nerv Syst 2012;28:557-63. 50. Shim KW, Park EK, Lee YH, et al. Treatment strategy for intracranial primary pure germinoma. Childs Nerv Syst 2013;29: 239-48. 51. Shim KW, Kim TG, Suh CO, et al. Treatment failure in intracranial primary germinomas. Childs Nerv Syst 2007;23: 1155-61. 52. Balmaceda C, Heller G, Rosenblum M, et al. Chemotherapy without irradiation--a novel approach for newly diagnosed CNS germ cell tumors: results of an international cooperative trial. The First International Central Nervous System Germ Cell Tumor Study. J Clin Oncol 1996;14:2908-15. 53. da Silva NS, Cappellano AM, Diez B, et al. Primary chemotherapy for intracranial germ cell tumors: results of the third international CNS germ cell tumor study. Pediatr Blood Cancer 2010;54:377-83. 54. Hoffman HJ, Otsubo H, Hendrick EB, et al. Intracranial germ-cell tumors in children. J Neurosurg 1991;74:545-51. 55. Dearnaley DP, A'Hern RP, Whittaker S, Bloom HJ. Pineal and CNS germ cell tumors: Royal Marsden Hospital experience 1962-1987. Int J Radiat Oncol Biol Phys 1990;18:773-81. 56. Schild SE, Haddock MG, Scheithauer BW, et al. Nongerminomatous germ cell tumors of the brain. Int J Radiat Oncol Biol Phys 1996;36:557-63. 57. Matsutani M, Sano K, Takakura K, Fujimaki T, Nakamura O. Combined treatment with chemotherapy and radiation therapy for intracranial germ cell tumors. Childs Nerv Syst 1998;14: 59-62. 58. Robertson PL, DaRosso RC, Allen JC. Improved prognosis of intracranial non-germinoma germ cell tumors with multimodality therapy. J Neurooncol 1997;32:71-80. 59. Schild SE, Scheithauer BW, Haddock MG, et al. Histologically confirmed pineal tumors and other germ cell tumors of the brain. Cancer 1996;78:2564-71. 60. Calaminus G, Bamberg M, Jürgens H, et al. Impact of surgery, 26 Vol. 23, No. 1, April 2016
Management of Central Nervous System Germ Cell Tumor chemotherapy and irradiation on long term outcome of intracranial malignant non-germinomatous germ cell tumors: results of the German Cooperative Trial MAKEI 89. Klin Padiatr 2004;216:141-9. 61. Goldman S, Bouffet E, Fisher PG, et al. Phase II trial assessing the ability of neoadjuvant chemotherapy with or without second-look surgery to eliminate measurable disease for nongerminomatous germ cell tumors: A Children's Oncology Group Study. J Clin Oncol 2015;33:2464-71. 62. Takahashi S, Yoshida K, Kawase T. Intracranial germ cell tumors: efficacy of neoadjuvant chemo-radiotherapy without surgical biopsy. Keio J Med 2011;60:56-64. 63. Sawamura Y, de Tribolet N, Ishii N, Abe H. Management of primary intracranial germinomas: diagnostic surgery or radical resection? J Neurosurg 1997;87:262-6. 64. Nam DH, Cho BK, Shin HJ, Ahn HS, Kim IH, Wang KC. Treatment of intracranial nongerminomatous malignant germ cell tumor in children: the role of each treatment modality. Childs Nerv Syst 1999;15:185-91. 65. Sawamura Y, Ikeda J, Shirato H, Tada M, Abe H. Germ cell tumours of the central nervous system: treatment consideration based on 111 cases and their long-term clinical outcomes. Eur J Cancer 1998;34:104-10. 66. Calaminus G, Bamberg M, Harms D, et al. AFP/beta-HCG secreting CNS germ cell tumors: long-term outcome with respect to initial symptoms and primary tumor resection. Results of the cooperative trial MAKEI 89. Neuropediatrics 2005;36:71-7. 67. Czech T, Nicholson J, Frappaz D, et al. Patients with intracranial non-germinomatous germ cell tumours (NGGCT): benefit from delayed surgery after neoadjuvant chemotherapy. final results of SIOP CNS GCT 96. Neuro Oncol (International Symposium on Pediatric Neuro-Oncology) 2012;14(Suppl 1): i49-55. 68. Geisler JP, Goulet R, Foster RS, Sutton GP. Growing teratoma syndrome after chemotherapy for germ cell tumors of the ovary. Obstet Gynecol 1994;84:719-21. 69. Kim CY, Choi JW, Lee JY, et al. Intracranial growing teratoma syndrome: clinical characteristics and treatment strategy. J Neurooncol 2011;101:109-15. 70. Tonkin KS, Rustin GJ, Wignall B, Paradinas F, Bennett M. Successful treatment of patients in whom germ cell tumour masses enlarged on chemotherapy while their serum tumour markers decreased. Eur J Cancer Clin Oncol 1989;25:1739-43. 71. Fujimaki T. Matsutani M. HCG-producing germinoma: analysis of japanese pediatric brain tumor study group results. Neuro Oncol (International Symposium on Central Nervous System Germ Cell Tumors) 2005;7:513-33. 72. Ogino H, Shibamoto Y, Takanaka T, et al. CNS germinoma with elevated serum human chorionic gonadotropin level: clinical characteristics and treatment outcome. Int J Radiat Oncol Biol Phys 2005;62:803-8. 73. Lim do H, Yoo KH, Lee NH, et al. Intensive chemotherapy followed by reduced-dose radiotherapy for biopsy-proven CNS germinoma with elevated beta-human chorionic gonadotropin. J Neurooncol 2014;117:279-85. 74. Al-Mahfoudh R, Zakaria R, Irvine E, Pizer B, Mallucci CL. The management of bifocal intracranial germinoma in children. Childs Nerv Syst 2014;30:625-30. 75. Phi JH, Kim SK, Lee J, et al. The enigma of bifocal germ cell tumors in the suprasellar and pineal regions: synchronous lesions or metastasis? J Neurosurg Pediatr 2013;11:107-14. 76. Lafay-Cousin L, Millar BA, Mabbott D, et al. Limited-field radiation for bifocal germinoma. Int J Radiat Oncol Biol Phys 2006;65:486-92. 77. Weksberg DC, Shibamoto Y, Paulino AC. Bifocal intracranial germinoma: a retrospective analysis of treatment outcomes in 20 patients and review of the literature. Int J Radiat Oncol Biol Phys 2012;82:1341-51. 78. Rasalkar DD, Chu WC, Cheng FW, Paunipagar BK, Shing MK, Li CK. Atypical location of germinoma in basal ganglia in adolescents: radiological features and treatment outcomes. Br J Radiol 2010;83:261-7. 79. Sonoda Y, Kumabe T, Sugiyama S, et al. Germ cell tumors in the basal ganglia: problems of early diagnosis and treatment. J Neurosurg Pediatr 2008;2:118-24. Clin Pediatr Hematol Oncol 27