Interpretazione dell’imaging radiologico dopo terapie a bersaglio molecolare

DANIELE REGGE

INSTITUTE FOR CANCER RESEARCH AND TREATMENTCANDIOLO-TORINO, ITALY

Rationale of cancer therapy

Since most cancer treatments, especially chemotherapies, have safety risks, a necessary condition that must be satisfied for a patient to accept treatment is that improvement in terms of relevant and reliable clinical benefits will outweigh the harm done by the treatment.

Rationale of cancer therapy

• Direct measures of how a patient feels, is able to function, or whether he or she survives following treatment are considered the only definite and meaningful endpoints of clinical benefit.

• Therefore, it would be logical to expect that most of the evidence provided by clinical research would be based on measures of definite clinical benefit important to the patients, expressed in terms of gains in survival and in the quality of life.

Surrogate end-points

• To detect a clinically meaningful and statistically significant difference in OS the required sample sizes, length of follow-up, and associated costs are often considered to be unaffordable.

• Surrogate endpoints are indirect measures of definite or true clinical benefit.

• Also called intermediate endpoints, surrogate markers, or biomarkers, comprise laboratory, imaging, and physical measurements considered as suitable substitutes for a clinically meaningful endpoints.

Surrogate end-points

• The validation of surrogate endpoints has received increasing attention due to the harm caused by treatments whose efficacy was assessed using non-validated surrogate endpoints.

Grimes DA, Schulz KF (2005) Surrogate end points in clinical research: hazardous to yourhealth. Obstet Gynecol 105:1114-1118

Surrogate end-points

Surrogate Endpoints of Clinical Benefit Giovannino Cicconeand Ileana Baldi, From Imaging Tumor Response to Therapy, Springer 2012

Surrogate end-points

Grimes DA, Schulz KF (2005) Surrogate end points in clinical research: hazardous to yourhealth. Obstet Gynecol 105:1114-1118

Surrogate end-points

Surrogate Endpoints of Clinical Benefit Giovannino Cicconeand Ileana Baldi, From Imaging Tumor Response to Therapy, Springer 2012

Surrogate end-pointsThe above-described experience highlights the critical dilemma surrounding the role of surrogate endpoints in clinical research: on the one hand, they have the potential to make new therapies more rapidly available to patients, but on the other they carry the risk of disseminating useless or harmful treatments, with negative consequences for patients and contributing to the waste of scarce resources.

Surrogate Endpoints of Clinical Benefit Giovannino Ciccone and Ileana Baldi, From Imaging Tumor Response to Therapy, Springer 2012

IMAGING• The aim of using imaging as a surrogate biomarker for

the response to treatment in oncology is threefold:– To obtain a measure of disease extent as a function of

treatment that is more objective and reproducible than achieved by considering symptoms or clinical status.

– To better understand tumour at an earlier time than is possible with other biomarkers or with primary end-points, such as overall survival/mortality or disease-specific survival/mortality.

– To reduce, as the combined consequence of points 1 and 2, either the time or the sample size in clinical trials testing new therapies, including drugs, surgery, or imaging-guided interventional procedures.

Surrogate Endpoints of Clinical Benefit Giovannino Cicconeand Ileana Baldi, From Imaging Tumor Response to Therapy, Springer 2012

IMAGING: WHO criteria (1979-1981)• [(Cross-productFollow-up – Cross-productBaseline)/Cross-

productBaseline] x 100

• In case of multiple lesions in an individual patient, cross-products were summed.

RECIST 1.0 (year 2000)

• Response Evaluation Criteria for Solid Tumors• From 2D to 1D (step backward?)• Use of CT or MRI• Sum of multiple measurements (maximum of 10

target lesions/5 per organ)• Minimum size for target lesions (10mm for spiral

CT; 20mm for non spiral CT and MRI)• Non target lesions were considered as non

measurable lesions

RECIST 1.0 (year 2000)Type of tumour response Category

In case of disappearance of all target and non-target lesions. Complete response (CR)

In case of a ≥ 30% decrease in the longest diameter (instead of the ≥ 50% of the WHO criteria for the cross-product) and/or persistence of non-target lesions.

Partial response (PR)

In case of a ≥ 20% increase in the longest diameter of the target lesions (instead of the ≥ 25% of the WHO criteria for the cross-product), the appearance of one or more new lesions, or unequivocalprogression of already existing non-target lesions.

Progressive disease (PD)

When the case cannot be categorized as CR, PR, or PD. The CR and PR categories needed to be confirmed after at least 28 days.

Stable disease (SD)

2D >>> 1D, a step backward?

1st reader 3cmx4cm = 12cm2 2nd reader 3,45cmx4,6=15,87cm3

WHO = 15,87cm2-12,0cm2/12,0cm2=0,32 i.e. PD (≥ 25%)

T1 T2

2D >>> 1D, a step backward?

1st reader 3cmx4cm = 12cm2 2nd reader 3,45cmx4,6=15,87cm3

RECIST = 4,6cm-4cm/4cm=0,15 i.e. SD (cutoff for PD ≥ 20%)

T1 T2

Higher cutoff for PD in RECIST 1.0

Assuming a spherical tumor volume: a 25% increase in the 2D cross-product is equal to a 40% increase in the 3D volume a 20% 1D increase in the longest diameter is equal to a 44% 2D increase in the cross-product and to a 73% increase in 3D volume

Technological bias

Hampers reliable longitudinal comparisons in clinical trials.

www.recist.com

www.recist.com

Two major limitations of RECIST

• Inter-observer variability• Different morphological behaviour of lesions

when using targeted therapies.

Oxnard G, JCO Vol 29; 2011

Oxnard G, JCO Vol 29; 2011

Specialized software

Lesion Segmentation

123.6 mm3

Pre

92.4 mm3

PostPost

Pre

Lesion Segmentation

Patient report

49

Liver Analysis

Courtesy of Philips

Courtesy of Philips

Liver Analysis

Courtesy of Philips

Resection planning

Two major limitations of RECIST

• Inter-observer variability• Different morphological behaviour of lesions

when using targeted therapies.

Clinical case n° 1

• 71 year old woman• Left radical nefrectomy (Fuhrmam type

I/IV, pT3, lung and pancreatic mets)• August 13th 2007 baseline CT scan

Clinical case n° 2

• 71 year old woman• Left radical nefrectomy (Fuhrmam type

I/IV, pT3, lung and pancreatic mets)• August 13th 2007 baseline CT scan• Three cycles of sunitinib (50mg/day)• Follow-up CT scan 28th of January 2008

SD or PR?

SLD=110mm SLD=93mm

Overall size reduction=15% (SD)

Clinical case n° 2

• 7.11.2011 >>> left radical nephrectomy (Fuhrman 2, pT1b-N1, Mo)

• 22.12.2011 >>> baseline CT scan• 10.1.2012 >>> sunitinib 50 mg/day

(IMA901-301)• 28.3.2012 follow-up CT scan

22.12.2011 28.3.2012

22.12.2011 28.3.2012

22.12.2011 28.3.2012

CHOI Criteria

12 cm 11 cm

93 UH 23 UH

< of lesion density > 15%

CHOI Criteria

CHOI Criteria: results

CHOI criteria (sorafenib 800

mg/die)

Hittinger M, Urologic Oncology: Seminars and Original Investigations 30 (2012) 695–703

CHOI Criteria• Although Choi criteria had a significantly better

predictive value for PFS and OS than RECIST at first evaluation in patients with PR, its predictive value for outcome was similar to that of RECIST at later time points.

• Because Choi criteria were not able to early identify patients with PD, these criteria will not change the management of sunitinib treated mRCC patients.

Van der Veldt AA, Meijerink MR, Van den Eertwegh AJ, Haanen JB, Boven E (2010) Choi response criteria for early prediction of clinical outcome in patients with metastatic renal cell cancer treated with sunitinib. Br J Cancer 102:803–809.

Criteria to evaluate response to treatment

104 UH45 UH

10,5 cm

8,3 cm

Criteria to evaluate response to treatment

JUNE 2011 DECEMBER 2011

MASS vs RECIST (84 mRCC)

Lesion volumetry

Lesion volumetry

AJR:194, January 2010

FUNCTIONAL IMAGING/QUANTITATIVE IMAGING

• DCE-US• PERFUSION CT• DCE-MRI• PET/CT

Axel Leon, Radiology. 1980Cerebral blood flow determination by rapid-sequence computed tomography: theoretical analysis

Radiology 2004

Mappa della permeabilitàMappa della permeabilità

Mappa flusso sanguignoMappa flusso sanguigno Mappa tempo medio di transitoMappa tempo medio di transitoMappa volume sanguignoMappa volume sanguigno

Perfusion CT: renal mass

Fournier LS, Radiology: Volume 256: Number 2—August 2010

Fournier LS, Radiology: Volume 256: Number 2—August 2010

Courtesy of Toshiba

4D perfusion CT

DCE-US

Williams R, Radiology: Volume 260: Number 2—August 2011

DCE-US

DCE-MRI

Decreased enhancement and T1 shortening of tumors on MRI may be useful biomarkers of RCC response to angiogenesis inhibitors.Response criteria combining early changes in size and enhancementlead to better correlation with clinical outcome compared with sizedecrease alone.

PERCIST: PET Response Criteria in Solid Tumor

PET/CT

• A negative PET/CT scan does not exclude the presence of RCC, on the other hand a positive scan is fairly conclusive.

• When mRCC is not FDG-avid then there is no role for FDG-PET.

FDG-PET

Conclusions• RECIST is still now the only criteria to evaluate tumor response

to treatment in the mRCC model, that has been extensively assessed.

• New specialized software will make measurements more reproducible (i.e. lesion segmentation), work-flow faster and yield more comprehensible reports.

• New criteria should include density measurements, but this needs to be validated on larger series.

• Functional Imaging is the future, but we still need to find reliable quantitative indexes, work on standardization of imaging protocols and quality assurance

GRAZIE

daniele.regge@ircc.it