Imaging of bevacizumab treated brain:traditional and emerging concepts

Asim K. BagJoel K Cure

Aparna SinghalDavid Wever

AK Bag: No disclosureJ Cure: No disclosureA Singhal: No disclosureD Wever: No disclosure

Outline

Physiology of bevacizumab

Indication of bevacizumab in glioblastoma multiforme (GBM)

Imaging changes induced by bevacizumab

Based on RANO criteriaPersistent diffusion restriction

What is bevacizumab?

Bevacizumab is a recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGF).

Mechanism of action

Bevacizuamb directly binds to VEGF extracellularly to prevent interaction of VEGF with VEGF receptors (VEGFRs) on the surface of endothelial cells.

The VEGFR family is primarily responsible for pro-angiogenic and other tumorigenic VEGF signaling.

Bevacizuamb blocks the downstream effects of VEGF signaling.

Mechanism of action

Blockade of normal VEGF action can lead to

Regression of existing tumor vesselsThis leads to reduction of tumor size

Inhibition of formation of new tumor vessels

This leads to potential inhibition of tumor growth.

Indication of bevacizumab in GBM

Based on demonstration of durable objective response rates observed in two single-arm trials, AVF3708g and NCI 06-C-0064E, the FDA granted accelerated approval to bevacizumab injection as

a single agent for patients with glioblastoma, with progressive disease following prior therapy.

Imaging changes induced by bevacizumab in the setting of GBM

Tumoral response based on RANO criteria:Complete responsePartial responseStable tumorProgressive diseasePseudoresponse

Tumoral and Extratumoral responsePersistent diffusion restriction

ProgressingImprovingStable

GBM: Complete response

Complete Response according to RANO criteria1:

Defined by ALL of the following:

1. Complete disappearance of all enhancing measurable sustained for at least 4 weeks;

2. No new lesions;

3. Stable or improved non-enhancing (FLAIR) lesions;

4. Patient was on steroids with physiologic replacement doses only;

5. Patient improved clinically.

1J Clin Oncol 28:1963-1972.

Pre-Avastin 2 mo post-Avastin 5 mo post-Avastin

Complete response

This patient met all of the RANO criteria for complete response:

1. Complete disappearance of all enhancing measurable sustained for at least 4 weeks;

2. No new lesions;

3. Improved non-enhancing FLAIR lesions;

4. Was on physiologic replacement doses only;

5. Patient improved clinically.

1J Clin Oncol 28:1963-1972.

GBM: Partial response

Partial Response according to RANO criteria1:

Defined by ALL of the following:

1. Fifty percent decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks;

2. No progression of non-measurable disease;

3. No new lesions;

4. Stable or improved non-enhancing FLAIR lesions on same or lower dose of corticosteroids compared with baseline scan (corticosteroid dose at the time of the scan evaluation should be no greater than the dose at time of baseline scan);

5. Stable or improved clinically.

1J Clin Oncol 28:1963-1972.

Pre-Avastin 2 mo post-Avastin 5 mo post-Avastin

Partial tumor response

This patient met all RANO criteria for partial tumor response:

1. 50% decrease in sum of the products of perpendicular diameters of enhancing lesions compared to baseline

2. NO new lesion

3. Improved non-enhancing FLAIR lesion

4. Stable clinically

GBM: Progression of tumor

Progression of tumor according to RANO criteria1:

Defined by ANY of the following:

1. 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement obtained at baseline

2. Significant increase in FLAIR non-enhancing lesion on increasing doses of corticosteroids compared with baseline scan

3. New lesion

4. Clinical deterioration not attributable to other causes apart from the tumor

1J Clin Oncol 28:1963-1972.

Progression of tumor

This patient met 3 of the 4 RANO criteria for progression of tumor:

1. 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared to baseline

2. Significant increase in non-enhancing FLAIR lesion

3. Clinical deterioration not attributable to other causes apart from the tumor

Pre-Avastin 2 mo post-Avastin 4mo post-Avastin

GBM: Stable tumor

Stable tumor according to RANO criteria1:

Defined by ALL of the following:

1. Does not qualify for complete response, partial response, or progression;

2.Stable non-enhancing FLAIR lesions on same or lower dose of corticosteroids compared with baseline scan.

1J Clin Oncol 28:1963-1972.

Pre-Avastin 2 mo post-Avastin 4 mo post-Avastin

Stable tumor

This patient met RANO criteria for stable tumor:

1. No change in enhancement

2. No new lesion

3. Stable –to-slightly improved non-enhancing FLAIR lesion

4. Stable clinically

GBM: Pseudoresponse

Bevacizumab may produces a rapid decrease in the degree of enhancement, sometimes within hours of beginning therapy1.

Can demonstrate radiologic response in up to 50% of GBMs based on McDonald criteria2.

These apparent responses may be partly a result of normalization of abnormally permeable tumor vessels and not always necessarily indicative of a true antiglioma effect.

RANO1 criteria suggests that radiologic responses should persist for at least 4 weeks before they are considered as true response.

1J Clin Oncol 28:1963-1972.2J Clin Oncol 8:1277-1280

Pre-Avastin 3 weeks post-Avastin 8 weeks post-Avastin

Pseudoresponse

This patient met RANO criteria for

pseudoresponse of tumor:

1. Significantly improved enhancement, non-enhancing FLAIR abnormality at 3 weeks

2. Worsening mass effect and FLAIR abnormality at 8 weeks.

Note: The degree of enhancement at 8th week is less intense but is more patchy and diffuse compared to the baseline scan suggesting change in tumor morphology.

Persistent diffusion restriction

Persistent diffusion restriction frequently develops after initiation of bevacizumab treatment.

The exact mechanism is still not known.

Persistent diffusion restriction could be due to tumor progression or due to atypical necrosis due to chronic hypoxia induced by blockade of tumoral/peritumoral blood vessels or due to combination of both of these.

Development of the persistent diffusion restriction has been associated with better survival.

Persistent diffusion restriction contd….

Biopsy of the area with persistent diffusion restriction has shown

Gelatinous necrotic tissue1

Prominent fibrosis of the blood vessels1

Upregulation of HIF-1alpha in endothelial, neuroepithelial and inflammatory nuclei2

Hyalinized and fibrotic blood vessels2

Presence of sideroblast, cholesterol clefts and multinucleated giant cells2

1http://dx.doi.org/10.3174/ajnr.A30532http://dx.doi.org/10.1007/s11060-009-0098-8

Persistent diffusion restriction contd….

Persistent diffusion restriction is frequently associated with

T1 shorteningSusceptibility effects on SWI and GRE sequences

This effect could be due to presence of iron in some form in the tissue (sideroblast)

Volume of area of persistent diffusion restriction has been shown to be stable up to 90% of cases1.

1http://dx.doi.org/10.3174/ajnr.A3053

Persistent diffusion retsriction

In addition to stable area of diffusion restriction, we are showing dynamic nature of the area of the diffusion restriction

Enlargement of area of diffusion restriction.

Reduction of area of diffusion restriction.

Enlargement of Atypical necrosis

Enlargement of area of diffusion restriction.We believe that this is secondary to enlargement of the necrotic area because

Progressive enlargement of the area of T1 shortening within the core of diffusion restriction with clearing of more central areas (see next slide)

Absence of worsening of mass effects over time in spite of enlargement of the area of diffusion restriction

The patient is stable clinically 2 years after the initiation of bevacizumab therapy

No increased rCBV in the area of persistent diffusion restriction.

Pre-Avastin

2 mo post-Avastin 6 mo post-Avastin

8 mo post-Avastin 11 mo post-Avastin 21 mo post-Avastin

Enlargement of atypical necrosis. The diffusion restriction is not associated with increased perfusion. The patient is alive 23 months after initiation of

Avastin therapy.

Decreased size of Atypical necrosis

Reduction of area of diffusion restriction.

We believe that this is secondary to change in the morphology of the atypical necrosis, likely due to more gliotic component. This is supported as because

Progressive enlargement of cystic encephalomalacia as seen on T1 and FLAIR images.

Absence of worsening of mass effects over time in spite of enlargement of the area of diffusion restriction.

No increased rCBV in the area of persistent diffusion restriction.

Pre-Avastin 2 mo post-Avastin 18 mo post-Avastin 30 mo post-Avastin

Metamorphosis of the atypical necrosis with more gliotic component

Reversal of diffusion restriction

Progressive enlargement of cystic necrosis as evidenced on T1 and FLAIR images

Very low rCBV

Absence of mass effect

Stable size of Atypical necrosis

Pre-Avastin 7 mo post-Avastin

11 mo post-Avastin 17 mo post-Avastin

Stable

Atypical necrosis

Conclusions

Treatment of with bevacizumab causes different types of imaging appearance. Changes can be

Classical Comple response, Partial response Tumor progression Stable tumor

PseudoresponseAtypical necrosis

EnlargingDecreasingStable