01. 항암제 임상시험 승인 현황02. General aspect of evaluation in cancer03. Endpoint in Cancer Clinical Trial04. Response Criteria05. Conclusions

CONTENTS

구분 종양 심혈관계 내분비계 중추신경계 소화기계 기타

효능군 계

2010 년 112 49 54 48 33 143 439

2011 년 112 69 41 47 29 205 503

2012 년 184 59 57 68 56 246 670

2013 년 157 80 51 46 40 233 607

식약처 신규 승인 임상시험

식약처 신규 승인 임상시험

2010

112건 /439건

25.5% 22.3% 27.5% 25.9%

2011

112건 /503건

2012

184건 /670건

2013

157건 /607건

1. Patient evaluation

2. Tumor evaluation by stag-ing

3. Treatment response evalu-ation

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

2. Tumor evaluation by stag-ing병기 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 있으며독립적인 분류법에 따라 진행단계를 결정하는 경우도 있음

T

N

.M

3. Treatment response evalu-ation

After anti-cancer therapy

Response after variable agents

Selection of proper agent

Residual disease status

Toxicities

ETC

Time-to-Event outcomes1) Time between the day of registration/randomization to the date of a

event2) Includes overall survival(OS), progression-free survival(PFS) or time-

to-progression(TTP), disease-free survival(DFS) or relapse-free sur-vival(RFS), or other event-free survivals

Tumor shrinkage or stabilization 3) Response rate4) Clinical benefit

Safety1) 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

Time-to-Event outcomes1) Time between the day of registration/randomization to the date of a

event2) Includes overall survival(OS), progression-free survival(PFS) or time-

to-progression(TTP), disease-free survival(DFS) or relapse-free sur-vival(RFS), or other event-free survivals

Tumor shrinkage or stabilization 3) Response rate4) Clinical benefit

Safety1) Toxicity (adverse events)

RECISTResponse Criteria

2000 년WHO

Response Criteria1979 년

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

WHO RECIST

Measurabil-ity

- Measurable, bidimen-sional(product of LD and greatest perpendicular diameter)

- Non-measurable/evalu-able

- Measurable, unidimen-sional (LD only, size with conventional techniques ≥ 20mm; spiral computed to-mograpy ≥ 10mm)

- Non-measurable: all other lesions, including small lesions. Evaluable is not recommended

Measurability of lesion at base-line

Measurable

Target le-sion

Non-target lesion

{ 병변의 반응 기준 }

Target le-sion

CRPRSDPD

Non-target lesion

Present=non-CR/non-PDAbsent=CRUnequivocal progression=PD

New lesion PresentAbsent

Baseline 에 선정된 Target lesion 은 연구 종료시점까지

동일하게 유지

Objective responseMeasurable disease / Target le-

sionsWHO RECIST

Change in sum of products of LDs and greatest perpendicular diameters, no maximum No. of lesions specified

Change in sum of LDs, maxi-mum of 5 per organ up to 10 to-tal, more than one organ

CRComplete re-

sponseDisappearance of all known dis-ease, confirmed at ≥ 4 week

Disappearance of all known dis-ease, confirmed at ≥ 4 week

PRPartial response

≥50% decrease from baseline, confirmed at ≥ 4 week

≥30% decrease from base-line, confirmed at ≥ 4 week

SDStable disease Neither PR or PD criteria met Neither PR or PD criteria met

PDProgressive dis-

ease

≥25% increase of one or more lesions, or appearance of new lesions

≥20% increase over smallest sum observed, or appearance of new lesions

Objective responseMeasurable disease / Target le-

sionsWHO RECIST

Change in sum of products of LDs and greatest perpendicular diameters, no maximum No. of lesions specified

Change in sum of LDs, maxi-mum of 5 per organ up to 10 to-tal, more than one organ Max-imal 5 lesions (2 per organ)

CRComplete re-

sponseDisappearance of all known dis-ease, confirmed at ≥ 4 week

Disappearance of all known disease, confirmed at ≥ 4 week(Required when response rate is primary endpoint)

PRPartial response

≥50% decrease from baseline, confirmed at ≥ 4 week

≥30% decrease from baseline, confirmed at ≥ 4 week(Required when response rate is primary endpoint)

SDStable disease Neither PR or PD criteria met Neither PR or PD criteria met

PDProgressive dis-

ease

≥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

Objective responseNon-measurable disease / Non-target le-

sionsWHO RECIST

CRComplete re-

sponse

Disappearance of all known dis-ease, confirmed at ≥ 4 week

Disappearance of all target le-sions and normalization of tu-mor markers, confirmed at ≥ 4 week

PRPartial response estimated decrease of ≥ 50% -

SDStable 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

PDProgressive dis-

ease

≥25% increase of one or more lesions, or appearance of new lesions

unequivocal progression of non-target lesions, or appear-ance of new lesions

Target lesion 반응 평가의 예Baseline 1 차 평가 2 차 평가 3 차 평가 4 차 평가

Sum 200 150 135 150 180

Baseline 대비 100% 75% 67.5% 75% 90%

Nadir 대비 100% 111% 133%

Baseline대비반응 SD PR SD SD

Nadir 대비반응 SD PD

치료제 변경 시점

Overall Response

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

Overall Response

Target Non-target New lesions Overall response

CR CR No CR

CR Non-CR/Non-PD No PR

PR Non-PD No PR

SD Non-PD No SD

PD Any Any PD

Any PD Any PD

Any Any Yes PD

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).

Best overall re-sponse

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 base-line. If the minimum time is not met when SD is other-wise the best time point response, the patient’s best re-sponse depends on the subsequent assessments.

Best overall re-sponse

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.

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