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

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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

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항암제 전

DNA Synthesis

Anti-metabolite

DNA

DNA Transcription DNA Replication

Alkylating agent

Antimitotic agents

Intercalating agentsMitosis

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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

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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

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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

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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

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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

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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

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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

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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)

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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