RESPONSE ASSESSMENT IN METASTATIC RCC: RECIST OR DWI?

Andrea G Rockall, MRCP, FRCR Imperial College London

Why is this important?

• In patients with RCC • 30% have metastatic disease at presentation • 30% with confined disease eventually develop

metastases

• Metastatic RCC (mRCC) is now treated with molecular targeted agents

Ratain, JCO 2006, Motzer, NEJM 2007, Motzer, JCO 2007, Hudes, NEJM 2007, Escudier, Lancet 2007

Mutations in VHL (suppressor) gene

Up-regulation of receptor and intracellular tyrosine kinase (TK)

TK inhibitors (TKIs)

Sunitinib Pazopanib Sorafenib

(axitinib and tivozanib)

mTOR inhibitors

Bevacizumab

VEGF/PDGF Tumor proliferation and

angiogenesis

Anti-angiogenic Anti-proliferative

Cytostatic

Why is this important?

• No benefit if ‘non-responders’ continue therapy – Side-effects – Costly

• Despite non-response to one TKI, there may be response to another TKI*

• Can we identify non-responders early? • If so, which is the best technique?

*Rini et al, JCO, 2009

What criteria do you use to report response to targeted

agents in mRCC?

A. RECIST (either 1.0 or 1.1) B. Modified RECIST or SACT C. MRI with DWI and/or DCE D. Arterial spin labelling E. FDG-PET/CT

Limitations of anatomic morphologic imaging

� Residual mass may not be biologically active

� Limited change in tumor size may not correlate with patient

outcome with targeted chemotherapy

Pre

Sunitinib Post

Sunitinib

Can RECIST criteria predict response?

� RECIST criteria had sensitivity of 16% for predicting favorable PFS (Smith et al, AJR ‘10)

� Response rates by RECIST did not predict survival

� Sunitinib 31% (Motzer et al, NEJM 2007)

� Sorafenib 10% (Escudier et al, NEJM, 2007)

� Sunitinib or cediranib 25% (Nathan et al, CBT, 2010)

Functional imaging

� Imaging that reflects the physiological milieu of the tumour e.g. � Vascularity of the tumour � Diffusivity of water within the tumour � Cell metabolism or cell wall turnover

� Qualitative as well as quantitative evaluations can be made

� Characterise the tumour – to predict behaviour and measure response

Effect of targeted agent on tumor

CT correlate MRI correlate

Decrease in vascularity

Necrosis

Moderate decrease in size

Baccala Ajr et al, Int J Urol 2007

Decrease in enhancement (ktrans, Kep, Ve)

Decrease in attenuation (HU)

Increase in water diffusivity (ADC)

Decrease in attenuation (HU)

Reduction in size (RECIST)

Reduction in size (RECIST)

GIST: Evaluation of response to imatinib

Choi H, Oncologist, 2008

Modified RECIST: Tumour density decrease of > 15%

OR Tumour size decrease of >10%

Criteria evaluated in mRCC

� Retrospective analysis � RECIST � Modified RECIST (Choi) � Modified Choi* � Mean volumetric tumor attenuation (non-lung

target lesions)

� Correlated with time to progression and disease-specific survival

Smith AD et al, AJR 2010 *Nathan PD et al, CBT, 2010

Response status

% of patients showing change in SIZE

> 30% decrease in size

> 20% decrease in size

> 10% decrease in size

> 20% increase in size

PFS > 250 days 16 39 70 2

PFS <250 days 0 0 22 22

Response status % of patients showing change in ATTENUATION

1 or more lesion decreases by > 40HU

At least half of lesions decrease by > 20HU

PFS > 250 days 59 68

PFS < 250 days 0 0

Response Size and Attenuation CT (SACT) Criteria

Favorable No new lesion and any of the following: 1. Decreased in tumor size of > 20% 2. Decrease in size of > 10% and > 20HU mean attenuation* 3. One or more lesions with > 40 HU decrease in attenuation*

Indeterminate Does not fit criteria for favorable or unfavorable

Unfavorable Any of the following: 1. Increase in tumor size of > 20% 2. New met, marked central fill-in of target lesion or new

enhancement of previously hypoattenuating non-enhancing lesion

Smith AD et al, AJR 2010 * Non lung target lesion

What about sequential FDG-PET/CT?

� In 44 patients, high SUVmax and increased number of PET + lesions correlated with inferior survival

� Decrease in SUVmax >20% at 4 wks did not correlate with PFS or OS

� Metabolic progression at 16wks predicted inferior survival

Kayani,...Rockall.. et al, Clin Can Res, 2011

What if patient is in renal failure?

� Can DWI / change in ADC predict response? � Up to a third of patients are unable to have contrast

� Change in ADC has been reported to predict response in: � Cervix cancer � Rectal cancer � Hepatocellular carcinoma

Nathan et al, CBiol &Ther 2010; Harry V et al, GynOncol 2008 Dzik-Jurasz A et al, Lancet, 2002; Kamel IR et al, JVIR 2006

Pre Sunitinib

Post Sunitinib

Change in ADC? Necrosis?

Early response?

DW-MRI pre and post sunitinib

* = involved lymph nodes; LK = left kidney

Right Renal Cell Carcinoma

Whole tumor pixel-by-pixel ADC histograms before and after three cycles of sunitinib

Bharwani N , Miquel M....Rockall ISMRM, RSNA 2011

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Bharwani N , Miquel M....Rockall ISMRM, RSNA 2011

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Bharwani N , Miquel M....Rockall ISMRM, RSNA 2011

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Histogram Analysis

Mean ADC values of the entire tumor volume

The area of the histogram in the 1st quartile of the x-axis (AUC25) was correlated with outcome

AUC25

P=.038

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Decrease in AUC > median Decrease in AUC25 < median

OS by %decrease in AUC25

Overall survival correlates with a decrease in AUC25

Decrease in ‘restricted’ pixels post Rx

Conclusions

� RECIST criteria are not adequate for assessing response in patients mRCC on targeted agents (SD may represent response)

� Size and attenuation CT (SACT) criteria are the ‘front runner’

� In patients unable to have contrast media, diffusion weighted imaging is a promising alternative