evaluation of clinical benefit in sarcomas: modern imaging modalities

Evaluation ofClinical Benefit in Sarcomas:Modern Imaging Modalities

Robert S. Benjamin, M.D.Department of Sarcoma Medical Oncology

The SARCOMA CenterQuickTime™ and a

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FREIREICH’S LAW #9

•Responders always live longer than “non-responders” unless they die of toxicity.



80

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20

100

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10 12 14 16 18 2086420

Months

Hematological Improvement

No Hematological Improvement

Hematological Improvement minus duration of Improvement

% S

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Freireich, et al: J Chron Dis 14:593-608, 1961

Acute Lymphocytic Leukemia, ages 0-19

Survival vs. Time with Hematological Improvement



0 5 10 15 20

0.0

0.2

0.4

0.6

0.8

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Time to Treatment Failure in GISTby WHO Response at 4 weeks

Time (Months)

Pro

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n F

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ree >50% Response

<50% Response

Logrank p=0.96

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++++++ +++

++++ +++++++++++ +++

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++ + +++ + + + + + ++ +++ ++++++++++ ++++ +++++++ + +++++++ ++

Months

Time to Progression by RECIST

302724211815129630

1

.9

.8

.7

.6

.5

.4

.3

.2

.1

0 Nonresponders n=54 Responders n=44

p = 0.1

Response Rate 45%



Time to Treatment Failure in GISTby best Response by RECIST

FREIREICH’S LAW #9

•Responders always live longer than “non-responders” unless they die of toxicity.

•Corollary: If not, you have not defined response correctly.



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Months

Time to Progression by Our Criteria

302724211815129630

1

.9

.8

.7

.6

.5

.4

.3

.2

.1

0

Nonresponders n=17Responders n=81

p = 0.0002

Response Rate 83%

+ + + +++ + ++++++ +++ +

++++++ +++

++++ +++++++++++ +++

++++++ +

++ + +++ + + + + + ++ +++ ++++++++++ ++++ +++++++ + +++++++ ++

Months

Time to Progression by RECIST

302724211815129630

1

.9

.8

.7

.6

.5

.4

.3

.2

.1

0 Nonresponders n=54 Responders n=44

p = 0.1

Response Rate 45%



We Should Desist Using RECIST

at Least in GIST


The SARCOMA Center



Karnofsky Criteriafor Partial Response

• I-A distinct subjective benefit with favorable objective changes (% not specified) in all measurable criteria for 1 month or more.

• I-B objective regression of >50% for 1 month or more in a relatively asymptomatic patient.

Karnofsky DA: Meaningful clinical classification of therapeuticresponses to anticancer drugs. Clin Pharmacol Ther 2: 709, 1961.



Criteriafor Objective Response

• Surrogate marker for meaningful endpoint such as survival or time to progression.

• Objective, Quantifiable, Reproducible




WHO Criteriafor Partial Response

• >50% decrease in the sum of the products of perpendicular diameters of all measurable disease

• Absence of appearance of any new lesions

WHO handbook for reporting results of cancer treatment.Publication No. 48. Geneva. 1979.

Miller et al. Cancer 47: 207-214, 1981



RECIST (Response Evaluation Criteria in Solid

Tumors)Partial Response

• >30% decrease in the sum of the single maximum diameters of all measurable disease

• Absence of appearance of any new lesions

Therase et al. JNCI 92: 205-216, 2000




Tumors)Partial Response

• Standardization and simplification• No major discrepancy in the

meaning and the concept of partial response to compare past and future results

• Not meant to discourage the development of new tools that may provide more reliable surrogate end pointsTherase et al. JNCI 92: 205-216, 2000



25% Reduction as

Partial Response• Bonadonna: Adriamycin

– Karnofsky Criteria (Cancer Res. 30: 2572-2582, 1970)

– 25% Reduction (Tumori. 60: 373-391, 1974)

• Jaffe: High-Dose Methotrexate(Cancer. 30: 1627-1631, 1072)



WHO Criteriafor Partial Response

“In the past, some groups and investigators have reported decreases of less than 50% in tumour size, but it is often not possible to determine this with precision.”

Ref. Moertel and Hanley





Moertel and Hanley

25% vs. 50%• 12 solid spheres covered by foam rubber up to 1.5 inches

thick

• 2 were identical and 2 others almost identical

• 16 experienced clinicians

• False positive responses:–25% reduction - 25%

–50% reduction - 6.8%

Cancer 38: 388-394, 1976



BaselineBaseline 8 Weeks8 Weeks

Effects of Imatinib on GIST:CT findings



What about Progression?

“We may differ about whether a patient qualifies for response, but we can all identify disease progression”

Verweij, Aarhus, April 2001 QuickTime™ and a


WHO Criteriafor Progressive

Disease• >25% increase in the sum of the products of

perpendicular diameters of all measurable disease

• Appearance of any new lesions

• If progressive disease exists in any lesion or when a new lesion appears, then the overall result will be “progressive disease.”





WHO Criteria for Progressive Disease

“The use of a 25% increase in one or more measurable lesions or appearance of a new lesion is recommended for defining progression of disease. This percentage should not necessarily be regarded as influencing the management of the patient.”






Tumors)

Progressive Disease• >20% increase in the sum of the single

maximum diameters of all measurable disease

• Appearance of any new lesions

• No comment about one or more areas of clear progression.

Therase et al. JNCI 92: 205-216, 2000




Tumors)

Progressive Disease• Standardization and simplification• No major discrepancy in the

meaning and the concept of partial response to compare past and future results

• Major discrepancy in the meaning and the concept of Progressive Disease prohibiting comparison past and future resultsTherase et al. JNCI 92: 205-216, 2000



Size may not Matter

• Osteosarcomas may not shrink.

• Sarcomas can become fibrotic, cystic, or myxoid and not change in overall size substantially.

• Inaccurate response definitions may explain partially why prognostic factors for response and survival are different



What about Functional Imaging?

• PET for metabolic activity.

• Dynamic Contrast-Enhanced MRI (or CT) for vascular changes.

• Better use of standard contrast-enhanced CT.



Challenge for this Symposium

• Explore the role of modern imaging in the evaluation of benefit or lack of benefit for sarcomas.

• Discuss the data over dinner after a break for the CTOS mixer.

• Reach a consensus on new, improved, criteria for response.

• Find a name.

• Publish our criteria.



What’s in a Name?• RECIST is a great name, but common

usage of RECIST (Response Evaluation Criteria in Solid Tumors) Criteria is redundant.

• New Names:– CTOS Criteria– SARC Criteria– Mixture: CTOS-SARC or SARC-CTOS– REIS (Response Evaluation in Sarcomas)

Criteria» Could be modified for other solid tumors

to REIST Criteria– ERIS (Evaluating Response in Sarcomas)

Criteria» Could be modified for other solid tumors

to ERIST CriteriaQuickTime™ and a


Evaluation ofClinical Benefit in Sarcomas:Modern Imaging Modalities


The SARCOMA CenterQuickTime™ and a


evaluation of clinical benefit in sarcomas: modern imaging modalities

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