2. 01. 항암제 임상시험 승인 현황 02. General aspect of evaluation in cancer 03. Endpoint in Cancer Clinical Trial 04. Response Criteria 05. Conclusions  CONTENTS

3. 구분종양심혈관계내분비계중추 신경계 소화기계기타 효능군 계 2010 년 11249544833143439 2011 년 11269414729205503 2012 년 18459576856246670 2013 년 15780514640233607

4. 2010 112 건 /439 건 25.5 % 22.3 % 27.5 % 25.9 % 2011 112 건 /503 건 2012 184 건 /670 건 2013 157 건 /607 건

5. 1. Patient evaluation 2. Tumor evaluation by staging 3. Treatment response evaluation

6. 1. Patient evaluation  평가기준 - ECOG (Eastern Cooperative Oncology Group) PS - KPS (Karnofsky Performance Status)  항암치료의 원칙 - ECOG 0, 1, 2 - KPS ≧ 70 환자의 일반적 건강상태 및 운동능력평가

7. 2. Tumor evaluation by staging 병기 결정을 통해 치료 방침 결정, 환자 예후 예측, 치료 결과분석 및 상호 정보교환  TNM 법 Tumor_ 원발종양의 크기, 침윤 정도 Node_ 주변 림프절 침범 정도 Metastasis_ 다른 장기로 전이 여부 ▷ TNM 법이 가장 많이 사용되나, 암의 종류에 따라 세부적인 차이 있으며 독립적인 분류법에 따라 진행단계를 결정하는 경우도 있음 TN.M.M

8. 3. Treatment response evaluation  After anti-cancer therapy Response after variable agents Selection of proper agent Residual disease status Toxicities ETC

9.  Time-to-Event outcomes 1) Time between the day of registration/randomization to the date of a event 2) Includes overall survival(OS), progression-free survival(PFS) or time-to- progression(TTP), disease-free survival(DFS) or relapse-free survival(RFS), or other event-free survivals  Tumor shrinkage or stabilization 1) Response rate 2) Clinical benefit  Safety 1) Toxicity (adverse events) √ OS(Overall survival, 전체생존 ): 무작위배정 ~ 사망 √ PFS(Progression free survival, 무진행생존 ): 무작위배정 ~ 종양진행 or 사망 √ TTP(Time to tumor progression, 종양 진행까지의 시간 ): 무작위배정 ~ 종양진행 ※ PFS 와 TTP 의 차이 ; TTP 는 종양진행 없는 사망은 제외

10.  Time-to-Event outcomes 1) Time between the day of registration/randomization to the date of a event 2) Includes overall survival(OS), progression-free survival(PFS) or time-to- progression(TTP), disease-free survival(DFS) or relapse-free survival(RFS), or other event-free survivals  Tumor shrinkage or stabilization 1) Response rate 2) Clinical benefit  Safety 1) Toxicity (adverse events)

11. RECIST Response Criteria 2000년 RECIST Response Criteria 2000년 WHO Response Criteria 1979년 WHO Response Criteria 1979년 Issue in WHO response criteria 1) Complexity - Needs bi-dimensional measurements - No minimum lesion size & number - Results may vary among research groups 2) New technologies 3) No longer regarded

12. WHORECIST Measurability - Measurable, bi-dimensional (product of LD and greatest perpendicular diameter) - Non-measurable/evaluable - Measurable,uni-dimensional (LD only, size with conventional techniques ≥ 20mm; spiral computed tomography ≥ 10mm) - Non-measurable: all other lesions, including small lesions. Evaluable is not recommended Measurability of lesion at baseline

13. Measurable Target lesion Non-target lesion { 병변의 반응 기준 } Target lesion CR PR SD PD Non-target lesion Present=non-CR/non-PD Absent=CR Unequivocal progression=PD New lesion Present Absent Baseline 에 선정된 Target lesion 은 연구 종료시점까지 동 일하게 유지

14. Objective response Measurable disease / Target lesions WHORECIST Change in sum of products of LDs and greatest perpendicular diameters, no maximum No. of lesions specified Change in sum of LDs, maximum of 5 per organ up to 10 total, more than one organ CR Complete response Disappearance of all known disease, confirmed at ≥ 4 week PR Partial response ≥50% decrease from baseline, confirmed at ≥ 4 week ≥30% decrease from baseline, confirmed at ≥ 4 week SD Stable disease Neither PR or PD criteria met PD Progressive disease ≥25% increase of one or more lesions, or appearance of new lesions ≥20% increase over smallest sum observed, or appearance of new lesions

15. Objective response Measurable disease / Target lesions WHORECIST Change in sum of products of LDs and greatest perpendicular diameters, no maximum No. of lesions specified Change in sum of LDs, maximum of 5 per organ up to 10 total, more than one organ Maximal 5 lesions (2 per organ) CR Complete response Disappearance of all known disease, confirmed at ≥ 4 week Disappearance of all known disease, confirmed at ≥ 4 week(Required when response rate is primary endpoint) PR Partial response ≥50% decrease from baseline, confirmed at ≥ 4 week ≥30% decrease from baseline, confirmed at ≥ 4 week(Required when response rate is primary endpoint) SD Stable disease Neither PR or PD criteria met PD Progressive disease ≥25% increase of one or more lesions, or appearance of new lesions ≥20% increase over smallest sum observed[+at least 5mm increase] or appearance of new lesions { Lymph nodes } Measuring short axis - ≥15mm: target node - <10mm: normal node

16. Objective response Non-measurable disease / Non-target lesions WHORECIST CR Complete response Disappearance of all known disease, confirmed at ≥ 4 week Disappearance of all non-target lesions and normalization of tumor markers, confirmed at ≥ 4 week PR Partial response estimated decrease of ≥ 50%- SD Stable disease Neither PR or PD criteria met [ non-CR/non-PD ] Persistence of one or more non- target lesions and/or tumor markers above normal limits PD Progressive disease ≥25% increase of one or more lesions, or appearance of new lesions unequivocal progression of non- target lesions, or appearance of new lesions

17. Target lesion 반응 평가의 예 Baseline1 차 평가 2 차 평가 3 차 평가 4 차 평가 Sum 200150135150180 Baseline 대비 100%75%67.5%75%90% Nadir 대비 100%111%133% Baseline 대비반응 SDPRSD Nadir 대비반응 SDPD 치료제 변경 시점

18. Overall Response Time point response: A response assessment occurs at each protocol specified time point. Target, Non-target, New lesion 의 모두 합한 반응 평가

19. Overall Response TargetNon-targetNew lesionsOverall response CR NoCR Non-CR/Non-PDNoPR Non-PDNoPR SD Non-PDNoSD PD Any PD Any PDAnyPD Any YesPD

20. BEST Overall Response The best overall response is the best response recorded from the start of treatment until disease progression/recurrence(taking as reference for progressive disease the smallest measurements recorded since the treatment started).

21. Best overall response For CR and PR criteria must be met again 4 weeks after initial documentation(this requirement ONLY for non-randomized trials with primary endpoint of response) When SD is believed to be best response, it must also meet the protocol specified minimum time from baseline. If the minimum time is not met when SD is otherwise the best time point response, the patient’s best response depends on the subsequent assessments.

22. Best overall response For example, 1. A patient who has "SD" at first assessment, "PR" at second assessment, and "PD" on last assessment has a best overall response of "PR". 2. A patient who has “SD” at first assessment, “PD” at second and does not meet minimum duration for SD, will have a best response of “PD”. The same patient lost to follow-up after the first SD assessment would be considered inevaluable.

23. 반응 평가는 치료제의 변경 결정 및 효과 판정 근거가 되므로 중요 반응 평가를 위한 영상검사는 반드시 계획된 일정한 시기에 시행 Baseline 시 영상검사는 follow-up 때 동일한 방법으로 시행 RECIST 1.1 에도 남아 있는 문제점이 있으므로 개정을 통해 보완