REVIEW ARTICLE ISSN: 2005-162X J Korean Thyroid Assoc 2013 May 6(1): 26-33 http://dx.doi.org/10.11106/jkta.2013.6.1.26 영상을이용한방사핵종치료의선량평가 한국원자력의학원원자력병원핵의학과 임일한 Ilhan Lim Department of Nuclear Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences (KIRAMS), Seoul, Korea Radionuclide therapies have been applied in the diverse fields of medicine, and it has been demonstrated the usefulness of it, especially in the field of oncology. Accurate dosimetric assessment is imperative during radionuclide therapy, in order to optimize the treatment efficacy for target sites and to minimize the radiation exposure for normal organ. Recent advancement in imaging technology permits the precise determination of the absorbed dose non-invasively. This imaging based dosimetry can be routinely applicable to the bedside in the near future. Key Words: Dosimetry, Radionuclide therapy, Image-based dosimetry 방사성동위원소를이용한치료가현재의학의다양한분야에서적용되고있으며, 특히종양의치료에서각광을받고있다. 1) 이들중갑상선치료와갑상선암에서의방사성요오드치료가가장많은부분을차지하고있어서, 2009년대한핵의학회통계에의하면연간 28,200여건이시행되고있다. 방사성동위원소치료에서정확한선량평가를하는것은치료부위에효과적인선량의도달과정상부위에방사선피폭을저감하기위하여필요하다. 최근의연구에따르면고위험갑상선분화암환자에서고정된용량의방사성요오드를처방받아치료한군에비하여, 선량평가를시행한후용량을결정하여치료한군의치료효과가더좋았음을보고하고있어, 2) 정확한선량평가의중요성이강조되고있다. 근래의 single photon emission computed tomography (SPECT), positron emission tomography (PET) 등의영상진단장비의기술발전은영상을이용하여보다정확한선량평가를가능하게해주었다. 영상을이용한선량평가로치료용량을결정하는실례를살펴보면, 소량의방사성의약품을치료전에주사한후, 영상검사로부터방사선선량 (cgy나 rad) 을계산하면, 이값을바탕으로치료조직과정상조직에적정량의방사선이도달하기위한치료주사용량 (mci 나 GBq 단위 ) 을결정할수있다 (Fig. 1). 3) 본논문에서는체내흡수선량평가의기본원리를살펴보고, 평면영상및 SPECT, PET을이용한선량평가를알아보겠으며, 갑상선암에서영상을이용한선량평가가활용된연구에관하여정리해보겠다. 체내흡수선량평가의기본원리 방사선흡수선량은조직에흡수된에너지를해당조직의질량으로나눈값이며, 이값은여러연구를통해생물학적효과와깊은관련이있기때문에방사선량평가에사용된다. 흡수선량을결정하는요인으로는핵종 Received October 10, 2012 / Revised May 10, 2013 / Accepted May 10, 2013 Correspondence: Ilhan Lim, MD, Department of Nuclear Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences (KIRAMS), 75 Nowongil, Nowon-gu, Seoul 139-706, Korea Tel: 82-2-970-2241, Fax: 82-2-970-2422, E-mail: ilhan@kcch.re.kr Copyright c 2013, the Korean Thyroid Association. All rights reserved. This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 26
Fig. 1. Imaging and dosimetry in clinical trials of targeted radionuclide therapy. 3) 의붕괴속도및에너지방출특성, 방사성의약품의투여 (administration)-분포(distribution)-대사(meta- bolism)-배설 (excretion), 선원장기와표적장기의구성및상호간의해부학적위치관계등이있다. 전리방사선을치료에이용할때, 종양과정상조직에대한정확한방사선흡수선량의평가는매우중요하다. 왜냐하면, 외부방사선조사치료나근접방사선조사치료와는다르게, 환자의체내로주입된방사성의약품은환자의체내에머무르며상대적으로낮은용량의방사선을장기간방출하기때문이다. 일반적으로새로운방사성의약품의치료능 ( 종양표적방사선량 ) 과안전성 ( 전신및골수방사선량 ) 을평가할때에는이미정해진모델을사용하여방사선흡수선량을평가하며, 이를사용하여환자의체중또는체표면적당정해진양의방사성의약품을투여하게된다. 현실적으로측정방법상의불확실성때문에흡수선량평가는개개의환자마다시행하지는않는경우가많으나, 핵의학영상정량분석기술의발전으로점점보다용이하게평가가시도되고있다. 그러나아직까지는치료전의계획보다는치료도중얻어진자료를이용하여후향적으로평가하는경우가많다. 기존의내부선량평가법은 Medical Internal Radiation Dosimetry (MIRD) 체계를이용한다. 이는 1960년대에처음표준화된방법으로진단과정에서표적장기에의평균선량을평가할목적으로고안되었다. 이방법은선원장기 (source organ) 및표적장기 (target organ) 를확인하여각각의경우에선원장기에서표적장기에전달되는특정 (i) 방사선에의한흡수선량 (Dt s) 을선원장기내의집적방사능량 (As) 과평형흡수선량계수 (Δi; equilibrium absorbed dose constant), 표적장기의무게, 흡수분획 (Φi; absorbed fraction) 의함수 로표현한것이다. 장기흡수선량 (absorbed dose) 의일반적인공식은다음과같다 : 4) D = 흡수선량 (rad 또는 Gy) Ã = 축적방사능 (μci. h or MBq. s) n i = 단위방사성붕괴시방출되는 i종류방사선의수 E i = i 종류방사선의평균에너지 (MeV) Φ i = 표적영역에흡수되는에너지의비 m = 표적영역의질량 (g 또는 kg) k = 비율상수 (rad. g/μci-h-mev 또는 Gy. kg/mbq. sec. MeV) MIRD 체계에따른선량계산을간략하게다음의 3 단계로요약할수있다. 3) (1) 선원의부피에대한축적방사능을구한다. 축적방사능 (Ã) 은선원장기또는영역에대한시간-방사능곡선의곡선아래면적으로정의된다. 축적방사능이란, 방사성동위원소의방사성붕괴에대한시간적분량 (time integral) 을말한다. 이는임상에서는영상을이용한정량화를통하여전임상에서는생분포 (biodistribution) 실험을통하여구할수있다. (2) i 종류방사능의축적방사능당평균방출에너지를구한다. 이것은보통각종동위원소의발표된자료를이용하거나 MIRDOSE와같은선량평가소프트웨어를 5) 이용하여구할수있다. (3) 표적부위내의흡수된에너지의분획을구한다. 이것은방사선의종류 ( 투과를하는지그렇지않은지 ), 27 J Korean Thyroid Assoc
Ilhan Lim 선원과표적부위간의해부학적또는기하학적위치에좌우된다. 평면감마영상을이용한선량평가 현재까지도대다수의영상을이용한선량평가는평면감마영상을사용한다. 대부분널리사용되는방법은환자의전면과후면상을얻은후, 이를정량화하여사용한다. 일반적으로전면상과후면상의방사능계수의기하평균을구하여선량평가에사용한다 (Fig. 2). 또한, 정확한정량화를위하여투과영상을얻는다. 감마선방출방사성동위원소 (I-131, Sm-153, Re-186, Re-188) 를치료에사용하는경우에는선량평가가가능하며, 순수베타선방출핵종의경우이물질의성질을대변할대리동위원소가필요하다 ( 순수베타방출핵종인 Y-90 의경우감마선방출핵종인 In-111을사용하여영상화한다. 6) ). 기하평균을사용할때큰장점은기하평균이선원의방사능을깊이정보없이도정량화할수있다는것이다. 이것은 computed tomography (CT) 나 magnetic resonance imaging (MRI) 등을사용하기힘들던 1970, 1980년대에는큰의미가있었으나, 지금은 CT나 MRI 에서선원의깊이정보를알수있기때문에중요도가줄었다. 기하평균을사용하는선량평가법의경우선원 의병소가뚜렷이보이지않는경우에는사용되지말아야한다. 왜냐하면, 95% 이상의방사능계수가주변조직의방사능계수에서생겨났을수있기때문이다. 이러한방사능계수가선량계산에개입될경우더많은오차가생겨날수있다. SPECT 영상을이용한선량평가 평면영상은여러선원들이겹쳐있을때 3차원정보의부족으로평가에한계가있다. SPECT 영상은방사능의 3차원분포정보를알게하므로환자별 3차원선량분포를결정할수있게한다 (Fig. 3). 그렇지만 SPECT의경우에도 (1) 긴영상획득시간, (2) 평면영상에비하여공간해상도의제한, (3) 산란광자에따른간섭이라는약점을가지고있다. 일반적으로 SPECT 영상에서만들어진방사능계수의 20-40% 가산란에따른방사능계수로설명된다. 7,8) 최근에는기능의영상인 SPECT 와동시에해부학적인 CT 영상을얻을수있는 SPECT/CT가임상에사용되고있어서보다정확한선량평가에사용될수있을것으로기대된다. PET 영상을이용한선량평가 PET 는현재조직내방사능집적을평가하는가장 Fig. 2. Dosimetry after I-131 Rituximab treatment for lymphoma using planar gamma camera imaging. 34) Vol. 6, No. 1, 2013 28
Fig. 3. Transaxial slice of a dose distribution resulting from I-131 mibg therapy of neuroblastoma, 35) (A) SPECT slice acquired post-therapy. (B) Corresponding absorbed dose distribution. (C) Rendered view of absorbed dose distribution. (D) Isodose contours from targeted therapy superimposed onto registered CT slice. 정확한방법이다. PET는소멸광자 (annihilation photon) 를검출하는것으로 SPECT에비하여우수한민감도를나타내며, 정량화방법도잘확립되어있다. 그러나임의동시발생 (random coincidence) 신호의제거, 불응시간고려, 감쇠보정, 산란보정등의기술적사항이필요하다. PET 영상을선량평가에사용하기위하여치료에사용되는동위원소와같은원소를사용하는것이이상적이다. I-131로치료하는경우 I-124를이용한 PET 영상을사용하고, Y-90의경우 Y-86을사용하여선량평가를실시할수있다. I-124는 1986년부터선량평가에사용되기시작했으며, 9) 양성갑상선질환의방사성요오드치료에널리적용되었다. 10,11) 1991년에 I-124를이용하여방사면역치료를위한생체내종양의방사선집적및방사선의체내분포를정량화하였다. 12-14) I-124의복잡한방사성붕괴과정때문에 F-18과같은방법으로는정량화를할수없고보다복잡한과정이필요하다. Pentlow 등 15) 은해상도, 선형성을측정하였고, 다양한 크기의구체에서방사능을정량화하였다. I-124의정량화는성공적으로이루어졌고, 통상의 PET 동위원소와비교할때에도해상도및정량화정도가약간만떨어질뿐이었다. 15,16) I-124 PET은갑상선부피를측정하는데이용되기시작하였고, 갑상선분화암에서 I-131 치료방침을결정하는데사용되고있다. 이러한 I-124 PET 활용은주로종양에의선량평가에이용된다 (Fig. 4). 17) PET을이용한선량평가로 Y-86을이용하여소마토스타틴수용체발현종양에서방사선치료를계획할때사용할수있다. 18,19) 그러나, Y-86 역시붕괴과정이복잡하여정량화를위하여많은과정의보정을필요로하기때문에일반적인 PET 스캐너로작업하기에는쉽지않다. 기존의연구에서 Y-86-DOTA-Phe 1 -Tyr 3 -octreotide 를이용하여선량평가를하는것이 In-111-pentetreotide 를이용하여선량평가를하는것보다더우수한결과를보인다고발표하였다. 18) In-111을이용하여선량평가를실시하였을때, 신장, 비장에의선량은과대평가되었 29 J Korean Thyroid Assoc
Ilhan Lim Fig. 4. I-124 PET imaging based dosimetry. 17) Representative coronal slices of absorbed dose (D) maps of two different data sets: torso (measured) (A) and head (modeled) (B). 고, 간조직의경우에는과소평가되었다. 이러한정확한선량평가는치료후발생할수있는신기능저하를예측하는데중요한역할을하는것으로나타났다. 19) 아직까지남겨진숙제들은많은대리동위원소들이치료에사용되는동위원소보다반감기가짧아서시간- 방사능곡선등을온전히그리고생체분포를정확히표현하는데한계가있다는점과 PET을이용한선량평가중에동시발생에너지에서추가적인감마선방출이나와서좀더전문적인정량화과정을필요로한다는점, 사이클로트론에서생산하기힘든동위원소를사용하는점, 그리고아직까지손쉽게사용할수있는소프트웨어가없다는점이지적된다. 갑상선암에서의적용 I-124 PET 을이용한치료선량평가 기존의연구에의하면갑상선암의전이병변에 I-131 치료의효과가나타나기위하여 80-100 Gy의흡수선량이필요하며, 20,21) 표적장기인골수에독성이나타나지않기위하여혈액의흡수선량은 2 Gy를넘지않게조절해야되는것이 22) 알려져있다. I-124를연속적으로촬영하는것은병변의선량평가를위한효과적인방법으로이는 PET 영상이감마카메라영상보다고해상도의영상을얻을수있고, 민감하며정량화가가능하기때문이다 (Fig. 5). 23,24) I-124 PET/CT를이용하여선량평가를실시할경우주사된 I-131 방사능당병변흡수선량 (lesional absorbed dose per administered I-131 activity; LDpA) 을구하여, 실제치료에사용되는 I-131 주사량을계산할수있다. 지금까지발표된연구들을살펴보면환자의 LDpA 값은환자간에많은차이가 Fig. 5. A pretherapy I-124 PET scan (A, 24 hours after administration of 25 MBq I-124) and a posttherapy I-131 whole- body scintigraphy scan (B, 7 days after administration of 10 GBq I-131) in the same patient demonstrate the advantages of PET including increased sensitivity and better spatial resolution. 36) In the PET image (A) two foci of increased activity can clearly be detected whereas in the whole-body scintigraphy scan (B) only diffuse activity is seen. 나며, 같은환자에서도꽤차이가나는것으로알려져있다. Eschmann 등 25) 의연구에따르면 LDpA는 10-21 Gy/GBq 정도로 2명의환자의 4개의전이병소에서측정되었고, Freudenberg 등 26) 의연구에따르면 28명의 Vol. 6, No. 1, 2013 30
갑상선분화암환자를대상으로 I-124 PET을이용한선량평가를실시하였을때, 73개의뼈전이병변의경우 LDpA 중간값이 95 Gy/GBq이었고, 32개의림프절전이의경우 113 Gy/GBq, 14개의폐전이병변의경우 86 Gy/GBq으로나타났다. 아직장기간추적관찰을하여 I-124 PET 선량평가의임상적우수성을밝힌연구는있지않지만, I-124 PET은고위험군갑상선암환자의 I-131 방사성요오드치료전선량평가에서유용하게사용될것으로기대된다. 특히종양이갑상선주위연부조직으로침범한경우, 종양제거수술후현미경으로관찰되는잔여종양이남은경우 (R1 절제 ), 조직학적으로확진된림프전이, 계속상존하는림프절전이, 원격전이환자에서정확한선량의평가목적과 18세이하의어린환자에서방사선피폭을줄이기위한목적으로활발히사용될수있을것으로생각된다. I-131 치료후스캔을이용한잔여갑상선조직의평가 이후방사성요오드치료를받을경우환자의목부분잔여갑상선에방사성요오드가섭취되는것을관찰할수있다. 이는수술로갑상선을완전히제거하는것이현실적으로불가능하기때문에수술후에남아있는정상갑상선조직에방사성요오드가섭취되는것이다. 목부위잔여갑상선조직은감마선계수기를이용해서도그양을측정할수있으나, 영상을얻는경우눈으로도구분이되고, 쉽게정량화할수있다. 이러한목부위잔여갑상선조직의정량화를이용하여양측겨드랑이 -유방접근내시경수술 (bilateral axillobreast approach, BABA) 이후에도절개수술을시행한것과잔여갑상선의섭취가유의한차이가나지않기에내시경수술의효과를객관적으로입증한연구가있다. 27) 또한, 목부위잔여갑상선조직을정량화한값이방사성요오드치료후관해 (ablation) 에도달하는것과무병상태를예측할수있는지표임을밝힌연구도있다 (Fig. 6). 28) 갑상선암발견후갑상선전절제술을받더라도수술 Fig. 6. Quantification of remnant thyroid tissue using whole body scan after I-131 treatment. 27,28) Measurement of neck remnant thyroid tissue count by ROI (A). Measurement of skull count by ROI (B). Calculated the thyroid-to-background ratio (TBR). Comparison of remnant thyroid tissue between after endoscopic thyroidectomy (ET) and open thyroidectomy (OT) (C). Another quantification method of remnant thyroid tissue (D). 31 J Korean Thyroid Assoc
Ilhan Lim I-124 PET을이용한침샘선량평가방사성요오드는갑상선과갑상선암세포뿐아니라, sodium iodide symporter (NIS) 를발현하는침샘들에도흡수된다. 29) 그래서 15-20% 의환자에서침샘염을일으켜구강건조증을일으킨다. I-131과 I-124를이용하여방사성요오드치료후침샘에서의흡수선량을구해보았을때, 방사선으로인한손상이일어나지않을정도의소량만이관찰되어 30-32) 실제환자의경우는균일하지않게방사성요오드가분포하고있을것을짐작할수있다. 현재많은병원에서침샘을보호하기위하여많은시도들이이루어지고있으며, I-131 투여직후신사탕이나레몬등을환자에게섭취하게하여, 침샘분비를촉진하는것으로침샘에서의방사성요오드배출을시켜침샘을보호하려는것이보편적으로행해지고있다. 그러나 I-124를이용한선량평가연구에서 32) 침샘을자극하지않는환자군이평균 28% 침샘에선량이더낮게노출된다는발표를하고있으며, 이선량의차이는귀밑샘에서유의한차이가나타나는것으로보고하고있다. 이러한현상의작용기전은오히려 I-131 투여직후신음식을섭취하는것이오히려침샘에방사성요오드의집적을가져오기때문으로설명된다. 이는 I-131 치료직후 1시간이내에신음식을섭취하는것이실제침샘보호효과가없으며오히려더안좋은효과를준다는전향적연구와도일치한다. 33) 아직더많은연구가필요하지만, 영상을이용한선량평가를이용하여 I-131로인해생기는부작용을예측하고보다입체적으로평가할수있음을알수있다. 결론 영상을이용하여방사성동위원소치료의선량을평가하는것은환자개개인의치료효과예측과부작용을막기위한효과적인방법으로아직은보편적으로임상에서사용되고있지않으나, 환자개개인의특성에따른맞춤치료를할수있기에조금더손쉬운새로운방법이개발되기를기대하고있다. 현재평면감마영상으로도선량평가가가능하며, SPECT와 PET 를이용할경우보다정확한선량평가가가능할것으로생각된다. 갑상선암의경우방사성요오드치료가널리사용되고있기때문에, 영상을이용한선량평가를지금도여러분야에서적용하고있다. I-124 PET 영상을이용하여갑상선암조직과표적장기인골수에서의 I-131의선 량을예측하고있고, 치료후요오드전신영상을이용하여잔여갑상선조직의양을평가할수있으며, 침샘에서의선량을평가하여침샘의부작용을예측할수있음을확인할수있었다. 앞으로임상에서선량평가에대한더많은관심을가지고, 이에걸맞은신기술이개발된다면, 더많은궁금증을효과적으로해결할수있을것으로생각한다. 중심단어 : 선량평가, 방사핵종치료, 영상을이용한선량평가. References 1) Kramer-Marek G, Capala J. The role of nuclear medicine in modern therapy of cancer. Tumour Biol 2012;33(3):629-40. 2) Klubo-Gwiezdzinska J, Van Nostrand D, Atkins F, Burman K, Jonklaas J, Mete M, et al. Efficacy of dosimetric versus empiric prescribed activity of 131I for therapy of differentiated thyroid cancer. J Clin Endocrinol Metab 2011;96(10):3217-25. 3) Reilly RM. Monoclonal antibody and peptide-targeted radiotherapy of cancer. In: Shen S, Fiveash JB, editors. Dosimetry for targeted radiotherapy. Hoboken: John Wiley & Sons; 2010. 4) Chung JK, Lee MC. Koh chang-soon nuclear medicine. 3rd ed. Seoul: Korea Medical Science; 2008. 5) Stabin MG. MIRDOSE: personal computer software for internal dose assessment in nuclear medicine. J Nucl Med 1996;37(3): 538-46. 6) DeNardo SJ, Kramer EL, O'Donnell RT, Richman CM, Salako QA, Shen S, et al. Radioimmunotherapy for breast cancer using indium-111/yttrium-90 BrE-3: results of a phase I clinical trial. J Nucl Med 1997;38(8):1180-5. 7) Tsui BM, Zhao X, Frey EC, McCartney WH. Quantitative single-photon emission computed tomography: basics and clinical considerations. Semin Nucl Med 1994;24(1):38-65. 8) Siegel JA, Thomas SR, Stubbs JB, Stabin MG, Hays MT, Koral KF, et al. MIRD pamphlet no. 16: Techniques for quantitative radiopharmaceutical biodistribution data acquisition and analysis for use in human radiation dose estimates. J Nucl Med 1999;40(2):37S-61S. 9) Akbari RB, Ott RJ, Trott NG, Sharma HL, Smith AG. Radionuclide purity and radiation dosimetry of 124I used in positron tomography of the thyroid. Phys Med Biol 1986;31(7): 789-91. 10) Flower MA, Irvine AT, Ott RJ, Kabir F, McCready VR, Harmer CL, et al. Thyroid imaging using positron emission tomography--a comparison with ultrasound imaging and conventional scintigraphy in thyrotoxicosis. Br J Radiol 1990;63(749): 325-30. 11) Ott RJ, Batty V, Webb BS, Flower MA, Leach MO, Clack R, et al. Measurement of radiation dose to the thyroid using positron emission tomography. Br J Radiol 1987;60(711):245-51. 12) Westera G, Reist HW, Buchegger F, Heusser CH, Hardman N, Pfeiffer A, et al. Radioimmuno positron emission tomography with monoclonal antibodies: a new approach to quantifying in Vol. 6, No. 1, 2013 32
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