response evaluation of mesothelioma therapy

RESPONSE EVALUATION OF MESOTHELIOMA

THERAPYDr. Muzaffer Metintaş

Eskişehir Osmangazi University Medical Faculty

Department of Chest Diseases

metintas@superonline.com

April 2007

We want to measure tumor response:

Objective tumor response is a pirimary end-point in phase II clinical trials to evaluate anti-cancer drugs.

The use of objective response allows active drugs to be fast tracked, and inactive drugs to be discarded early

within a short-time frame, with fewer patient numbers than required phase III trials.

Determination of response is very important to be able to compare different studies!

Park JO. Jpn J Clin Oncol 2003; 33: 533.

Nowak AK. Lung Cancer 2005; 49S1: S37.

How can you objectively measure

responses:1. WHO criteria; two - dimension,

2. Response Evaluation Criteria in Solid Tumors -RECIST criteria, one – dimension.

Miller AB. Cancer 1981; 47: 207.James K. J Natl Cancer Inst 1999; 91: 523.

Therasse P. J Natl Cancer Inst 2000; 92: 205.

Response evaluation in mesothelioma WHO criteria

If the disease could be measured bidimensionally, it was accepted as ‘measurable disease’,

If the tumor size could not be clearly defined, it was accepted as ‘evaluable disease’.

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M. Metintaş Archive

Response evaluation in mesothelioma WHO criteria

Visit 4

Baseline

Complete response:

Defined as complete disappearance of all measurable or evaluable lesions, as well as the absence of signs and symptoms for longer than 4 weeks without relapse of lesions.

Response evaluation in mesothelioma WHO criteria

Defined as a decrease in the sum of the products of perpendicular diameters of all measurable lesions greater than 50 % compared with pre-treatment measurements, and no relapse of lesions over a period of four weeks.

Partial response

Defined as an assured decrease in tumor size for lesions not bidimensionally measurable, agreed on by two independent investigators, and no relapse of lesions over a period exceeding 8 weeks.

Regression

M. Metintaş Archive

Response evaluation in mesothelioma WHO criteria

Defined as less than 50 % reduction or less than 25 % increase in the sum of the products of the perpendicular diameters of all measurable lesions in relation to the size at entry, over a period exceeding 8 weeks, with no relapse of lesions.

Stable diseases for measurable

Defined as the absence of clear-cut change in an assessable tumor size and the absence of new lesions over a period exceeding 8 weeks, with no relapse of

lesions.

Stable diseases for evaluable

Response evaluation in mesothelioma WHO criteria

Defined for measurable disease as an increase in the sum of product of two perpendicular diameters of all measured lesions by more than 25 % over the initial tumor size at entry, and for evaluable disease as an assured increase in the tumor size.

Progressive diseases

Response evaluation in mesothelioma Six different patients

M. Metintaş Archive

Response evaluation in mesothelioma WHO criteria

In theory, the changes in diameter relate more closely to the fixed proportion of cells killed by a standart dose of chemotherapy than do changes in the bidimensional product.

Measuring in two dimensions and then calculating their products and their sums is laboraious and has the risk of error.

Park JO. Jpn J Clin Oncol 2003; 33: 533.

The use of WHO criteria is poorly reproducible between one investigator, or group of investigators, and another.

Therasse P. Cancer 2002; 38: 1817.

Therasse P. Cancer 2002; 38: 1817.

Response evaluation in mesothelioma WHO criteria

. As a rind around the hemithorax,

. Multiple thoracic levels may be involved,

. Separete nodules / pleural thickening,

. Fissural involvement,

. With atelectasies, pleural fluid, fibrosis.

The previously widely-used WHO tumor response criteria were poorly suited to the growth pattern of pleural mesothelioma.

Response (R) Evaluation (E) Criteria (C) in (I) Solid (S) Tumors (T)

RECIST criteria has been suggested for all solid tumors.

• Measurable lesions in at least one dimension: Longest diameter (LD)

• Must be at least 20 mm conventional X-ray, 10 mm CT scan

• Target lesions: up to 5 per organ, up to 10 total.

Response evaluation in mesothelioma RECIST criteria

Therasse P. J Natl Cancer Inst 2000; 92: 205.

• CR = Complete response = disappearance of all target lesions (and all non-target ones)

• PR = Partial Response = at least 30% decrease in the Sum LD

• PD = Progressive Disease = at least 20% increase in the Sum LD or occurrence of new lesions or obvious progression of non-target lesions

• SD = Stable disease = all else.

Response evaluation

Therasse P. J Natl Cancer Inst 2000; 92: 205.

Response evaluation in mesothelioma RECIST criteria

Response evaluation in mesothelioma RECIST criteria

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Which one is the longest diameter ?

Outer extension of hemithorax can change measurements falsely in responsive patients,orThe rich fibrous tissue in the tumour will shrink = hemithorax will get smaller = LD will DECREASE in size!

Change in fixed structers may prevent true estimation of diameter.

Despite simple use, application of the RECIST criteria is not simple in pleural mesothelioma:

Novak AK. Lung Cancer 2005; 49S1: S37.van Klaveren RJ. Lung Cancer 2004; 43:

63.

Response evaluation in mesothelioma RECIST criteria

Authors determined that the agreement

between WHO and RECIST response evaluation

is poor and that RECIST in the majority of the

cases underscores the tumor response.

Monetti F. Lung Cancer 2004; 43: 71.van Klaveren RJ. Lung Cancer 2004; 43:

63.

Response evaluation in mesothelioma RECIST criteria

Response evaluation in mesothelioma Modified RECIST criteria

Byrne MJ. Ann Oncol 2004; 15: 257.

Response evaluation in mesothelioma Modified RECIST criteria

• Tumor thickness perpendicular to the chest wall or mediastinum,

• Two seperate positions at three seperate levels on thoracic CT scan,

• Sum of six = pleural unidimensional measure.

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In 73 patients, response according to modified

RECIST criteria predicted for superior survival

in responders than non-responders (15.1

versus 8.9 months; p=0.03) and a signficiant

correlation between change in linear tumor

measurement and FVC was seen (R=0.63,

p=0.0001). Byrne MJ. Ann Oncol 2004; 15: 257.

Response evaluation in mesothelioma Modified RECIST criteria

Response evaluation in mesothelioma Modified RECIST criteria

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M. Metintaş Archive

Response evaluation in mesothelioma Modified RECIST criteria

M. Metintaş Archive

Response evaluation in mesothelioma Modified RECIST criteria

M. Metintaş Archive

Response evaluation in mesothelioma Modified RECIST criteria

M. Metintaş Archive

M. Metintaş Archive

Response evaluation in mesothelioma Modified RECIST criteria

M. Metintaş Archive

Response evaluation in mesothelioma Mesothelioma

M. Metintaş Archive

Response evaluation in mesothelioma Mesothelioma

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Response evaluation in mesotheliomaCan we change the undefinable shapes to saphere ?

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Response evaluation in mesotheliomaCan we change the undefinable shapes to saphere ?

Can we use the Cavallieri volumetric estimation method ?

Response evaluation in mesothelioma Volumetric method

Volume (mm3) = t x a2 x ∑Pit: Distance between two scans (mm)a2: Area for each point on the gridPi: Total amount of points on each scan

Response evaluation in mesothelioma Volumetric method

THREE DIMENSIONAL EVALUATION OF CHEMOTHERAPY RESPONSE IN MALIGN

PLEURAL MESOTHELIOMA

Guntulu Ak1, Muzaffer Metintas1, Selma Metintas2, Ragip Ozkan3, Hilmi Ozden4

Osmangazi University Medical Faculty, Department of Chest Diseases1, Public Health2, Radiology3, Anatomy4, Eskisehir,

TURKEYAk G. TTS 10. Annual Meeting, Antalya, April 2007

Response evaluation in mesotheliomaCan we change the undefinable shapes to sphere ?

Number of patients 43

Mean age, yrs (Range) 57.2±12.5 (26-81)

Male : Female 24 : 19

KPS 80.4±9.0 (60-100)

Response evaluation in mesotheliomaCan we change the undefinable shapes to sphere ?

Ak G. TTS 10. Annual Meeting, Antalya, April 2007

Progressiven (%)

Stablen (%)

Partial response n (%)

WHO 16 (37.2) 16 (37.2) 11 (25.6)

RECIST 13 (30.3) 16 (37.2) 14 (32.5)

Volumetric 20 (46.5) 15 (34.9) 8 (18.6)

Ak G. TTS 10. Annual Meeting, Antalya, April 2007

Response evaluation in mesotheliomaCan we change the undefinable shapes to sphere ?

Criteria Progressive Stable Partial response

Test value

WHO 12.0 (11.52-12.47)

16.0(2.28-29.72)

13.0(5.45-20.55)

p=0.075Log-

Rank=5.19

RECIST 11.3(8.78-13.81)

13.0(7.12-18.88)

13.0(3.83-22.16)

p=0.087Log-

Rank=4.87

Volumetric

11.3(9.84-12.76)

15.0(8.68-21.31)

16.0(6.29-25.70)

p=0.038Log-

Rank=6.53

Response evaluation in mesotheliomaCan we change the undefinable shapes to sphere ?

Ak G. TTS 10. Annual Meeting, Antalya, April 2007

Response evaluation in mesothelioma Future directions

Therapy response evaluation in malignant pleural mesothelioma with integrated PET-CT imaging.

Ceresoli GL. J Clin Oncol 2006; 24: 4587.

Evaluation of semi-automated measurements of mesothelioma tumor thickness on CT scans.

Armato III SG. Acad Radiol 2005; 12: 1301.