항암치료의원칙및 심사기준 순천향대학교병원 종양혈액내과박희숙

항암치료의원칙및 심사기준 순천향대학교병원 종양혈액내과박희숙

암치료의목표 일차목표 : to eradicate the cancer( 암제거 ) 일차목표가불가능한경우 (Palliation, 완화요법 ) 진행방지 ( SD PR CR) 증상의완화생명연장삶의질개선 ( 통증완화등 )

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

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

항암화학요법 수술후보조요법 수술가능한병기인경우수술후보조항암요법을 Guideline ( 공고안 ) 에준해서시행함 보조요법을시행하는경우반응평가는하지않고병의재발여부를관찰하기위해일정기간 (6 개월 ) 후검사 완화요법 (palliative therapy) 재발후치료. 전이암치료 국소치료가불가능한진행성, 재발암의경우 2-3 개월의간격으로반응평가를시행하여치료의효능을검증

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

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

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

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

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

Hand-Foot Syndrome caused by capecitabine(5fu 제재 )

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

Paradigm shift - 2000: Cytotoxic agents 2000 2010: Combination 2010- : Targeted agents

Targeted Drug 표적치료 (Targeted Therapy) Personalized Therapy Indivisualized Therapy 맞춤치료 (Tailored Therapy)

Targeted therapy 특정질병을유발하는 signal transduction( 신호전달체계 ) 의분자생물학적수준에서유전자나단백질등을표적으로하여차단시킴으로써암세포의성장을막는새로운치료방법

분자생물학을이용한암진단 분자생물학의발전 암발생과정에대한이해의증대 암은다양한유전적변화의결과 암발생에관여하는유전자 원발유전자 (proto-oncogene) 암억제유전자 (tumor suppressor gene) DNA 복제실수교정유전자

암과유전자 암은유전자의형질변환으로부터시작된다. 그러나한개의암유전자 또는종양억제유전자의변화가단독으로암을일으키는것은아니며, 정상세포가암세포로변화하기위해서는긴시간에걸쳐여러개의암

Targeted agent Conventional chemotherapy Targeted therapy

EGFR signal transduction EGFR expression 27 95% PTE N EGFR mutation <1% KRAS mutation 30 50% BRAF mutation 10%

Targeted therapy 약물 Anti-HER2 MAbs Herceptin, Omnitarg TM Farnesyl-transferase inhibitors R115777, SCH66336, BMS 214662 Ras signalling Apoptosis HER signalling HER tyrosinekinase inhibitors Tarceva TM, gefitinib VEGF signalling Anti-VEGF MAbs Avastin TM Apoptotic agents

HER receptor 를차단하 는약물 Extracellular targeting Herceptin, Omnitarg TM, cetuximab Signal transduction 억제 r Intracellular targeting Tarceva TM, gefitinib Nuclear targeting antisense oligonucleotides, ribozymes Gene activation CELL DIVISION

Target: Ligand, Receptor, TK

Imatinib (Gleevec)

Molecular targeted agents Classification Drug Target Disease Tyrosin Kinase Imatinib (Gleevec) BCR/ABL, C- CML,ALL, GIST, SCLC inhibitor Gefitinib (Iressa) kit NSCLC Erlotinib (Tarceva) EGFR NSCLC, Panc, H&N SU5416 (Sutent) EGFR VEGFR+EGFR Pazopanib(Tykerb) BC RCC Sorafinib(nexavar) RCC Hepatoma Monoclonal Cetuximab (C225) EGFR Colorectal, NSCLC antibody Trastuzumab (Herceptin) Her-2 Breast ca. Bevacizumab (Avastin) VEGFR Colorectal Rituximab CD20 NHL B-cell Alemtuzumab CD52 NHL T-cell Gemtuzumab CD33 AML

Chimeric antibody & Humanized antibody - ximab - zumab

R. Herbst, 2000

항암약제투여기준 요양급여에대한세부사항은중증질환심의위원회의심의를거쳐심사평가원장이공고 허가사항범위내에서사용함을원칙으로함 허가사항초과및요법외로처방투여하고자하는경우에는별도의신청양식에의해사전신청후사용 ( 다학제위원회를구성하여협의한경우신청 ) 투여기준공고 투여요법및반응평가기준

급여에관한빈번한문제 공고안에없는요법으로치료대책 : 공고안에없는요법이나 evidence 가있다면사전신청을통해암질환심의위원회에서토의후결정하여공지된후사용 반응평가문제 측정가능병변이있을경우반드시그병변에대한영상의학적반응평가필요 (RECIST 혹은 WHO) 평가가능병변만있는경우 ( 뼈전이, 복막전이등 ) 종양인자 ( Tumor Marker) 자료및이학적소견필요

같은계통의약제를중복해서사용할수없음 ( 질병진행의경우 ) Ex)Topoisomerase II inhibitor (irrinotecan-topotecan) Taxol genexol genexol PM Futron- TS1 Capcitabine 유방암에사용되는호르몬제 (AI- AI) 허가사항에 2 차,3 차로되어있는약제는 1 차로사용할수없음 (1 차사용약을규정한경우는반드시규정약제사용후사용하여야함 ) ( 예 ; 유방암의 Gemcitabin, Herceptine 단독요법시, 또는 Lapatinib 의경우 )

Response evaluation in oncology Tumor burden Tumor Tumor burden Baseline Treatment Follow-up

반응평가측정도구 Anatomic( 해부학적측정 ) : CT, MRI Tumor size Enhancing lesion Tumor density (HU) Functional (metabolic)( 기능적측정 ) Glycolysis ; PET Cellular metabolite transport ; MR spectroscopy Diffusion of water molecule ; DW-MRI Perfusion of contrast agents ; DCE-MRI, perfusion CT Tumor marker CTC (circulating tumor cells) Molecular markers

Response evaluation criteria (anatomic) WHO RECIST 1.0 RECIST 1.1 Macdonald RANO Criteria PCWG 1 PCWG 2 IWG 1 IWG 2 GIST 1980 1990 2000 2010 irrc

How to measure? WHO/RECIST SPD SOD Sum of products of diameters Sum of diameters

RECIST : Terminologies Baseline lesions Measurable Lesions Targt target Lesion s Nonmeasurable Lesions Non-target Lesions New Lesion s

Measurable lesions : baseline RECIST 1.0 CT (MRI) 10 mm spiral 20 mm non-spiral Chest x-ray Clinical 20 mm LN Not mentioned RECIST 1.1 CT (MRI) 10 mm Chest x-ray 20 mm Clinical 10 mm (by caliper) LN (short axis) ³ 15 mm

Truly non-measurable lesion (RECIST 1.1) Leptomeningeal disease Ascites Pleural or pericardial effusion Inflammatory breast disease Lymphangitic involvement of skin or lung Bone lesions removed Cystic disease removed Abdominal organomegaly by P/E added

Lymph nodes Short axis Measurable ³ 15 mm Non-measurable 10-14 mm Normal < 10 mm 17 mm 9 mm 13 mm

Chest x-ray ³ 2 cm Should be clearly defined and surrounded by aerated lung

Clinical lesion Superficial lesion ³ 1 cm : Include taking a lesion color picture with a ruler

Breast cancer

Bone Lesion Lytic or lytic-blastic lesions with soft tissue component Osteoblastic : nonmeasurable

Method of assessment : Consistency (CT) Optimal vascular phase Arterial phase for hypervascular metastases Carcinoid, Breast cancer, GIST Portal phase for hypovascular metastases Colorectal cancer Measured at the same window setting

Target lesions Maximum of 5 lesions total Maximum of 2 lesions/organ Selected on the basis of size Representative of all involved organs Should be reproducible

Method of assessment : Consistency Hypervascular : Neuroendocrine tumor Portal phase Arterial phase

Method of assessment : Consistency Hypovascular metastasis : NSCLC Portal phase Arterial phase

Target lesion : RECIST 1.0 v 1.1

Target lesion : Calculation Asymmetry -30% +43% 100 mm 70 mm 100 mm Reference value Change = After PR 0.7 Before PD ³ 1.2

Reference value Baseline SD PR PD Change = After Before PR : Baseline PD : Nadir

Target lesion : Response criteria Measure ment WHO RECIST RECIST 1.1 Bidimensional Longest diameter Longest diameter Short axis for LN CR Disappearance Disappearance Disappearance LN < 10 mm PR 50% 30% 30% SD PD 25% New lesion 20% New lesion 20% + absolute 5 mm New lesion

New lesion : No baseline images Baseline 치료시작 2 개월후 No image Lesion seen in anatomical region not imaged at baseline = new lesion

New lesion : No baseline anatomic coverage A lesion later identified in a body part not scanned at baseline = new lesion

New lesion(s) in PET scan Baseline PET CT Negative New PET positive PD No PET New PET positive New lesion Pre existing lesion PD Not PD No lesion F/U

Response assessment Protocol specified On a calendar schedule Normally, all target and non-target sites Bone scans may be repeated only when CR is identified or when progression in bone is suspected. EUROPEAN JOURNAL OF CANCER 4 5 ( 2

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