online ML Comm J Korean Brain Tumor Soc 9:97-102, 2010 임 상 큰청신경초종치료를위한의도적아전절제술후방사선수술 : 단일기관관찰연구 가톨릭대학교의과대학서울성모병원신경외과학교실 최두용 강석구 전신수 홍용길 김문찬 박춘근 Intended Subtotal Resection Followed by Radiosurgery for Large Vestibular Schwannoma: Single Institute Observational Study Doo Yong Choi, M.D., Seok-Gu Kang, M.D., Ph.D., Sin Soo Jeun, M.D., Ph.D., Yong Kil Hong, M.D., Ph.D., Moon Chan Kim, M.D., Ph.D., Chun Kun Park, M.D., Ph.D. Department of Neurosurgery, The Catholic University of Korea College of Medicine, Seoul St. Mary s Hospital, Seoul, Korea ABSTRACT Objective:Although there have been many reports about the management options for vestibular schwannoma(vs), the lack of high evidence prospective clinical trials made us choose proper management based on clinician s personal priorities. In terms of functional outcome(hearing and facial nerve preservation), the surgical results for large VS may be worse compared to small VS. The aim of this study was to report our treatment strategy for large VS. We have performed a prospective observational study to evaluate this treatment strategy. Methods:Between March 2005 and December 2008, we treated 16 large VSs with maximal diameter of 3.0 cm or greater using intended subtotal removal followed by radiosurgery. Median observation time was 42(26-62) months. The selected surgical approach was retrosigmoid suboccipital approach. Radiosurgery was performed 3 month after surgery. We evaluated tumor control, symptomatic relief, facial nerve preservation, hearing preservation, other cranial nerve preservation, and complications. Results:Our treatment strategy showed 93.8%(15/16) tumor control rate, excellent facial nerve preservation(93.8%, 15/ 16), retaining preoperative serviceable hearing(75%, 3/4) and low treatment morbidity. Conclusion:Although there was a limitation of the follow-up period, case numbers, and single institute results, in the case of large VS, intended subtotal removal followed by radiosurgery might be an excellent option for maintaining facial, auditory, and other cranial nerve function and tumor control. KEY WORDS:Facial nerve preservation Observational study Radiosurgery Subtotal resection Vestibular schwannoma. 서 청신경초종진단후선택되는치료의종류로는경과관찰, 1) 본연구는 2010 년도정부 ( 교육과학기술부 ) 의재원으로한국연구재단의지원을받아수행된기초연구사업임 (2010-0004506). 논문접수일 :2010 년 6 월 7 일논문채택일 :2010 년 9 월 9 일교신저자 : 강석구, 137-701 서울서초구반포동 505 가톨릭대학교의과대학서울성모병원신경외과학교실전화 :02) 2258-2101, 전송 :031) 696-5239 E-mail:seokgu9@kornet.net 론 방사선수술, 2,7,17) 수술적제거, 19) 혹은수술과방사선수술의병행치료 6) 등이알려져있다. 각각의치료법에대한무작위비교시험이없는현시점에서어떠한치료법의선택이가장좋은지단언하기는힘들다. 16) 그동안각치료의치료결과는청신경초종환자의치료후객관적인증거 ( 종양적출정도, 청력보존정도, 안면신경마비정도등 ) 로판단해왔으나, 최근단순한몇가지의객관적결과보다는치료후환자의삶의질을다양하고포괄적으로평가해야한다는보고가증가하고있다. 9,21) 청신경초 97
의도적아전절제술후방사선수술 종치료후삶의질을평가함에있어종양의적출정도못지않게중요한것이남아있는청력보존과안면신경기능의보존이라고할수있다. 18,20) 수술단독과방사선수술단독치료를비교해보았을때, 비록장기추적결과는아니지만안면신경기능및청력보존, 그리고환자삶의질모두방사선수술만으로치료한군에서좀더우수하다는보고가있었으나, 13) 방사선수술은종양이큰경우는불가능하여큰청신경초종의경우방사선수술단독요법을택할수없다는문제점이있다. 2,17) 비록후향적인연구결과이지만, 큰청신경초종의경우뇌신경손상을줄이기위해종양피막안쪽에서만종양을제거하고, 수술후장기적인종양조절 (tumor control) 을위해방사선수술을시행하여소기의목적을달성했다는연구결과가보고되었다. 6) 저자들은안면신경기능과청력보존을종양조절못지않게중요하게생각하고, 이에방사선수술단독만으로는치료가불가능한크기가큰청신경초종의경우, 의도적인아전절제술후방사선수술을시행하는방법이종양조절및안면신경기능보존과남아있는청력보존에좋은치료전략이라는사실을전향적인연구를통해관찰하고자하였다. 대상및방법 2005년 3월부터 2008년 12월까지본원에서치료한청신경초종중아래의기준에해당되는청신경초종 16예를대상으로하였다. 1. 포함및제외기준자기공명영상 (magnetic resonance imaging, MRI) 에서최대직경이 3 cm 이상인청신경초종의소견이있는경우, 청신경초종때문에발생된것으로생각되는임상증상이있는경우, 만 20세이상 75세미만의환자를포함시켰으며, 이전에두부방사선치료를받았던경우, 현재다른임상시험을진행하고있는경우, 혹은 30일전에임상시험약을투여받은경우, 악성종양의병력, 그리고환자와가족이동의하지않은경우등은대상에서제외하였다. 2. 치료전략포함기준과제외기준에합당한환자들의경우, 의도적인아전절제술을시행하였고수술후 3개월에사이버나이프 (Cyberknife system TPS ver. 3.3, Accuray, CA, USA) 를이용하여방사선수술을시행하였다. 아전절제술에대한정의는종양을 95% 미만으로제거하는것으로하였으며 ( 잔존종양이 5% 이상 ), 8) 저자들은종양제거술을시행할때안전한범 위하에서최대한종양을많이제거하는것을원칙으로하였다. 수술중안면신경자극모니터링과뇌간-청신경유발전위모니터링을통하여, 안면신경의주행부위를확인하여안면신경과종양과의유착부위에서는절제를시행하지않았고, 뇌간-청신경유발전위가저하될때역시절제를멈추었다. 내이도관 (internal acoustic meatus) 내의종양은절제를시도하지않았다. 이렇게의도적인아전절제술을시행후잔존하는종양에대하여방사선수술을시행하는치료전략이다. 3. 수술방법뇌간유발전위와안면근육전기감시를미리설치한후, 환자는 3/4 앙와위에서약간머리를굴곡시킨후상방으로올린자세로후S상정맥동후두하접근법 (retrosigmoid suboccipital approach) 을시행하였다. 12) S자모양으로 ( 좌측은역 S모양 ) 머리카락선뒤쪽에피부절개를한후에근육층을절개하였고횡정맥동과 S상정맥동의일부가노출되도록뼈를충분히크게제거하였다. L자모양으로경막절개후바로소뇌를아랫쪽에서상방으로부드럽게견인한후소뇌연수수조 (cerebellomedullary cistern) 의뇌척수액을충분히뽑아내어수술공간을자연스럽게확보하였다. 아래쪽의 9, 10, 11번뇌신경을먼저확인하였고종양의후면이노출되면지주막을박리한후, 종양피막과주변정상조직간의경계를세심히유지하면서종양내감압을시행하였다. 안면신경감시로안면신경의위치를파악하고안면신경과종양이유착되어있는부위는보존하면서종양을제거하였으며, 내이도관내종양과뇌신경의유착이심한부위는남겨놓았다 (Fig. 1). 4. 방사선수술수술후 3개월가량지난후에사이버나이프방사선수술을시행하였다. 경계선량 (marginal dose) 은 1,800~2,000 cgy이며 3회분할로시행하였고 80~90% 의등선량선 (isodose line) 으로치료하였다. 잔존종양의부피는평균 7.1 cc(0.32~14.1) 이며중앙값은 6.9 cc이었다. 5. 추적검사내용수술전청력검사, MRI, 측두골전산화단층촬영 (computed tomography, CT) 을시행하였으며, 수술직후및 3개월째에 MRI 를시행하였고, 청력검사는필요한경우에시행하였다. 방사선수술후에는최초 6개월째에 MRI 를촬영하였으며이후에는 12개월간격으로시행하여종양의크기변화및종양주변부종발생여부등을관찰하였고, CT는환자의증상과증후에따라필요시검사를진행하였다. 환자상태에대한평가는종양반응 (tumor response), 수술전후기 98 J Korean Brain Tumor Soc 9:97-102, 2010
최두용등 A B C Fig. 1. Magnetic resonance images(mri) of a patient with a large vestibular schwannoma before and after surgery. A:A preoperative MRI shows a large(2.7 3.5 3.0 cm)-sized, lobulated cystic mass with septation in right cerebellopontine(cp) angle. This mass shows typical ice cream cone appearance with internal auditory canal(iac) enlargement. Ipsilateral CP cistern is enlarged, and adjacent cerebellum and pons are displaced and buckled with mild 4th ventricle compression. After contrast infusion, this mass shows peripheral and septal enhancement. B:A postoperative MRI shows that there is small enhancing portion along the anteromedial aspect of right CP angle and internal auditory canal, which should be remaining mass after intended subtotal resection. C:A pre-radiosurgery MRI shows a thick enhancement along the right IAC, lateral surface of the pons, and right CP angle. 능과, 청력상태, 수술후합병증등이었으며, 최초 6개월째, 그후에는 12개월간격으로진행하였다. 결과 1. 연령및성별분포처음수술당시환자의평균연령은 49.3 세 (34~68 세 ) 였고, 남자가 8예, 여자가 8예로총 16명이저자들의치료전략에따른치료에포함되었다. 추적기간은 26~62 개월이며중앙값은 42개월이다. 2. 임상증상및징후수술전가장흔한임상증상및징후는현훈 (93.7%) 과이명 (87.5%) 이었으며, 다음으로청력저하및어지러움증이 75% 에서관찰되었고, 68.8% 에서두통이관찰되었다. 그밖에삼차신경증상과연하곤란을호소하는환자가각각 1명 (6.3%) 씩있었으며, 안면신경기능은수술전모든환자에서잘보존되어있었다 (Table 1). 3. 종양반응 (Tumor response) 총 16명중 1명을제외한모든환자에서아전절제술후남은종양의크기가방사선수술후줄어들거나유지되어 98.3% 의종양조절율을보여주었다 (Table 2). 나머지한명에서는의도적아전절제술과사이버나이프방사선수술후에종양이더커지면서어지러움증이심해져재수술을시행하였고, 재수술후에는 14개월간추가성장없이종양이안정적으로유지되고있다. Table 1. Pre-treatment symptoms and signs on admission in 16 patients with a large vestibular schwannoma Clinical symptoms and signs 4. 안면신경기능보존 수술전안면신경마비가 House-Brackmann(H-B) grade II 이상으로관찰되던환자는없었으며한명의환자를제외하곤모두수술전과같은안면신경기능을유지하였다 (Table 3). 수술전안면신경마비가없었지만수술후진행되었던한예의경우는종양이방사선수술후커지면서안면신경마비도 H-B grade III로악화되었고재수술후에도같은정도의안면신경마비상태로남아있다. 5. 청력의보존 Number of patients (n=16) Percentage (%) Headache 11 68.8 Dizziness 12 75.0 Hearing impairment 12 75.0 Tinnitus 14 87.5 Vertigo 15 93.7 Facial weakness 00 00 Facial sensory change 01 06.3 Swallowing difficulty 01 06.3 Gait disturbance 00 00 수술전청력은대부분 (75%) 저하되어있었으며, 4예 (25%) 에서만유용한 (serviceable) 청력을유지하고있었다. 수술전유용한청력을유지하고있었던 4예중, 한예에서는수술후청력이더나빠져유용하지않은상태였으며방사선 99
의도적아전절제술후방사선수술 Table 2. Post-treatment(surgery plus radiosurgery) tumor volume response(n=16) Volume response Number of patients(%) Remarks Decreased or stable 15(093.8) Ventriculoperitoneal shunt for hydrocephalus were done in 2 patients Increased 01(006.3) Reoperation was done Total 16(100)0. Table 3. Pre-treatment and post-treatment facial nerve function House-Brackmann grade Pre-treatment(%) Post-treatment(%) Sparing rate(post/pre) 100 I-II 16(100) 15(93.8) 93.8% III-IV 00 01(06.2) V-VI 00 00 Total 16 16 Table 4. Pre-treatment and post-treatment hearing function Hearing Pre-treatment(%) Post-treatment(%) Sparing rate(post/pre) 100 Serviceable 04(025) 03(018.8) 75 % Non-serviceable 12(075) 13(081.2) Total 16(100) 16(100)0. Table 5. Post-treatment complications Complication Number of patient(%) Management Cerebrospinal fluid leakage 1(06.3) Lumbar drainage Postoperative hematoma 0 Bacterial meningitis 0 Brain edema after radiosurgery 6(37.5) Steroid Hydrocephalus 2(12.5) Ventriculoperitoneal shunt 수술후에도종양이재성장하여, 재수술을시행한경우로청력은더이상호전되지않았다. 나머지 3명 (75%) 의환자들은수술및방사선수술후에도현재까지는수술전과유사한유용한청력상태를유지할수있었다 (Table 4). 6. 치료후합병증의도적아전절제술을시행하였기때문에수술로인한합병증은매우낮았다. 청력저하와안면신경마비의위험성은이런치료전략으로낮게유지할수있었으며, 수술로인한직접적인합병증으로는수술부위를통한일시적뇌척수액유출이유일하였다 (Table 5). 사이버나이프방사선수술후 37.5% 에서뇌부종이발생하였으며 (6예중 2예는치료후 5~6 개월, 4예는 12개월에발생 ), 대부분스테로이드약물로치료하였고 2~3 개월후에는부종이사라졌다. 뇌부종이발생한 6예의종양부피는평균 12.6cc(9.8~14.1) 였다. 종양의크기가줄었던환자중 2명 (12.5%) 에서추적관찰중에종양의재성장없이교통성수두증이발생하여뇌실- 복강단락술을시행하였다. 고찰 본연구는방사선수술만으로치료할수없는, 증상을유발하는큰청신경초종의경우, 수술후환자의삶의질에지대한영향을미치는안면신경마비와청력저하등을최소화하기위해의도적아전절제술과방사선수술을병행하여치료한결과에대한단일기관관찰연구이다. 청신경초종환자에게선택할수있는치료옵션에는정기적인추적검사를하면서관찰하는방법, 방사선수술이나방사선치료를시행하는방법, 수술적제거를시행하는방법등이있다. 16) 수술중감시장치, 수술현미경, 미세수술술기등의발달로인하여수술이많이시행되어져왔지만수술적제거만이청신경초종치료의최선의방법이라고말할수는없다. 1,2,13,16,17) 각각의치료방법에특이적인적응증이있지만, 일반적으로종양의크기, 환자의나이, 전신질환유무, 증상등을참고로하여구체적인치료방법을결정하게된다. 청신경초종은세계보건기구신경계종양분류에의하면 1 등급에해당되는양성종양으로, 10) 치료에대한결과를판 100 J Korean Brain Tumor Soc 9:97-102, 2010
최두용등 단할때아주오랜기간동안그결과를추적하여야의미있는연구결과를얻을수있다. 일반적으로표준치료법으로인정받기위해서는주장하고자하는치료법과기존의대표적치료법에대한무작위배정에따른맹검법을이용한비교시험이세밀한연구군과대조군의등록숫자를통계적으로계산하여이루어져야하지만, 3) 질병자체가흔하지않아단시간에충분한연구군과비교군의숫자를충족시키기가쉽지않으며, 수술법에대하여는맹검법이란것이무의미하고, 개인의수술능력의차이가분명히존재하기때문에청신경초종과같은질환에대해서는이런잘계획된비교시험자체가매우어렵다. 이런경우근거의질은좀떨어지지만후향적비교시험이나단일기관의치료경험에대한결과들을치료자가개별적으로잘분석하고비교해서최선의치료를선택하여야한다. 일반적으로 3 cm 미만의청신경초종의경우이자체로생명에위협을주는경우는거의없기때문에환자들은이질병의치료가자신의삶의질에어떻게영향을주는지더궁금해한다고한다. 21) 추적검사를시행하면서관찰하는경우와, 수술, 방사선수술에대한결과를후향적으로비교한논문들이보고되었다. 종양조절, 청력상태, 안면신경기능보존상태등이일반적인비교항목이며, 14) 여기에환자의삶의질에대한연구결과가추가된보고들도있다. 14,21) 크기가작은청신경초종의경우의사의입장이아닌환자의입장에서실시된, 삶의질이가장잘유지되는치료방법은정기적인검사를동반한추적관찰이라는연구결과가보고되었으며, 방사선수술이수술적제거보다삶의질유지에더좋았다고하였다. 21) 또한, 수술적제거가필요한크기가큰청신경초종의경우완전절제 (grossly total resection) 보다는거의완전절제 (nearly total resection) 나아전절제 (subtotal resection) 를시행한경우가청력보존, 안면신경기능보존및환자의삶의질유지에더좋았다는보고도있었다. 9,15) 물론경험이풍부한신경외과의사의경우는위의보고에대한반박이있을수있겠지만, 18-20) 한기관의혹은한전문가의결과를모든환자에게적용하도록객관화시킬수는없다사료된다. 기능적인치료결과에초점을맞추면큰청신경초종의경우일반적으로는작거나중간크기의청신경초종보다그결과가좋지않기때문에뇌신경을보존하기위해종양피막내제거술이소개되었다. 11) 그러나아전절제술의경우재발의위험이높기때문에, 4) 피막내제거술후남아있는종양을방사선수술을이용하여치료함으로써뇌신경의보존율을높이고종양조절능도높일수있다는치료결과도보고되었다. 6) 본연구에서는비록약물로조절은잘되었지만방사선수술후뇌부종의비율이비교적높게관찰되었다. 사이버나이프나감마나이프를이용한치료결과를직접적으로비교한연구는없지만각각의서로다른장비로보고된결과들을보면치료후뇌부종발생에큰차이는없는것으로판단된다. 2,5,17) 일반적으로방사선수술후에약 1~6% 에서뇌부종이발생하는것으로보고되고있으나, 5,17) 본연구결과처럼수술후 3개월에시행한방사선수술후에발생하는뇌부종에대한직접적인보고는없다. 다만, 잔존종양이큰경우, 방사선양이높은경우에발생율이더높을것으로예상되며, 선량계획도결과에어느정도영향을줄것으로생각된다. 본연구결과를기존에보고된연구와간접적으로비교해볼때, 잔존종양의부피가상대적으로커서 (9.8~14.1 cc), 이로인해총방사선조사량이높았고, 또한수술후 3개월째라는시기도방사선수술후의뇌부종발생률을높였을가능성을생각해볼수있다. 수술후 3개월째방사선수술은기존에보고된문헌을참고로정하였지만, 6) 잔존종양의축소시기, MRI 에서잔존종양확인의정확성등을고려하여다시수술후방사선수술의적절한시기를판단할필요가있다고사료된다. 본연구는기존에보고된후향적인단일기관의보고들을극복하고자전향적으로연구를진행하였지만, 비교군이없는관찰연구라는단점또한내포하고있다. 또한, 양성종양의치료결과인데도추적기간이짧다는단점도가지고있다. 그러나, 저자들의잘계획된의도적아전절제술후방사선수술치료전략은 93.8% 의종양조절율과 (Table 2), 높은안면신경기능보존율 (93.8%)(Table 3), 높은청력보존율 (75%)(Table 4), 그리고아주낮은치료합병증발생율을보여주고있다 (Table 5). 이결과들은저자들의치료전략이크기가큰청신경초종을치료하는데안면신경기능과청력보존, 그리고종양조절을위해매우유용한방법이될수있음을나타낸다고할수있다. 결론 크기가큰청신경초종에대하여, 치료후기능적결과를좋게하여환자의삶의질을유지하기위해의도적아전절제술후방사선수술을전향적계획하에시행하였으며, 좋은치료결과를보여큰청신경초종의유용한치료전략이될수있을것으로판단된다. 그러나, 추적기간이짧고증례의수가많지않은문제점을내포하고있어, 추후좀더많은증례에대한장기추적결과를보고해야할것으로사료된다. 101
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