RESPONSE EVALUATION CRITERIA IN SOLID TUMORS

(RECIST)

New Guidelines to Evaluate the Response to Treatment in Solid Tumors

P Therasse, SG Arbuck, EA Eisenhauer,J Wanders, RS Kaplan, L Rubinstein,

J Verweij, M Van Glabbeke, AT van Oosterom, MC Christian, SG Gwyther

Journal of the National Cancer Institute

92: 205-216, 2000

TUMOR RESPONSE CRITERIA WORLD HEALTH ORGANIZATION

(WHO)

WHO Handbook for Reporting Results of Cancer Treatment

World Health Organization Offset Publication No. 48

Geneva, Switzerland, 1979————————————————————————————

Reporting Results of Cancer Treatment

AB Miller, B Hogestraeten, M Staquet, A Winkler

Cancer 47:207–14, 1981

Tumor Measurement Criteria

milestones - 1981 & 2000

Baseline 8 Weeks

WHO bi-linear measurement

RECIST CriteriaResponse Evaluation Criteria In Solid Tumors

• Simplification of former methods• 4 response categories (CR, PR, PD, SD)

• Based on linear 1-D being as good as 2-D• Least effort, conservative, for widest acceptance

RECIST Criteria • CR = disappearance of all target lesions• PR = 30% decrease in the sum of the longest

diameter of target lesions• PD = 20% increase in the sum of the longest

diameter of target lesions• SD = small changes that don’t meet above

criteriaCR = complete response

PR = partial response

PD = progressive disease

SD = stable disease

RECIST criteria

‘Target’ lesions

• All measurable lesions up to a maximum of five lesions per organ, and 10 lesions in total

• Sum of the longest diameter of all of the target lesions

RECIST

• RECIST criteria may be employed by NCI-funded cooperative groups which are encouraged, but not required, to use

• RECIST criteria are a voluntary, international standard, and not an NCI standard

• That doesn’t mean Clinical Trial groups are satisfied with it

20 weeks (PR at - 39%)baseline

24 weeks (PR confirmed - 52%) 52 weeks (- 74%)

metastatic renal cell

baseline 13 wks (– 7 %)

27 wks (PR – 43 %)

metastatic renal cell

FDA reform plans

The Value of Image Data

Validated image data could lead to:

• Smaller clinical trials with fewer patients

• Earlier go/no decisions on compounds

• Faster regulatory approval

• Shorter time to market

Biomarker• a measurable characteristic that predicts a clinical

endpoint• “surrogate marker” is a biomarker that substitutes for a

clinical endpoint– “surrogate marker” is a special case biomarker, i.e,

not just a predictor of a clinical endpoint, but a reliable substitute for a clinical endpoint

• the distinction has regulatory implications

• Outcome data is needed to establish validity of a surrogate marker

First steps

• Appropriate, disease-sensitive imaging

• Uniformly acquired with objective QA

• Quantitatively assessed

• Centrally accessible with metadata

Image Processing ‘validation’

Time Difference = 130 dayslinear dimension increased 8 mm -> 11 mm in 4 months

A.P.Reeves, Cornell University, 1999

Lung nodule volume growth

Why not calculate volumes?

• No fully automatic, objective methods

• Semi-automatic methods are time-consuming, labor-intensive, and/or not user-friendly.

Inhomogeneity problem

“Non-cytoreductive”(i.e. functional) measures

• FDG-PET• DCE-MRI• MR spectroscopy• CT density and contrast dynamics• Future:

– Other PET ligands– Macromolecular MR agents– Optical methods

G. W. Goerres et al, Univ Hosp Zurich

PET, CT, hybrid PET/CT forGIST response to imatinib (Gleevec)

baseline7 wks post rx

Visual: subjective

Standardized Uptake Value (SUV): semi-quantitative

Kinetic analysis: quantitative

Concerns about assessing 18FDG uptake in malignant tissue:

DCE MRI VEGF Inhibition time after contrast bolus (PTK/ZK TK inhibitor oral dose results on colon mets)

Morgan B et al, JCO 2003

Chemotherapy Response by MRI & MRS1 wk

pre-Tx76 cc

Day 1 AC x179 cc

Day 42AC x326 cc

Day 70AC x425 cc

Day 112taxol x2

11 cc

Day 178taxol x4

6 cc

partial response to AC, regrowth on taxolfinal pathology - viable IDC and extensive DCIS

593 486 267 79 481 595

Univ. of Minnesota

NCI-FDA Interagency Oncology Task Force

• Imaging Science Development for Oncologic Applications – Work in Progress– Develop volumetric anatomical imaging for oncology

e.g. revise (RECIST)– Develop standard dynamic (contrast) imaging

techniques for oncologic drug development and as surrogate endpoint for drug approvals

– Validate FDG-PET for oncologic drug development and as a surrogate endpoint for drug approvals

– Develop a pathway for accelerating molecular imaging including ‘first in human’ studies in diagnosed cancer patients

Foci on imaging

• NCI: Development and optimization of cancer specific CAD methods

• NIBIB: Development of advanced algorithms and generic image processing methods, code documentation, open source software.

• NLM: Open source software and related data processing platforms.

• NSF: Advanced algorithm development, specialized hardware, GRID computing resources.

• FDA: Development of standards for database development and

• NIST: Measurement of performance of application specific software.

Imaging methods validated as cancer biomarkers.

Objectives:1. Increase imaging studies, using standardized

acquisition protocols, in NCI-funded therapy trials2. Collate imaging data from all NCI-funded trials,

e.g., in Cancer Centers, Cooperative Groups, CCR, etc.

3. Engage FDA through Inter Organization Task Force4. Develop cadre of oncology imaging specialists in

Cancer Centers5. Develop functional imaging committees in all

Cooperative Groups6. Develop volumetric and functional “RECIST”

criteria

CIP Near Term Goals: Data Collection

Develop validated data collections:

• Lung nodules (FNIH Demonstration Project)– for Detection, Classification, rx. Response

• Liver mets - rx response• Colon polyps - screening detection,

classification• Breast digital mammo - detection,

classification

Clinical Imaging Concerns• Only 2% of all cancer patients are in formal

clinical trials• Unless genetics is found to be deterministic, (all)

cancer therapy will continue to be experimental• Conventional diagnostic imaging provides

(barely quantitative) information when following a course of therapy