항암치료의 이해 순천향 대학교 병원 종양혈액내과 박희숙
항암 료 해
순천향 학 병원
종양 액내과 희숙
Introduction
Ø 한 에 암 난 10년간 망원 1 , 암생 적 로 가 추 에 다.
Ø 최근 암 조 견과 암 료 전 로 암 생존향 에 라 생존 간뿐 아니라 암 료에 한
적 향과 생존 에 한 심 높아 고다.
Ø 한 주 암 5년 생존 : 46.3% (2002년)
2
나라 암 생 , 2003~2005
생건수 조 생
연령 생
124 132143
69 72 78
55 6065
0
90
180
2003년 2004년 2005년
천
전체 남자 여자257.1 284.1
229.9
272.3 297.9 246.5
292.9 317.8
268.0
0
100
200
300
400
전체 남자 여자
2003년2004년2005년
235.5
298.8
196.6
242.1
301.6
206.3
252.5
310.7
218.5
0
100
200
300
400
전체 남자 여자
2003년
2004년
2005년
(단 : 10만 당)
(단 : 10만 당)
3
25.5 %(4 1 )
31.9%(3 1 )
평균수생존 시암 생
82 75 평균수 * (2005년)
여남전체
79
29.6%(10 3 )
평균수평균수 생존생존 시시 암 생암 생 , 2003~2005, 2003~2005
* 자료원: 통계청
※ 1999~2002년 암 생전체: 25.6% ( 여 : 77 )남 : 27.7% ( 여 : 73 )/ 여 : 22.2% ( 여 : 81 )
4
주 암종 생 , 2003~2005
(단 : %)
5
주 암종 생 , 2003~2005
(단 : %)
남 여
6
암 료
Ø 차 : to eradicate the cancer(암 제거)
Ø 차 가 가능 한 경 (Palliation, )
Ø
Ø 생 연
Ø 개 ( 등)
7
항암 료
Ø 수술
Ø 료
Ø 항암 학 – 포 료
Ø 역
Ø 생물학적 료
Ø 전
Ø 체
Ø 맞춤 료 (Tailored Therapy)( 적 료)
8
어 정
Ø Neoadjuvant chemotherapy : 행(보조)항암 학• Organ preservation : H & N cancer, Rectal cancer
• breast cancer (non-metastatic),
• Osteosarcoma
Ø Adjuvant chemotherapy: 보조 항암 학• Colorectal, Breast, NSCLC, Osteosarcoma,
Ø Definitive CCRT : • Inoperable NSCLC(non-metastatic) , Esophageal cancer
Ø Palliative chemotherapy : 가 가한 경
Ø Induction chemotherapy : 항암 학• Hematologic malignancy – 전 해 적 로 하는 CTx
Ø Salvage : 1st line chemotherapy 실패한 경
9
항암 학
10
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
12
항암제 전
DNA Synthesis
Anti-metabolite
DNA
DNA Transcription DNA Replication
Alkylating agent
Antimitotic agents
Intercalating agentsMitosis
13
Tumor cell Kinetics
L1210 murine leukemia system
14
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
16
Antimetabolite(pyrymidine analogue (5-Flurouracil)(5FU)
Ø 암, 암, 암, 췌 암, 식 암, 경 암 등
Ø Tumor cells incorporate radiolabled uracil more efficiently in to DNA than normal cell
Ø Metabolize to 5’FdUMP, which inhibits thymidylate synthetase
Ø Inactivated by DPD (dihydropyrimidine dehydrogenase)
Ø Bolus versus continuous infusion
• Bone marrow suppression after short infusions vs. stomatitis and diarrhea after prolonged infusion
Ø 5FU pro-drugs:
• Capecitabine: intra-tumoral metabolism
• UFT
• S1: Forafur + 5-chloro-2,4,-dihdroxypyridine + oxonic acid 17
Alkylating agents
Ø Cyclophosphamide
• most frequently used alkylating
agent
• 암, 폐암, 난 암, 암, 악
파종, 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, 고 암, 종, 악 파종
• Mesna protection for
hemorragic cystitis
• Vigorous hydration and frequent
bladder empty
• CNS effects
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Platinums
Ø Cisplatin
• 고 암, 폐암, 난 암,
암, 암, 경 암, 각종
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, 고 암, 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, 포씨 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 21
What Are the Goals of Chemotherapy?
항암 과 : 적절한 량 (dose) 적절한 스케 (Schedule) 적절한 투여 (Route)
Efficacy Toxicity
Cure, Control, Palliation22
Toxicity Overview
Ø 포 항암제는 정 포 암 포 하
한다
No magic bullet(?)( 탄 함)
Ø 안정 역 좁다 (MTD, DLT)
Ø 포 열 한 정 조 골수 포,
포 등에 강하게 나타남
Ø 특 한 에 생 하는 (심 , 신 폐 등)
Ø 항암제에 한 적 합병
23
Classification of chemotherapeutic toxicity
onset
Immediate hours to days
Early days to weeks
Delayed weeks to months
Late months to years
24
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)
25
Side Effects of Chemotherapy
Mucositis
Nausea/vomiting
Diarrhea
Cystitis
Sterility
Myalgia
Neuropathy
Alopecia
Pulmonary fibrosis
Cardiotoxicity
Local reaction
Renal failure
Myelosuppression
Phlebitis
26
Specific Organ Toxicity (1)
신 : cisplatin, methotrexate
( 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
27
Specific Organ Toxicity (2)
생식 : alkylating agents, vinblastine, procarbazine
착: 5-fluorouracil, bleomycin
수족 (hand-foot syndrome): 5-FU(infusion),
oral fluoropyrimidine, Sunitinib, Sorafenib, TSU-68….
출 염: cyclophosphamide, ifosfamide
피 (vesicants): anthracyclines, vinca alkaloids, mitomycin C
차암: alkylating agents, epipodophylotoxin, nitrosourea, procarbazine
28
Doxorubicin
Ø 암, 악 파종, 연 조 종, 폐암
, 암, 간암, 병
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 ®
29
Capecitabine
Intestine Liver
Xeloda®
5'-DFCR
5'-DFUR
CyD
5'-DFCR
5'-DFUR
5-FU
TumourCapecitabine (Xeloda® )
Thymidine phosphorylase
CyD
CE
Ø 암 암
Ø Novel oral fluoropyrimidine carbamate
Ø Selective 5-FU activation in tumor tissue
Ø Equivalent to prolonged infusion of 5-FU and more favorable toxicities profile
Ø Hand-foot syndrome, diarrhea
30
Hand-Foot Syndrome caused by capecitabine
31
Cardiac Toxicity
Anthracycline
• 450 - 500 mg/m2 ; 10% incidence
• Increased cardiac toxicity
Ø age > 70, prior anthracyclines, prior cardiac disease
Ø high BP or DM
Ø prior chest wall irradiation
Ø concomitant cyclophosphamide
32
Secondary malignancy
Ø 암 주 망원
Ø Primary cancer related malignancy • H & N cancer : Lung cancer ↑ (d/t smoking ???)
• Breast cancer: contralateral breast cancer
• HD : NHL ↑
Ø RT related : radiation field내에 cancer 생 험 가à 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
Ø 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
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)
34
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
35
Chemoport
36
널 - 비 널
포트(Chemoport)
히크만
(Hickman catheter)
투
(Perm cath)
단 내강
(temporary dual lumen catheter)
말초 심정맥
(PICC: peripherally inserted
central catheter)
단 액투 내강
37
Hickman
catheter
*** Indication
- 항암제 투여
- 비경 적 총 양수액 (TPN)
- 말초 보가 어려
- 수
- 간 항생제 투여
- 액검
- 액투
38
Early Toxicity (days to weeks)
Common 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)
39
Nausea and VomitingMost 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
Nausea and Vomiting
Highly emetogenic drugs (level 5)
Cisplatin ( >50 mg/M)
Nitrosourea
Cyclophosphamide ( > 1500 mg/M)
DTIC
Streptozotocin
Mechlorethamine
41
Bone Marrow Suppression(1)
Most common dose-limiting toxicity
- Neutropenia
Nadir: 1-2 weeks
Recovery within 3-4 weeks
- Thrombocytopenia
- Anemia
42
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
Specific Organ Toxicity (1)
신 : cisplatin, methotrexate
( 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
44
Specific Organ Toxicity (2)
생식 : alkylating agents, vinblastine, procarbazine
착: 5-fluorouracil, bleomycin
수족 (hand-foot syndrome): 5-FU(infusion),
oral fluoropyrimidine
출 염: cyclophosphamide, ifosfamide
피 (vesicants): anthracyclines, vinca alkaloids, mitomycin C
차암: alkylating agents, epipodophylotoxin, nitrosourea, procarbazine
45
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)
46
Cardiac Toxicity
Anthracycline
• 450 - 500 mg/m2 ; 10% incidence
• Increased cardiac toxicity
Ø age > 70, prior anthracyclines, prior cardiac disease
Ø high BP or DM
Ø prior chest wall irradiation
Ø concomitant cyclophosphamide
47
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
48
또는 최 하는
Ø 전처 약제
Ø 제
Ø Hydration, 수액
Ø 약
Ø 휴식 량 감
Ø 심정맥
Ø 정 적 검 + 초 에 료, 조 촉
Ø 나 신 믿 말라.
• 가 한 것 ?
• 돌보는 람 가짐, !
49
포 항암제포 항암제 문제점문제점
• 택 결여 (Low therapeutic index)
• 약제 저항 (Drug resistance)
• (정 포 )
50
Paradigm shift
- 2000: Cytotoxic agents
2000 – 2010: Combination
2010- : Targeted agents
51
Targeted Drug
Ø 적 료(Targeted Therapy)
ØPersonalized Therapy
Ø Indivisualied Therapy
Ø맞춤 료(Tailored Therapy)
52
적 료제적 료제(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 therapy53
Targets
54
Target: Ligand, Receptor, TK
55
Imatinib(Gleevec)
56
57
Nomenclature of Mab
-ximab
Rituximab
Cetuximab
-zumab
Bevacizumab
Trastzuzumab
-umab
Panitumumab
-omab
58
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
59
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
60
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
61
R. Herbst, 2000
62
감 합니다
희숙
63