Introduction 한국인에서암은지난 10 년간사망원인 1 위였으며, 암발생은지속적으로증가추세에있다. 최근암조기발견과암치료의발전으로암생존율이향상됨에따라생존기간뿐아니라암치료에의한장기적영향과생존자의삶의질에대한관심이높아지고있다. 한국인의주요암의 5 년상대생존율 : 46.

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해숙 궉
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1 항암치료의이해 순천향대학교병원 종양혈액내과박희숙

2 Introduction 한국인에서암은지난 10 년간사망원인 1 위였으며, 암발생은지속적으로증가추세에있다. 최근암조기발견과암치료의발전으로암생존율이향상됨에따라생존기간뿐아니라암치료에의한장기적영향과생존자의삶의질에대한관심이높아지고있다. 한국인의주요암의 5 년상대생존율 : 46.3% (2002 년 ) 2

우리나라암발생률, 2003~2005 천 180 90 발생건수 전체 남자 여자 143 124 132 69

0 317.8 292.9 272.3 297.9 268.0 257.1 284.1 246.5 229.

2003 년 2004 년 2005 년 300 200 100 252.5 242.1 235.5 310.

3 우리나라암발생률, 2003~2005 천 발생건수 전체 남자 여자 조발생률 년 2004 년 2005 년 전체남자여자 연령표준화발생률 400 ( 단위 : 10 만명당 ) ( 단위 : 10 만명당 ) 년 2004 년 2005 년 년 2004 년 2005 년 0 전체남자여자 3

4 평균수명까지생존시암발생확률, 2003~2005 전체 남자 여자 평균수명 * (2005년) * 자료원 : 통계청 79 세 75 세 82 세 평균수명까지생존시암발생확률 29.6% (10 명중 3 명 ) 31.9% (3 명중 1 명 ) 25.5 % (4 명중 1 명 ) 1999~2002 년기준암발생확률전체 : 25.6% ( 기대여명 : 77 세 ) 남자 : 27.7% ( 기대여명 : 73 세 )/ 여자 : 22.2% ( 기대여명 : 81 세 ) 4

5 주요암종발생분율, 2003~2005 ( 단위 : %) 5

6 성별주요암종발생분율, 2003~2005 ( 단위 : %) 남자 여자 6

7 암치료의목표 일차목표 : to eradicate the cancer( 암제거 ) 일차목표가불가능한경우 (Palliation, 완화요법 ) 증상의완화 생명연장 삶의질개선 ( 통증완화등 ) 7

8 수술 방사선치료 항암치료 항암화학요법 세포독성치료 면역요법 생물학적치료 유전자요법 대체요법 맞춤치료 (Tailored Therapy)( 표적치료 ) 8

9 용어정리 Neoadjuvant chemotherapy : 선행 ( 보조 ) 항암화학요법 Organ preservation : H & N cancer, Rectal cancer breast cancer (non-metastatic), Osteosarcoma Adjuvant chemotherapy: 보조항암화학요법 Colorectal, Breast, NSCLC, Osteosarcoma, Definitive CCRT : Inoperable NSCLC(non-metastatic), Esophageal cancer Palliative chemotherapy : 완치가불가한경우 Induction chemotherapy : 유도항암화학요법 Hematologic malignancy 완전관해를목적으로하는 CTx Salvage : 1 st line chemotherapy 실패한경우 9

10 항암화학요법 10

11 (Mitosis) CELL DIVISION CELL DIFFERENTIATION G 1 PERIOD G 2 PERIOD (Cell prepare to divide) CELL LIFE CYCLE TIME (CHROMOSOME REPLICATION) S-PHASE 11

12 항암제란??? 세포내의 DNA 에직접결합작용하여 DNA 의 replication, transcription, translation 을차단 핵산합성의대사경로에개입하여핵산합성을방해 세포분열을저해 암세포에대한세포독성을나타내는약제 12

13 항암제의작용기전 DNA Synthesis Anti-metabolite DNA Alkylating agent DNA Transcription DNA Replication Intercalating agents Mitosis Antimitotic agents 13

14 Tumor cell Kinetics L1210 murine leukemia system 14

15 Dose / Therapeutic Index The degree of separation between toxic and therapeutic doses Anti-cancer drugs: narrow TI Dose-limiting toxicity (DLT) Maximum tolerated dose (MTD) 15

16 Chemotherapeutic agents 16

17 Antimetabolite(pyrymidine analogue (5-Flurouracil)(5FU) 유방암, 대장암, 위암, 췌장암, 식도암, 두경부암등 Tumor cells incorporate radiolabled uracil more efficiently in to DNA than normal cell Metabolize to 5 FdUMP, which inhibits thymidylate synthetase Inactivated by DPD (dihydropyrimidine dehydrogenase) Bolus versus continuous infusion Bone marrow suppression after short infusions vs. stomatitis and diarrhea after prolonged infusion 5FU pro-drugs: Capecitabine: intra-tumoral metabolism UFT S1: Forafur + 5-chloro-2,4,-dihdroxypyridine + oxonic acid 17

18 Alkylating agents Cyclophosphamide Ifosfamide most frequently used alkylating 폐암, 고환암, 육종, 악성임파종 agent Mesna protection for 유방암, 폐암, 난소암, 방광암, 악성 hemorragic cystitis 임파종, 호지킨씨병등 Parent form: no direct cytotoxic Vigorous hydration and frequent effects bladder empty must be activated to cytotoxic CNS effects forms by microsomal enzymes Maintain fluids intake and frequent bladder empty Hemorrhagic cystitis 18

19 Platinums Cisplatin 고환암, 폐암, 난소암, 자궁암, 방광암, 두경부암, 각종소화기암, 연부조직육종, 악성임파종 Vigorous hydration with diuresis to prevent renal toxicity Neurotoxicity Carboplatin Equivalent efficacy Less nephro-, oto- and neurotoxicity than DDP More frequent myelosuppression Exclusive renal excretion Hypomagnesemia and hypokalemia Highly emetogenic agent 19

20 Etoposide (VP-16) Plant product podophylotoxin Binds directly to topoisomerase II and DNA in a reversible ternary complex stabilized enzyme-dna complex Epipodophyllotoxins Topoisomerase II 폐암, 위암, 고환암, 악성림파종 Melosuppression, hypersensitivity reaction 20

21 Taxanes Paclitaxel 유방암, 난소암, 폐암, 두경부암, 위암, 방광암, 자궁암, 악성흑색종, 카포씨육종 Anaphylaxis: premedication!! Myalgia, arthralgia and peripheral neuropathy Docetaxel 유방암, 폐암, 두경부암, 난소암, 전립선암 Hypresensitivity reaction Capillary leak syndrome: pre- & post medication myalgia, general weakness Pacific yew tree European yew tree 21

22 What Are the Goals of Chemotherapy? 항암효과증대 : 적절한용량 (dose) 적절한스케쥴 (Schedule) 적절한투여방법 (Route) Efficacy Toxicity Cure, Control, Palliation 22

23 Toxicity Overview 세포독성항암제는정상세포와암세포를구별하지못한다 No magic bullet(?)( 마법의탄환이되지못함 ) 안정영역이좁다 (MTD, DLT) 세포분열이활발한정상조직즉골수세포, 소화기관모발세포등에급성독성이강하게나타남 특별한장기에발생하는독성 ( 심장, 신장폐등 ) 항암제에의한장기적합병증 23

24 Classification of chemotherapeutic toxicity onset Immediate hours to days Early days to weeks Delayed weeks to months Late months to years 24

25 Immediate Toxicity (Hours to Days) Common to many agents Predominantly seen with one or two agents Nausea/vomiting Local tissue necrosis Phlebitis Hyperuricemia Renal failure Anaphylaxis Skin rash Hemorrhagic cystitis(ctx) Hypocalcemia(Mithramycin) Facial flushing(mithramycin) Radiation recall(actinomycin-d) Fever/chills(Bleomycin) Hypertension(Procarbazine) Hypotension(Etoposide) 25

26 Side Effects of Chemotherapy Mucositis Alopecia Pulmonary fibrosis Nausea/vomiting Diarrhea Cystitis Sterility Myalgia Neuropathy Cardiotoxicity Local reaction Renal failure Myelosuppression Phlebitis 26

27 Specific Organ Toxicity (1) 신장 : cisplatin, methotrexate 소화기 ( 구내염, 설사 ): 5-fluorouracil, anthracyclines, methotrexate 간 : L-asparaginase, methotrexate, 6-mercaptopurine 심장 : anthracycline, cyclophosphamide 폐 : bleomycin, busulfan, BCNU 신경계 : 말초신경계 - vincristine, platinum compounds 중추신경계 - procarbazine, L-asparaginase 27

28 Specific Organ Toxicity (2) 생식기 : alkylating agents, vinblastine, procarbazine 색소침착 : 5-fluorouracil, bleomycin 수족증후군 (hand-foot syndrome): 5-FU(infusion), oral fluoropyrimidine, Sunitinib, Sorafenib, TSU-68. 출혈성방광염 : cyclophosphamide, ifosfamide 피부괴사 (vesicants): anthracyclines, vinca alkaloids, mitomycin C 이차암 : alkylating agents, epipodophylotoxin, nitrosourea, procarbazine 28

function Toxicity Myelosuppression, alopecia, emesis and mucositis

29 Doxorubicin 유방암, 악성림파종, 연부조직육종, 폐암, 위암, 간암, 백혈병 Intercalating into DNA, thereby altering DNA structure, replication and topoisomearse II function Toxicity Myelosuppression, alopecia, emesis and mucositis Cardiac toxicity Vesicant Skin necrosis caused by extravasation of ADR 29

30 Capecitabine Intestine Liver Capecitabine (Xeloda ) Xeloda CE Tumour 5'-DFCR CyD 5'-DFCR CyD 유방암및소화기암 5'-DFUR Novel oral fluoropyrimidine carbamate Selective 5-FU activation in tumor tissue Equivalent to prolonged infusion of 5-FU and more favorable toxicities profile Hand-foot syndrome, diarrhea Thymidine phosphorylase 5'-DFUR 5-FU 30

31 Hand-Foot Syndrome caused by capecitabine 31

32 Cardiac Toxicity Anthracycline mg/m 2 ; 10% incidence Increased cardiac toxicity age > 70, prior anthracyclines, prior cardiac disease high BP or DM prior chest wall irradiation concomitant cyclophosphamide 32

33 Secondary malignancy 완치된암환자의주요사망원인 Primary cancer related malignancy H & N cancer : Lung cancer (d/t smoking???) Breast cancer: contralateral breast cancer HD : NHL RT related : radiation field 내에 cancer 발생위험증가 à The risk is modest in first decade after treatment, but reaches 1% per year in the second decade, such that populations followed for 25years or more have a 25% chance of developing a second tx-reated tumors Chemotherapy related : MDS & Acute leukemia Alkylating agent : peak 4-6ears The risk returns to baseline if no disease has developed within 10 years of treatment Topoisomerase II inhibitors (doxorubicin, etoposide) ; Incidence < 1%, 1.5~3 years after treatment à No preventive strategy Tamoxifen : Endometrial cancer (1 ~ 2%) 33

34 Irritant Drugs Pain at the injection site or along the vein, with or without an inflammatory reaction Camustine CDDP DTIC (dacabazine) 5-FU Bleomycin Paclitaxel Vinorelbine Phlebitis caused by vinorelbine (Navelbine) 34

35 Vesicant Drugs Anti-cancer chemotherapeutic agent capable of forming a blister and/or causing tissue destruction. Actinomycin Daunorubicin Doxorubicin Epirubicin Idarubicin Mitomycin Vinblastine Vincristine Extravasation caused by doxorubicin 35

36 Chemoport 36

37 터널형도관 - 비터널형도관 포트 (Chemoport) 히크만도관 (Hickman catheter) 영구투석도관 (Perm cath) 단기이중내강도관 (temporary dual lumen catheter) 말초삽입중심정맥도관 (PICC: peripherally inserted central catheter) 단기혈액투석용이중내강도관 37

38 Hickman catheter *** Indication - 항암제투여 - 비경구적총영양수액법 (TPN) - 말초혈관확보가어려운환자 - 수혈 - 장기간항생제투여 - 혈액검사 - 혈액투석 38

39 Early Toxicity (days to weeks) Common Predominantly seen Leukopenia Thrombocytopenia Alopecia Stomatitis Diarrhea Megaloblastosis Paralytic ileus(vcr) Hypercalcemia(Estrogen, Antiestrogen) Hypomagnesemia(cisplatin) Psychosis(Corticosteroids) DIC(L-asparaginase) Pancreatitis(L-asparaginase) Fluid retension(estrogen, corticosteroids, taxanes) Pul. infiltrates(mtx, Bleomycin) Hyperglycemia(corticosteroids) Cerebral ataxia(5-fu) Ototoxicity(cisplatin) 39

Nausea and Vomiting Most common toxicity: nausea Mechanisms 1) Stimulation of chemoreceptor trigger zone 2) Peripheral mechanisms damage of GI mucosa stimulation of GI

40 Nausea and Vomiting Most common toxicity: nausea Mechanisms 1) Stimulation of chemoreceptor trigger zone 2) Peripheral mechanisms damage of GI mucosa stimulation of GI neurotransmitter receptors 3) Cortical mechanisms direct cerebral activation indirect(psychogenic) mechanism 4) Vestibular mechanism 5) Alterations of taste and smell 40

41 Nausea and Vomiting Highly emetogenic drugs (level 5) Cisplatin ( >50 mg/m) Nitrosourea Cyclophosphamide ( > 1500 mg/m) DTIC Streptozotocin Mechlorethamine 41

42 Bone Marrow Suppression(1) Most common dose-limiting toxicity - Neutropenia Nadir: 1-2 weeks Recovery within 3-4 weeks - Thrombocytopenia - Anemia 42

43 Oral Mucositis Incidence Standard chemotx: 35-40% BMT or PBSCT : 75% Radiotherapy in head and neck cancer : >90% Clinical outcome Significant pain Quality of life Nutritional compromise Portals of entry of microorganism sepsis Suboptimal tumor response direct impact on survival 43

44 Specific Organ Toxicity (1) 신장 : cisplatin, methotrexate 소화기 ( 구내염, 설사 ): 5-fluorouracil, anthracyclines, methotrexate 간 : L-asparaginase, methotrexate, 6-mercaptopurine 심장 : anthracycline, cyclophosphamide 폐 : bleomycin, busulfan, BCNU 신경계 : 말초신경계 - vincristine, platinum compounds 중추신경계 - procarbazine, L-asparaginase 44

45 Specific Organ Toxicity (2) 생식기 : alkylating agents, vinblastine, procarbazine 색소침착 : 5-fluorouracil, bleomycin 수족증후군 (hand-foot syndrome): 5-FU(infusion), oral fluoropyrimidine 출혈성방광염 : cyclophosphamide, ifosfamide 피부괴사 (vesicants): anthracyclines, vinca alkaloids, mitomycin C 이차암 : alkylating agents, epipodophylotoxin, nitrosourea, procarbazine 45

46 Delayed Toxicity (weeks to months) Common to many agents Anemia Aspermia Hepatocellular damage Hyperpigmentation Pulmonary fibrosis Predominantly seen with one or two agents Peripheral neuropathy(vcr) Cardiac neurosis(adr, CTX) Cushing s syndrome(corticosteroids) SIADH(CTX, VCR) Musculinization(Androgen) Raynaud s phenomenon(bleomycin) Feminization(Estrogen) Cholestatic jaundice(6-mp) Addison-like syndrome(busulfan) Lacrimal duct fibrosis(5-fu) Hemolytic uremic syndrome(mmc) 46

47 Cardiac Toxicity Anthracycline mg/m 2 ; 10% incidence Increased cardiac toxicity age > 70, prior anthracyclines, prior cardiac disease high BP or DM prior chest wall irradiation concomitant cyclophosphamide 47

48 Late Toxicity (months to years) Common to many agents Sterility Hypogonadism Premature menopause Acute leukemia, MDS Lymphoma Solids tumors Predominantly seen with one or two agents Hepatic fibrosis/cirrhosis(mtx) Encephalopathy(MTX, CNS RT) Carcinoma of the bladder(ctx) Osteoporosis(Corticosteroids) Cataracts(Busulfan) 48

49 부작용을예방또는최소화하는방법 전처치약제 진토제 Hydration, 수액요법 부작용예방약 휴식혹은용량감소 중심정맥관삽입 정기적인검사 + 초기에치료, 조혈촉진인자 나자신도믿지말라. 가장중요한것은? 환자를돌보는사람의마음가짐,! 49

50 세포독성항암제의문제점 선택성결여 (Low therapeutic index) 약제저항 (Drug resistance) 독성 ( 정상세포손상 ) 50

51 Paradigm shift : Cytotoxic agents : Combination : Targeted agents 51

52 Targeted Drug 표적치료 (Targeted Therapy) Personalized Therapy Indivisualied Therapy 맞춤치료 (Tailored Therapy) 52

53 표적치료제 (Molecular target) 암세포와정상세포를선택적으로구분할수있는 "molecular target" 을대상으로소위 small molecule 에대한연구가진행되고있다. small molecule 이란약 500 kd 이하의질량을갖는작은제재로암조직으로의약제투여가용이하고, 약제내성과도관련되지않는장점을갖고있다. 1. Growth factor and Growth factor receptor : monoclonal antibody, tyrosine kinase inhibitor 2. Angiogenesis inhibitor 3. Signal inhibitors 4. Vaccines 5. Gene and antisense therapy 53

54 Targets 54

55 Target: Ligand, Receptor, TK 55

56 Imatinib (Gleevec) 56

57 57

58 Nomenclature of Mab -omab -ximab -zumab -umab Rituximab Cetuximab Bevacizumab Trastzuzumab Panitumumab 58

59 Targeted Agents Small Molecule (-nib) Imatinib (Glivec R ) BCR/ABL, c-kit TK CML, GIST Gefitinib (Iressa R ) EGFR TK NSCLC Erlotinib (Tarceva R ) EGFR TK NSCLC, Pancreatic C Sorafenib (Nexavar R ) Raf, VEGFR, PDGFR TK Clear cell RCC Hepatoma Sunitinib (Sutene R ) VEGFR, PDGFR TK RCC, GIST 59

60 Targeted agent Y Monoclonal Antibody (-mab) Bevacizumab (Avastin R ) VGEF mcrc, NSCLC, MBC Rituximab (Mabthera R ) CD20 NHL Trastuzumab (Herceptin R ) Her2/neu EBC, MBC Cetuximab (Erbitux R ) EGFR mcrc, HNC Panitumumab EGFR mcrc Bortezomib (Velcade R ) Proteasome MM 60

61 Summary Compounds Main Antiangiogenic Targets Main Antiproligerative Targets VEGF VEGFR PDGFR EGFR Raf c-kit BCR-ABL Imatinib O O Sorafenib O O O Sunitinib O O O Gefitinib Erlotinib O O Bevacizumab O Cetuximab O 61

62 R. Herbst,

63 감사합니다 박희숙 63

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<B0E6C8F1B4EBB3BBB0FA20C0D3BBF3B0ADC1C E687770> 2012 개원의와함께하는임상강좌 경희대학교의과대학종양혈액내과학교실 백선경 한국인사망원인 평균수명까지생존시암발생확률 길라잡이 : 개정된가이드라인을중심으로 History of anti-cancer chemotherapy Chabner BA & Roberts TG Jr. Nat Rev 2005 Use standard therapies 2012 개원의와함께하는임상강좌