항암치료의원칙 - HIRA · 2016-04-22 · Alkylating agents ØCyclophosphamide • most...

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

7

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)

8

항암치료

Ø 수술

Ø 치료

Ø 항암화학 – 포 치료

Ø 역

Ø 생물학적치료

Ø 전

Ø 체

Ø 맞춤치료 (Tailored Therapy)( 적치료)

9

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

10

항암화학

11

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)

12

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

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

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

17

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

18

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

19

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

22

Classification of chemotherapeutic toxicity

onset

Immediate hours to days

Early days to weeks

Delayed weeks to months

Late months to years

23

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)

24

Side Effects of Chemotherapy

Mucositis

Nausea/vomiting

Diarrhea

Cystitis

Sterility

Myalgia

Neuropathy

Alopecia

Pulmonary fibrosis

Cardiotoxicity

Local reaction

Renal failure

Myelosuppression

Phlebitis

25

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

26

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

27

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 ®

28

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)

30

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

31

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

34

Bone Marrow Suppression(1)

Most common dose-limiting toxicity

- Neutropenia

Nadir: 1-2 weeks

Recovery within 3-4 weeks

- Thrombocytopenia

- Anemia

35

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

38

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)

39

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

40

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

51

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

53

R. Herbst, 2000

54

감 합니다

희숙

55