항암치료의 원칙 순천향 대학교 병원 종양혈액내과 박희숙
항암치료 원칙
순천향 학 병원
종양혈액내과 희숙
Introduction
Ø 한 에 암 난 10년간 망원 1 , 암생 적 로 가 추 에 다.
Ø 최근 암 조 견과 암 치료 전 로 암 생존향 에 라 생존 간뿐 아니라 암 치료에 한
적 향과 생존 에 한 심 높아 고다.
Ø 한 주 암 5년 생존 : 46.3% (2002년)
2
25.5 %(4 1 )
31.9%(3 1 )
평균수생존 시암 생 확
82 75 평균수 * (2005년)
여남전체
79
29.6%(10 3 )
평균수평균수 생존생존 시시 암 생암 생 확확 , 2003~2005, 2003~2005
* 자료원: 통계청
※ 1999~2002년 암 생 확전체: 25.6% ( 여 : 77 )남 : 27.7% ( 여 : 73 )/ 여 : 22.2% ( 여 : 81 )
3
주 암종 생 , 2003~2005
(단 : %)
4
주 암종 생 , 2003~2005
(단 : %)
남 여
5
5년 생존 추 : 든 암
41.2
31.7
53.4
44.0
35.3
55.3 52.2
43.7
62.4
0
20
40
60
80
전체 남자 여자
'93-'95 '96-'00 '01-'05
6
1) Ries LAG, et al (eds). SEER Cancer Statistics Review, 1975-2005, National Cancer Institute, 20082) National Cancer Center in Japan. Cancer Statistics in Japan, 2008
단 : %
주 암 5년 생존 제비
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암치료
Ø 차 : to eradicate the cancer(암 제거)
Ø 차 가 가능 한 경 (Palliation, 화 )
Ø 화
Ø 생 연
Ø 개 ( 화 등)
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항암치료
Ø 수술
Ø 치료
Ø 항암화학 – 포 치료
Ø 역
Ø 생물학적치료
Ø 전
Ø 체
Ø 맞춤치료 (Tailored Therapy)( 적치료)
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어 정
Ø Neoadjuvant chemotherapy : 행(보조)항암화학• Organ preservation : H & N cancer, Rectal cancer
• breast cancer (non-metastatic),
• Osteosarcoma
Ø Adjuvant chemotherapy: 보조 항암화학• Colorectal, Breast, NSCLC, Osteosarcoma,
Ø Definitive CCRT : • Inoperable NSCLC(non-metastatic) , Esophageal cancer
Ø Palliative chemotherapy : 치가 가한 경
Ø Induction chemotherapy : 항암화학• Hematologic malignancy – 전 해 적 로 하는 CTx
Ø Salvage : 1st line chemotherapy 실패한 경
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항암화학
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CELLCELLDIFFERENTIATIONDIFFERENTIATION
CELLCELLLIFE CYCLELIFE CYCLE
TIMETIME
CELLCELLDIVISIONDIVISION
GG22 PERIODPERIOD
(CHROMOSOME REPLICATION) (CHROMOSOME REPLICATION) SS--PHASEPHASE
GG11 PERIODPERIOD
(Cell prepare to divide) (Cell prepare to divide)
(Mitosis) (Mitosis)
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항암제란 ???
포내 DNA에 접 결합 하여 DNAreplication, transcription, translation 차단
핵 합 경로에 개 하여 핵 합 해
포 열 저해
암 포에 한 포 나타내는 약제
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Tumor cell Kinetics
L1210 murine leukemia system
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Dose / Therapeutic Index
The degree of separation between toxic and therapeutic doses
Anti-cancer drugs: narrow TIDose-limiting toxicity (DLT)
Maximum tolerated dose (MTD)15
Chemotherapeutic agents
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Alkylating agents
Ø Cyclophosphamide
• most frequently used alkylating
agent
• 암, 폐암, 난 암, 암, 악
파종, 호 킨씨병 등
• Parent form: no direct cytotoxic
effects
• must be activated to cytotoxic
forms by microsomal enzymes
• Maintain fluids intake and frequent
bladder empty
• Hemorrhagic cystitis
Ø IfosfamideØ 폐암, 고환암, 종, 악 파종
• Mesna protection for
hemorragic cystitis
• Vigorous hydration and frequent
bladder empty
• CNS effects
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Platinums
Ø Cisplatin
• 고환암, 폐암, 난 암,
암, 암, 경 암, 각종
화 암, 연 조 종, 악
파종
Ø Vigorous hydration with
diuresis to prevent renal
toxicity
• Neurotoxicity
• Hypomagnesemia and
hypokalemia
• Highly emetogenic agent
Ø Carboplatin • Equivalent efficacy
• Less nephro-, oto- and neurotoxicity than DDP
• More frequent myelosuppression
• Exclusive renal excretion
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Etoposide (VP-16)
Ø Plant product podophylotoxin
Ø Binds directly to topoisomerase II and DNA in a reversible ternary complex ® stabilized enzyme-DNA complex
Ø 폐암, 암, 고환암, 악 파종Ø Melosuppression, hypersensitivity reaction
EpipodophyllotoxinsEpipodophyllotoxinsTopoisomerase IITopoisomerase II
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Taxanes
Ø Paclitaxel
• 암, 난 암, 폐암, 경
암, 암, 암, 암
, 악 흑 종, 카포씨 종
• Anaphylaxis:
premedication!!
• Myalgia, arthralgia and
peripheral neuropathy
Ø Docetaxel
• 암, 폐암, 경 암, 난 암, 전 암
• Hypresensitivity reaction
• Capillary leak syndrome: pre- & post medication
• myalgia, general weakness
European yew treePacific yew tree 20
What Are the Goals of Chemotherapy?
항암효과 : 적절한 량 (dose) 적절한 스케 (Schedule) 적절한 투여 (Route)
Efficacy Toxicity
Cure, Control, Palliation21
Toxicity Overview
Ø 포 항암제는 정 포 암 포 하
한다
No magic bullet(?)( 탄환 함)
Ø 안정 역 좁다 (MTD, DLT)
Ø 포 열 활 한 정 조 골수 포, 화
포 등에 강하게 나타남
Ø 특 한 에 생 하는 (심 , 신 폐 등)
Ø 항암제에 한 적 합병
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Classification of chemotherapeutic toxicity
onset
Immediate hours to days
Early days to weeks
Delayed weeks to months
Late months to years
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Immediate Toxicity (Hours to Days)
Common to Predominantly seen
many agents with one or two agents
Nausea/vomiting Hemorrhagic cystitis(CTX)
Local tissue necrosis Hypocalcemia(Mithramycin)
Phlebitis Facial flushing(Mithramycin)
Hyperuricemia Radiation recall(Actinomycin-D)
Renal failure Fever/chills(Bleomycin)
Anaphylaxis Hypertension(Procarbazine)
Skin rash Hypotension(Etoposide)
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Side Effects of Chemotherapy
Mucositis
Nausea/vomiting
Diarrhea
Cystitis
Sterility
Myalgia
Neuropathy
Alopecia
Pulmonary fibrosis
Cardiotoxicity
Local reaction
Renal failure
Myelosuppression
Phlebitis
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Specific Organ Toxicity (1)
신 : cisplatin, methotrexate
화 ( 내염, ): 5-fluorouracil, anthracyclines, methotrexate
간: L-asparaginase, methotrexate, 6-mercaptopurine
심 : anthracycline, cyclophosphamide
폐: bleomycin, busulfan, BCNU
신경계: 말초신경계- vincristine, platinum compounds
추신경계- procarbazine, L-asparaginase
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Specific Organ Toxicity (2)
생식 : alkylating agents, vinblastine, procarbazine
침착: 5-fluorouracil, bleomycin
수족 후 (hand-foot syndrome): 5-FU(infusion),
oral fluoropyrimidine, Sunitinib, Sorafenib, TSU-68….
출혈 염: cyclophosphamide, ifosfamide
피 (vesicants): anthracyclines, vinca alkaloids, mitomycin C
차암: alkylating agents, epipodophylotoxin, nitrosourea, procarbazine
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Doxorubicin
Ø 암, 악 파종, 연 조 종, 폐암
, 암, 간암, 혈병
Ø Intercalating into DNA, thereby
altering DNA structure, replication
and topoisomearse II function
Ø Toxicity
• Myelosuppression, alopecia, emesis
and mucositis
• Cardiac toxicity
• VesicantSkin necrosis caused by extravasation of ADR ®
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Hand-Foot Syndrome caused by capecitabine
29
Irritant Drugs
Ø Pain at the injection site or along the vein, with or without an inflammatory reaction
• Camustine
• CDDP
• DTIC (dacabazine)
• 5-FU
• Bleomycin
• Paclitaxel
• VinorelbinePhlebitis caused by vinorelbine
(Navelbine)
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Vesicant Drugs
Ø 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
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Chemoport
32
Early Toxicity (days to weeks)
Comm on Predominantly seen
Leukopenia Paralytic ileus(VCR)
Thrombocytopenia Hypercalcemia(Estrogen, Antiestrogen)
Alopecia Hypomagnesemia(cisplatin)
Stomatitis Psychosis(Corticosteroids)
Diarrhea DIC(L-asparaginase)
Megaloblastosis Pancreatitis(L-asparaginase)
Fluid retension(Estrogen, corticosteroids, taxanes)
Pul. infiltrates(MTX, Bleomycin)
Hyperglycemia(corticosteroids)
Cerebral ataxia(5-FU)
Ototoxicity(cisplatin)
33
Nausea and Vomiting
Highly emetogenic drugs (level 5)
Cisplatin ( >50 mg/M)
Nitrosourea
Cyclophosphamide ( > 1500 mg/M)
DTIC
Streptozotocin
Mechlorethamine
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Bone Marrow Suppression(1)
Most common dose-limiting toxicity
- Neutropenia
Nadir: 1-2 weeks
Recovery within 3-4 weeks
- Thrombocytopenia
- Anemia
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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
36
Specific Organ Toxicity (1)
신 : cisplatin, methotrexate
화 ( 내염, ): 5-fluorouracil, anthracyclines, methotrexate
간: L-asparaginase, methotrexate, 6-mercaptopurine
심 : anthracycline, cyclophosphamide
폐: bleomycin, busulfan, BCNU
신경계: 말초신경계- vincristine, platinum compounds
추신경계- procarbazine, L-asparaginase
37
Specific Organ Toxicity (2)
생식 : alkylating agents, vinblastine, procarbazine
침착: 5-fluorouracil, bleomycin
수족 후 (hand-foot syndrome): 5-FU(infusion),
oral fluoropyrimidine
출혈 염: cyclophosphamide, ifosfamide
피 (vesicants): anthracyclines, vinca alkaloids, mitomycin C
차암: alkylating agents, epipodophylotoxin, nitrosourea, procarbazine
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Delayed Toxicity (weeks to months)
Common to Predominantly seenmany agents with one or two agents
Anemia Peripheral neuropathy(VCR)
Aspermia Cardiac neurosis(ADR, CTX)
Hepatocellular damage Cushing’s syndrome(Corticosteroids)
Hyperpigmentation SIADH(CTX, VCR)
Pulmonary fibrosis 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)
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Late Toxicity (months to years)
Common to Predominantly seen many agents with one or two agents
Sterility Hepatic fibrosis/cirrhosis(MTX)
Hypogonadism Encephalopathy(MTX, CNS RT)
Premature menopause Carcinoma of the bladder(CTX)
Acute leukemia, MDS Osteoporosis(Corticosteroids)
Lymphoma Cataracts(Busulfan)
Solids tumors
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또는 최 화하는
Ø 전처치 약제
Ø 제
Ø Hydration, 수액
Ø 약
Ø 휴식 혹 량 감
Ø 심정맥
Ø 정 적 검 + 초 에 치료, 조혈촉
Ø 나 신 믿 말라.
• 가 한 것 ?
• 환 돌보는 람 가짐, !
41
포 항암제포 항암제 문제점문제점
• 택 결여 (Low therapeutic index)
• 약제 저항 (Drug resistance)
• (정 포 )
42
Paradigm shift
- 2000: Cytotoxic agents
2000 – 2010: Combination
2010- : Targeted agents
43
Targeted Drug
Ø 적 치료(Targeted Therapy)
ØPersonalized Therapy
Ø Indivisualied Therapy
Ø맞춤치료(Tailored Therapy)
44
적치료제적치료제(Molecular target)(Molecular target)암 포 상 포를 택 으 분할수있는"molecular target"을 상으 위 small molecule에한연 가진행 고있다. small molecule 이란약 500 kd 이하의질량을갖는작은 재 암 직으 의약 투여가이하고, 약 내 과도 지않는장 을갖고있다.
1. Growth factor and Growth factor receptor
: monoclonal antibody, tyrosine kinase inhibitor
2. Angiogenesis inhibitor
3. Signal inhibitors
4. Vaccines
5. Gene and antisense therapy45
Targets
46
Target: Ligand, Receptor, TK
47
Imatinib (Gleevec)
48
49
Nomenclature of Mab
-ximab
Rituximab
Cetuximab
-zumab
Bevacizumab
Trastzuzumab
-umab
Panitumumab
-omab
50
Targeted Agents
· Small Molecule (-nib)
Ø Imatinib (GlivecR) BCR/ABL, c-Kit TK CML, GIST
Ø Gefitinib (IressaR) EGFR TK NSCLC
Ø Erlotinib (TarcevaR) EGFR TK NSCLC,
Ø Pancreatic C
Ø Sorafenib (NexavarR) Raf, VEGFR, PDGFR TK Clear cell RCC
Ø Hepatoma
Ø Sunitinib (SuteneR ) VEGFR, PDGFR TK RCC, GIST
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Targeted agent
Y Monoclonal Antibody (-mab)
Ø Bevacizumab (AvastinR) VGEF mCRC, NSCLC, MBC
Ø Rituximab (MabtheraR) CD20 NHL
Ø Trastuzumab (HerceptinR) Her2/neu EBC, MBC
Ø Cetuximab (ErbituxR) EGFR mCRC, HNC
Ø Panitumumab EGFR mCRC
Ø Bortezomib (VelcadeR) Proteasome MM
52
Summary
CompoundsMain 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 O
Erlotinib O
Bevacizumab O
Cetuximab O
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R. Herbst, 2000
54
감 합니다
희숙
55