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1 대한내과학회지 : 제 71 권부록 2 호 2006 임상강좌 Role of Radiotherapy in Induction CCRT 연세대학교의과대학방사선종양학교실 서창옥 기존에여러종류의암에적용되고있는방사선치료의효과를높이기위하여정상조직에는보다적은선량을조사하면서종양에는보다많은방사선량을조사하는기술적혁신과함께방사선에의한생물학적반응을조절하는여러방법들이시도되어왔다. 그중에서항암제를방사선치료와병행하는방법이가장큰효과를보이고있다. 특히방사선과항암제를동시에사용하는 concurrent chemoradiotherapy는많은암에서방사선치료단독요법에비하여우월한국소제어율과생존율을보이고있다. 1. Basic Concepts in Combining Radiation Therapy and Chemotherapy 방사선치료와항암화학요법을병행하는궁극적인목표는당연히 therapeutic ratio를높이는것이다. 즉정상조직에대한독성을최소화하면서항종양효과를높이는것이다, 그림 1 과같이왼쪽종양의 S자형생존곡선과합병증발생율을나타내는오른쪽의 S자곡선이멀리떨어질수록 therapeutic ratio 는커지게된다.( 그림 1) 병합치료에서 therapeutic ratio가높아지기위해서는각각의치료의표적이다르거나 (spatial cooperation), 각치료가중복되지않는별개의부작용을가지거나 (independent toxicity), 종양반응을증강시키거나, 정상조직을보호할수있어야한다 (Steel). Spatial cooperation은 adjuvant chemotherapy 의근거가된다. 즉방사선치료로원발병소를치료하고화학요법으로는전신의미세전이를치료하는식이다. 또한혈액암의치료에서약제가잘침투하지않는 sanctuary site( 뇌, 고환등 ) 는방사선치료를하는것도 spatial cooperation의개념이다. Independent toxicity를이용하여치료효과를높이기위해서는약물의부작용과작용기전, 약물역동학에대한지식이충분해야한다. Figure 1. Therapeutic ratio is defined as the ratio of the doses of an agent (or agents) that produce the same probability of normal tissue damage (curve C) and antitumor effect (curves A and B). Curve A illustrates an agent with a positive (beneficial) therapeutic ratio, one that produces more damage to tumor than to normal tissue; curve B illustrates a negative (undesirable) therapeutic ratio in which the damage to normal tissue exceeds the damage to the tumor. 2. 약- 방사선상호작용의기전 (Mechanisms of Drug- Radiation Interaction) 1) Increasing initial radiation damage: DNA가방사선에의한세포손상에서결정적인표적인데어떤약물이 DNA를방사선손상에더예민해지도록만들수있다면 cell killing 효과를증강시킬수있을것이다. halogenated pyrimidine이대표적인예이다 (Kinsella). 2) Inhibition of cellular repair 많은항암화학요법약물이방사선에의해생긴 sublethal damage(sld) 와 potentially lethal damage (PLD의복구를방해함으로써결과적으로방사선에의한반응을증강시키게된다. Halogenated pyrimidine은 - S 766 -

2 - 서창옥 : Role of Radiotherapy in Induction CCRT- Table 1. Mechanisms of Chemotherapy-induced Radiation Sensitization Class of Compound Platinum-based compounds Taxanes Topoisomerase I inhibitors Hypoxic cell cytotoxins Antimetabolites Mechanism of Radiosensitization Inhibition of DNA synthesis Inhibition of transcription elongation by DNA interstrand cross-links Inhibition of repair of radiation-induced DNA damage Cellular arrest in the G2M phase of the cell cycle Induction of apoptosis reoxygenation of tumor cells Inhibition of repair of radiation-induced DNA strand breaks Redistribution into G2 phase of the cell cycle Conversion of radiation-induced single-strand breaks into double-strand breaks Complementary cytotoxicity with radiation on euoxic and hypoxic tumor cells Nucleotide pool perturbation Lowering apoptotic threshold Cell cycle redistribution Tumor cell reoxygenation DNA 손상을증가시킬뿐만아니라손상복구도방해한다. Fludarabine 이나 gemcitabine 같은 nucleotide analogue 가방사선에의해생긴 DNA와염색체의손상복구를강력하게억제함이밝혀졌고전임상연구를거쳐임상에널리적용되고있다. 3) Cell cycle redistribution 방사선이나항암제나모두분화하지않는세포보다분화하는세포에더효과적이다. 또한세포주기의어느위치에있는지에따라세포치사효과가다르다. G2와 M phase에있는세표들이 S phase에있는세포보다방사선에예민하다는사실은이미 30년전에알려졌다. 따라서세포들을방사선에예민한 G2, M phase에모으거나 S phase의세포를없앨수있는항암제를사용한다면치료효과를높일수있을것이다. Taxanes 은세포들을 G2, M phase에모으는대표적인약물이다. Fludarabine 이나 gemcitabine 같은 nucleotide analog는 S phase 세포에들어가서 apoptosis 를유도함으로써 S phase 세포를제거한다. 또한약물주입후 1-2일후에는남아있는세포들을 G2. M phase로모으기때문에이때가방사선증강효과가가장높을때이다. 세포의성 장속도가빠른종양들이느리게성장하는세포보다세포주기재배치방법으로효과를볼가능성이높다. 4) Counteracting hypoxia-associated tumor radioresistance 혈관에서 μm이상떨어지면저산소증 (hypoxia) 이생기고저산소증이생기면종양세포는더욱독해지고전이가잘되며방사선과대부분의항암화학약제에대한내성이증가한다. 저산소증세포는산소가풍부한세포에비하여 배나내성이증가한다. 혈색소가낮고종양내산소분압이낮은경우에치료실패율이높기때문에저산소증은방사선치료에서완치를저해하는요소로생각하고있다. 실제로 hypoxic cell sensitizer나 hyperbaric oxygen을사용하였을때종양의국소제어율을높일수있었다. 화학요법의효과측면에서볼때저산소증영역은항암제가도달하기어려울뿐만아니라저산소증세포는증식을하지않거나증식률이낮기때문에약물에반응이좋지않다. 대부분의항암제는혈관주변의산소가풍부한증식하는세포들을먼저죽이게되고이세포들이없어지면저산소영역의세포들이모세혈관과가까워져서 - S 767 -

3 - 대한내과학회지 : 제 71 권부록 2 호 산소공급이증가하게된다. 또한항암제로종양이줄어들면간질압이낮아져서막혔던모세혈관을열리게하는효과도있다. Taxane 에반응이좋은종양에서 taxane 에의해방사선효과가증강되는주된기전은 'tumor reoxygenation' 임이밝혀졌다. 저산소증의역기능을없애는또다른기전은저산소증세포만선택적으로죽이는것이다. Tirapazamine, mitomycin 이대표적이약이다. 또한 misonidazole 같이산소와비슷한효과를내는약제를사용하여저산소증세포를방사선에민감하도록하는연구들이있어왔는데임상시험에서는향상된결과를가져오지못하였고신경독성때문에효과적인용량을주기어려웠다. 5) Inhibition of tumor cell repopulation 정상세포와마찬가지로종양세포도방사선이나항암제로세포소실이일어나면보상적으로세포증식이일어난다. 이를 'accelerated repopulation' 이라한다. 방사선치료중에일어나는 accelerated repopulation에 대해서는두경부암에서연구가되었는데치료기간이 1달을초과하는경우같은치료효과를얻기위해서더많은방사선이필요하다고하였다. (Withers) 항암제를방사선과동시에투여한경우세포증식을감소시켜치료효과를높일수있지만증식속도가빠른정상조직에대한독성도같이증가하는것이문제이다. 또한항암제를방사선치료전에사용하는 induction 또는 neoadjuvant chemotherapy 의경우항암제에의해유도된 accelerated repopulation이치료효과를감소시킬수있다. 따라서항암제에반응이좋은경우에도 induction chemotherapy 한후방사선치료하는치료방법의성적이괄목할만큼좋지는않다. 어떤연구에서는항암제로야기된 accelerated repopulation이방사선치료성적을더나쁘게하였다.(milas 1994) 3. Sequencing of Chemotherapy and Radiotherapy 치료효과를높이기위하여항암제를언제투여하는가가중요한데항암제를병용하는목적에따라서방사 Table 2. Advantages and Disadvantages of Different Chemoradiation Sequencing Strategies Strategy Advantages Disadvantages Sequential chemoradiation Least toxic Maximizes systemic therapy Increased treatment time Lack of local synergy Smaller radiation fields if induction shrinks tumor Concurrent chemoradiation Shorter treatment time Radiation enhancement Compromised systemic therapy Increased toxicity No cytoreduction of tumor Concurrent chemoradiation and adjuvant chemotherapy Maximizes systemic therapy Increased toxicity Radiation enhancement Increased treatment time Both local and distant therapy delivered upfront after Difficult to complete chemotherapy chemoradiation Induction chemotherapy and concurrent chemoradiation Maximizes systemic therapy Radiation enhancement Increased toxicity Increased treatment time Difficult to complete chemoradiation after induction therapy - S 768 -

4 - 서창옥 : Role of Radiotherapy in Induction CCRT- 선치료전 (induction or neoadjuvant), 방사선치료와동시에 (concurrent or concomitant), 또는방사선치료후 (adjuvant) 에화학요법을한다. 각경우의장, 단점을표 2에요약하였다. Induction chemotherapy 는전신에퍼져있는암세포들을죽일뿐만아니라원발종양도죽임으로써저산소증세포들에산소가재공급되게하고또한종양의크기가줄기때문에방사선치료범위를줄일수있어서부작용을감소시킬수있다. 이방법은소아고형종양이나림프종에서효과적으로적용되고있다. Concurrent chemotherapy 할때중요한것은방사선치료과정중약물을주는시기이다. 적절한항암제투여시기를결정하기위해서는약제와방사선이작용하는기전과독성에대한충분한지식이있어야한다. 예를들면 taxane 에예민한종양에서는방사선효과를증강시키는기전이저산소증세포의 reoxygenation 방사선치료 1-3일전에 taxane 을주는것이가장좋기때문에방사선치료기간중 1-2 주에한번씩 taxane 을 bolus 로주는것이바람직하다. 반면에 taxane 에민감하지않은종양에서는 taxane 을매일주는것이좋다. 왜냐하면 taxane 을투여한후 6-12 시간이지나면종양세포들이방사선에민감한 G2, M phase에모이기때문이다. 또 accelerated repopulation을막기위해서라면방사선치료 일정의후반기에항암제를병용하는것이좋을것이다. Adjuvant chemotherapy 는전신에전이된암세포를죽이는것이일차목표이지만방사선치료후살아남은종양세포를제거하는데에도도움이될것이다. 4. Emerging strategies for improvement in chemoradiation therapy 1) Increasing antirumor efficacy of chemotherapeutic drugs Taxanes, nucleoside analogs, topoisomerase inhibitor 같은신약들은강력한항암효과를가지고있지만동시에정상조직에대한부작용때문에방사선치료와같이사용할때한계가있다. 항암제의항암효과를높이면서정상조직에대한독성은낮추는방법중의하나가약제를 polyglutamic acid 같은 water-soluble polymeric drugs에결합시켜서투여하는것이다. 이결합체는종양내에축적되었다가서서히종양내에방출되어오랜기간동안고농도로유지된다 (Li). 2) Incorporation of molecular targeting 최근분자생물학적연구를통하여많은분자물질이방사선또는항암제에대한종양의저항성과관련이있음이알려졌다. Epidermal growth factor receptor (EGFR), cyclooxygenase-2 (COX-2) enzyme, mutated Table 3. The Long-term Toxicity of Combined Chemoradiation Therapy Agent Toxicity Mechanism Bleomycin Pneumonitis/ pulmonary fibrosis Undefined but related to total drug dose and effects on pulmonary macrophages, type I and II alveolar cells; effects/lethality exacerbated by the administration of radiation Actinomycin D Hepatopathy Altered liver function postradiation leads to decreased metabolism of agents, including actinomycin, which in turn worsens the hepatopathy. Doxorubicin Cardiomyopathy There is an additive interaction between doxorubicin and radiation with recall of radiation effects occurring. Primary radiation effect is on the endothelial cell, whereas doxorubicin affects the connective tissue stroma of the myocardium. Methotrexate Leukoencephalopathy Methotrexate may cause this syndrome on its own. Radiation effects on the blood-brain barrier and the choroid plexus can alter methotrexate clearance, leading to higher levels in the brain. Effects are increased when both modalities are used. - S 769 -

5 - 대한내과학회지 : 제 71 권부록 2 호 Table 4. Chemotherapeutic Agents Which Reveal Synergistic Effect with Radiation Compounds Class Chemotherapeutic Agent Alkylating agents Unique / Major Toxicity Synergy with Radiation Carmustine (BCNU) Weak synergy with RT + Dacarbazine Strong synergy with RT +++ Lomustine (CCNU) Strong synergy with RT + Atypical alkylating agents Cisplatin (Platinol) Antibiotics Intermediated synergy with RT ++ Bleomycin Strong synergy with RT +++ Dactinomycin Strong synergy with RT +++ Doxorubicin (Adriamycin) Strong synergy with RT Recall skin reactions that correspond to prior RT treatment fields may develop, can be severe. Concurrent RT or initiation of RT within 2 weeks of administration of doxorubicin should be avoided. Mitomycin C Strong synergy with RT +++ Antimetabolites 5-Fluorouracil Intermediate synergy with RT ++ Capecitibine (Xeloda) [Antimetabolite prodrug] Gemcitabine (Gemzar) Strong synergy with RT even at low doses of drug ++++ Hydroxyurea Weak synergy with RT + Methotrexate (MTX) Weak synergy with RT + Targeted therapy Cetuximab (Erbitux) Taxanes ++++ Intermediate synergy with RT ++ Strong synergy with RT Self-limiting sterile, nonsuppurative acne like skin rash is common. Resolves with cessation of drug. Hypersensitivity reactions are less common. Paclitaxel (Taxol) Weak synergy with RT ras, angiogenic molecules 이대표적인예이다. 따라서이런분자물질을억제하는약제기개발되면방사선치료또는항암제의치료효과를높일수있을것이다. anti-egfr antibody 인 cetuximab 은두경부암에서방사선과같이사용하였을때강한치료증강효과를보임이확인되었다.(Bonner) 5. 임상적용수술로써치료가가능한경우에도암이발생한기관을보존하기위하여또는생존율을증가시키기위하여 수술전에방사선치료를시행하여왔고최근에는방사선치료효과를증가시키기위하여방사선치료와함께화학요법을병행하는연구가많이진행되고있다. 식도암에서는방사선과화학요법을병행하여치료한후수술하는방법을시도하였는데 adenocarcinoma 에서는수술단독치료보다생존율을증가시켰으나 (Walsh) squamous cell carcinoma 에서는이득이없었다. (Bosset) 일찍이기능을보존하기위하여수술대신방사선치료를시행하였던대표적인암이항문암이다. 현재는방 - S 770 -

6 - 서창옥 : Role of Radiotherapy in Induction CCRT- 사선-화학병행요법이항문암의표준치료법으로방사선치료와 5-FU에 mitomycin 을추가하는것이도움이되는지연구중이다. 항문암에서의성공을토대로하부직장암에서항문을보존하기위하여수술전에방사선-화학요법을하여서종양의크기를줄인후제한된수술을함으로써 abdomino-perineal resection and permanent colostomy 을가능한피하고자시도하고있다. 진행된후두암에서후두절제술후방사선치료하는방법과화학요법후 50% 이상의반응을보인환자들은수술하지않고방사선치료하는방법을비교해보았을때생존율의변화가없으면서 60% 이상의환자들에서후두절제술을피할수있었다는보고는이미 1990년대초에보고된바있다. 이를근거로진행된 prospective randomized trial에서는화학요법후방사선치료, 방사선치료와화학요법 (cisplatin) 을동시에하는방법, 방사선치료단독요법을비교하였는데방사선-화학동시요법이가장후두보존율이높았다.(Forastiere) 또한 87개연구를대상으로한 meta-analysis 에서도방사선-화학동시요법이 5년생존율을 8% 증가시킴을볼수있었다.(Pignon) 침윤성방광암에서도방사선치료와화학요법을병용하여방광을보존하고있다. T2-T4a 방광암에서경요도절제술 (tranurethral resection) 후화학요법 (methotrexate, cisplatin, vinblastine) 2-4 cycle 하고그후 cisplatin을쓰면서방사선치료하는방법으로치료하였을때 40-50% 의환자들에서방광을보존하면서치료할수있었다고보고하였다. 방광절제술은방사선치료후방광경으로추적검사하면서잔류종양이있을때에만시행되었다. (Tester) 6. 독성일반적으로항암제와방사선치료를동시에사용하지않고순차적으로사용하는경우는독성이크게문제되지않지만 bleomycin에의한 pulmonary toxicity는 subsequent radiation 때문에악화될수있다. 상기한바와같이방사선치료와항암제를동시사용하였을때독성이크게증가한다 ( 표 3). doxorubicin 과 gemcitabine 은보통사용하는용량에도 RT 효과를크게증가시킬수있다. 통상사용하는방사선량에도치명적 인부작용이생길수있으므로주의해야한다. 방사선치료후 doxorubicin 을사용하였을때방사선치료받은부위에심한피부반응이나타날수있는데이를 'recall phenomenon' 이라한다. 또한방사선치료와동시에주지않도록하며 doxorubicin 투여후 2 주이내에는방사선치료를시작하지않도록권장된다. 폐암의치료에서도방사선치료를 cisplatin과 etoposide 와같이주었을때식도염이심해지는것을볼수있다. 방사선과 synergistic effect를보이는약제를표4에요약하였다. 이런부작용을최소화할수있는방법중하나는삼차원입체조형치료 (conformal radiotherapy) 로심한부작용을나타날수있는정상조직을피하는방법이고또다른방법은 amifostine 같이정상조직을보호할수있는약제를사용하는것이다. REFERENCES 1) Bonner JR et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Eng J Med 2006;354: ) Bosset J-F, Gignou M, Triboulet J-P et al. Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med 1997;337: ) Choy H, Macrae R, Milas L. Basic concepts of chemotherapy and irradiation interaction. In : Perez CA, Blady LW, Halperin EC, Schmidt- Ullrich RK, eds. Principles and practice of radiation oncology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins. 2004: ) Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349: ) Li C, et al. Tumor irradiation enhances the tumorspecific distribution of poly(l-glutamic acid)-c onjugated paclitaxel and its antitumor efficacy. Clin Cancer Res 2000;6: ) Kinsella TJ, et al. Enhancement of x ray induced DNA damage by pre-treatment with halogenated pyrimidine analogs. Int J Radiat Oncol Biol Phys 1987;13: ) Milas L et al. Enhancement of tumor radioresponse in vivo by gemcitabine. Cancer Res 1999;59: ) Milas L, et al. Dynamics of tumor cell clonogen repopulation in a murine sarcoma treated with cyclophosphamide. Radiother Oncol 1994;30: S 771 -

7 - 대한내과학회지 : 제 71 권부록 2 호 ) Milas L, Cox JD. Principles of combining radiation therapy and chemotherapy. In : Cox JD, Ang KK eds. Radiation Oncology:rationale, techniques, results. 8th ed. St.Louis, Missouri: mosby. 2003: ) Pignon JP, Bourjis J, Domenge C, et al. Chemotherapy added to locoregional treatment for head and neck squamous cell carcinoma: three meta-analyses of updated individual data. MACH- NC Collaborative Group; meta-analysis of chemotherapy on head and neck cancer. Lancet 2000; 355: ) Steel GG, Peckham MJ. Exploitable mechanism in combined radiotherapy-chemotherapy: the concept of additivity. Int J Radiat Oncol Biol Phys 1979;5: ) Walsh TN, Noonan N, Hollywood D, et al. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 1998; 339: ) Withers HR, Taylor JM, Maciejewski B. The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol 1988;27: S 772 -

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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