Response Assessment in Neuro-Oncology

M.J. van den Bent

the Brain Tumor Center at Erasmus MC Cancer Center
Rotterdam, the Netherlands
disclosures

 Grant/research support from Abbvie

 Honoraria from Celgene, BMS, Abbvie, Agios, Daichi Sankyo
Imaging and neuro-oncology

 Today: just some elements

 Realising pitfalls
 RANO essentials
 How to assess a tumor within a clinical trial using RANO criteria
Fluctuating deficits in an anaplastic
oligodendroglioma patient
baseline admission
baseline
 50 year old female,
treated 13 yrs ago for
AOD with RT/PCV
 November 2010: stable
MRI scan
 February 2011:
admission because of
fluctuating paresis right
arm, aphasia for days
 MRI: new enhancement,
rCBV (perfusion image)
increase (ratio 2.24)
 Fluctutating deficits 13 years after RT/PCV
for Anaplastic Oligodendroglioma
 What treatment would you propose?
a. Temozolomide
b. Re-irradiation
c. Bevacizumab
d. New anticonvulsant
Fluctuating deficits in an anaplastic
oligodendroglioma patient
baseline admission 3 months later
 Our choice: d

 Clue: fluctuating
deficits
 EEG: continuous
epileptic discharges
 MRI three months
later: normalization
 Diagnosis: peri-ictal
enhancement
 Peri-ictal enhancement and the SMART syndrome
(stroke-like migraine attacks after radiation therapy)
• Multiple case reports on irradiated brain tumor patients
• Presenting with or without seizures, headache and focal
deficits
• Or non-convulsive status epilepticus
• Treat the seizures pro-actively!
• Increasing enhancement, & increased rCBV

Take home message:

increase in enhancement does not equal progression!

Rath et al, J Neurol 2012, Kerklaan et al, J Neurol 2011;258:1098-104;

Rheims et al, Neuro Oncol 2011;13:775-82
Endpoints

 Endpoint
 Overall Survival
 Imaging Related Endpoints
 PFS according to RANO criteria and assessed by central
review and local investigators
 Objective response rate (ORR)
 Quality of Life/Survival endpoints
 HRQoL
 Cognition
 etc

8
Temozolomide in recurrent anaplastic
astrocytoma
male, 44 yrs of age, first surgery and RT in 1996,
recurrence in 8/01 & start temozolomide, TTP 8 mo
 T1 contrast enhanced MR in brain tumors:
limitations
 Basically: uses area of enhancement as the primary target

 Enhancement implies leaky vessels = endothelial proliferation?

blood brain barrier disruption

 Enhancement does not equal tumor but reflects high grade tumor
activity

 Enhancement is aspecific

 Other causes: infarction, inflammation, necrosis

 Brain tumors are frequently difficult to measure

RANO criteria: no magic

 Current standard for assessing treatment response for high-grade

gliomas

1
Surgery for T2 T1 T1C ADC
low grade
1p/19q co-
deleted OD
 Sept 2014 1st
seizure

 November
2014 resection,
wait and see

 March 2015:
new enhance-
ment: PD?
 Post surgical assessment: need to
obtain a further scan at baseline…
• 49 year old male, treated
for glioblastoma
• Recurrence in July 2012
• Gross total re-resection
August 2, 2012
• Start chemotherapy 4
weeks after surgery, 1/8/12 3/8/12
• New baseline MRI scan 4
weeks later: increase

• Without a new baseline

scan: SD would have been 30/8/12

diagnosed as PD PD
 Pseudoprogression
 Treatment effects may mimic progression within 12 weeks of RT
 True progression can be called within the 12 weeks if there is new
enhancement outside of the radiation field (beyond the high-dose region or
80% isodose line)
 If there is no new enhancement outside of the radiation field, progression
must be confirmed by imaging >12 weeks from radiation therapy
 If disease burden is no longer increasing, true progression is not confirmed
and the timepoint with the largest SPPD within the 12 weeks from radiation
therapy should be considered the ‘new baseline’ for % change purposes
After RT/TMZ After 3 adj cy After 9 adj cy
Before surgery After surgery + 1 adj cy TMZ TMZ TMZ
Glioblastoma
patient treated
with
radiotherapy
and
temozolomide

1
Non-1p/19q co-deleted oligodendroglioma
 Female, 30 years
4 months 2 years
 Asymptomatic right Pre-RT
post RT post RT
frontal lesion
 Complete resection,
oligodendroglioma
 No 1p/19q loss
 RT 59,4 Gy
 4 mo post RT: new
enhancement
 2 years later: rCBV: no
disappearance of all increase
(but small
enhancement lesion)
3290448
Incidence of pseudoprogression in low- van West et al, NeuroOncol
grade gliomas treated with radiotherapy 2017;19:719-25

 63 cases of low grade glioma treated with RT, median f-up 5 yrs (range
1-10 yrs): PsPD observed in 13 patients (20.6%),
 Occurred after median of 12 months (range 3-78 months); median
duration 6 months (range 2-26 months)
 Always occurred within the RT high dose fields (> 45 Gy).
 Area of the enhancement of psPD smaller compared to "true" PD
 median size 54mm2 [range 12-340mm2] vs 270mm2 [range 30-3420mm2], p = .009)
Imaging protocol: standardization

 EORTC/International standardized MR protocol

 Basic
 Advanced Imaging
 2014: international wish to develop a standardized imaging protocol
 NBTS
 Jumpstarting Brain Tumor Drug Development Coalition
 All current MR imaging within consortia, big pharma needs to be
performed according to the imaging recommendations by the NBTS
 You can do this at home…

Ellingson et al. Neuro Oncol. 2015 Sep;17(9):1188-98. doi:

10.1093/neuonc/nov095 17
The EORTC Imaging Protocol
3D T1w pre- DWI 2D FLAIR 3D FLAIR (optional)
contrast Transverse
MPRAGE, 3D IR
FSPGR T1w
• minimum TE • minimum TE TE: 90-140ms • TE: 90-140ms
• TI, TR and flip • •
TR > 3000 ms •TR: 6000-10000 ms • TR: 6000-10000 ms
angle according to • •
Spectral fat •TI: 2000-2500 ms • TI: 2000-2500 ms
manufacturer suppression (use TI according to (use TI according to
specific / field • •
b: 0 and 1000 optimized protocol for optimized protocol
strength specific s/mm2 (3 specific inversion for specific
recommendations directions) pulses and field inversion pulses
for optimum image • •
SENSE / SMASH / strength) and field strength)
quality GRAPPA / ASSET: •SENSE / SMASH / • SENSE / SMASH /
• SENSE / SMASH / optional for 1.5 T, GRAPPA / ASSET GRAPPA / ASSET /
GRAPPA / ASSET obligatory for 3 T. allowed ARC allowed
allowed • •
Slice orientation: •Slice orientation: • Slice orientation:
• Slice/3D slab transverse transverse sagittal or
orientation: sagittal • •
Slice thickness: •Slice thickness: 5mm transverse
or transverse 5mm •Slice gap: 0 • Slice thickness: 
• FOV: 256 mm x • •
Slice gap: 0 •Number of slices: 1.5 mm
256 mm • •
Number of slices: same as sequence 2 • Number of slices:
• Matrix: 256x256 Full brain coverage •FOV: 240 mm x 240 Full brain coverage 0.1 mmol/kg BW
• Slice thickness: ≤ • •FOV: 240 mm x mm • FOV: 250 mm x of a Gd-based
1.5 mm 240 mm •Matrix: 256 x 256 or 250 mm
contrast agent
• Full brain coverage • •
Matrix: 128 x 128 or higher • Matrix: 224 x 224 or
higher •Slice positioning as in higher
• •
Postprocessing: sequence 2 • Slice positioning as
Calculation of ADC in sequence 1
maps (diffusion
trace maps)

18
 *SPPD: Sum of Perpendicular Diameters
The essentials

 Complete Response (CR)

 100% decrease in SPPD* from Baseline

 Partial Response (PR)

 ≥ 50% decrease in SPPD from Baseline

 Stable Disease (SD)

 < 50% decrease in SPPD from Baseline and <25% increase
from nadir

 Progressive disease
 > 25% increase from nadir
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The essentials cont-ed

 Steroids
 No response possible in case of increase
 In case of taper: tumor area may increase
 Steroids increase alone does not equal progression

 Clinical status
 In case of deterioration: equals progression

 New Lesion
 Equals progression

 T2/FLAIR to be assessed
20
 T2 and FLAIR in RANO
BELOB case 144: Well defined local recurrence:
after one cycle decrease in enhancement, but
increase in T2 abnormalities and mass effect

• Introduction of T2/FLAIR in
RANO criteria was driven by
anti-VEGF treatment
associated pseudo-
responses
• T2/FLAIR abnormalities
considered not measurable
• Significant increase is
considered PD
• Limited relevance in
evaluation of other non-anti-
VEGF treatments
Measuring

 Measure the sum of products of

perpendicular diameters of all
measurable enhancing lesions
 Measure at least two if more than
1 lesion is present
 Up to a maximum of 5 lesions
 Additional lesions are non-target
 Measure on the plane & slice
where the lesion is largest
 adjust the perpendicular
measurement to the longest short
axis
Measurable disease
Too small lesions cannot be measured reliably

Measurable (RANO):
• Enhancing disease

• Minimal bidirectional diameter of ≥ 10 mm

and visible on at least two axial slices that
are preferably, at most, 5 mm apart with
0-mm skip

• Rationale: too small lesions cannot be

measured reliably

• For progression: ideally, the change

should be significant (5mm increase in
maximal diameter or 25% increase in sum
of the products of perpendicular
diameters of enhancing lesions)
Special Considerations for classification of lesions:
Lesions with cysts or surgical cavities

 Lesions around a cyst or surgical cavity are to be considered non-

measureable unless there is an enhancing component meeting the
measurable disease criteria
 The cystic or surgical cavity should not be measured in
determining response
 Lesions with a necrotic component
 Lesions with a necrotic component can be selected as target if
they are the only lesion(s) present, otherwise they should be
selected as non-target.

The necrotic/cystic part is unlikely to

shrink even in responding tumors
Defining Lesions at Baseline

Lesions

Measurable Non-measurable
Measurable
lesions
not selected
as target

Target Non-target

25
MR measurements for study evaluation

 Preferably: done by the same person

 Document the used MRI series and slice(s)
 Review previous measurements at the time of new
measerements (for consistency)
 A different plane may be used compared to the
baseline scan
 Do also document measurements in the patient file
(source document)
% Change of Sum of PerPendicular Diameter
(SPPD)

 The % change in SPPD is determines response or progression of the

target lesions
.
From Baseline (for response):
(Current SPPD-Baseline SPPD) x 100 = % change from Baseline
Baseline SPPD

From Nadir (for progression):

(Current SPPD-Nadir SPPD) x 100 = % change from Nadir
Nadir SPPD

27
Sum of the Product of the Perpendicular
Diameters (SPPD)

 SPPD is calculated at every evaluation for all target lesions

Lesion 1 Lesion 2

+ = 450mm2
15 x 10 = 150 20 x 10 = 300

 The change in SPPD determines response or progression of the target

lesions
 In case of multiple lesions: select at least two
 Emphasis to be placed on lesions that are likely to allow reproducible
repeated measurements.

2
Overall Assessment

 Complete Response – all the following must be true

 Complete disappearance of all enhancing measurable and
non-measurable disease sustained for at least 4 weeks
 No new lesions
 Stable or improved non-enhancing non-measureable
(T2/FLAIR) lesions
 Patients must be off corticosteroids (or on physiologic
replacement doses only)
 Stable or improved clinically.

Note: Patients with non-measurable disease only cannot have a CR; the
best response possible is SD.

29
Overall Assessment

 Partial Response – all the following must be true

 ≥50% decrease compared with baseline in SPPD of all
measurable enhancing lesions sustained for at least 4
weeks
 Enhancing non-measureable disappeared or is stable
 No new lesions
 Stable or improved non-enhancing non-measureable
(T2/FLAIR) lesions
 Corticosteroids dose at the time of the scan evaluation
should be no greater than the dose at time of baseline scan
 Stable or improved clinically

Note: Patients with non-measurable disease only cannot have a PR; the
3
best response possible is SD.
Overall Assessment

 Stable Disease – all the following must be true

 Does not qualify for CR, PR, or PD
 Stable non-enhancing non-measureable (T2/FLAIR) lesions
 Corticosteroids dose at the time of the scan evaluation
should be no greater than the dose at time of baseline scan

Note: If the corticosteroid dose was increased for new symptoms

and signs (no radiographic confirmation of PD) and follow-up
imaging shows PD, the last scan considered SD will be the scan that
coincides with corticosteroid dose equivalent to the baseline

3
Dexamethasone: key factor in response evaluation
• 32 year old male glioblastoma patient
• March 20 2014 progressive disease:
52 x 34 mm
• April 3 admission: headache, right
sided weakness; start dexamethason
16 mg daily, with taper to 12 mg daily
• April 11 new baseline MRI scan at
start new treatment: decrease in size,
50 x 27 mm (76%)
April 3 April 11
Works in both directions:
• Decrease SPPD after start or increase steroids
• Increase SPPD at decrease or discontinuation of steroids
Always: register steroid dosage at time MR evaluation

9570191
Overall Assessment

 Progressive Disease – if any of the following are true

 ≥25% increase in SPPD of enhancing lesions compared with
the nadir, on stable or increasing doses of corticosteroids
 Clear progression of non-measurable disease
 Significant increase in non-enhancing non-measureable
(T2/FLAIR) lesions on stable or increasing doses of
corticosteroids compared with baseline scan or best response
after initiation of therapy
 Increase should not be caused by comorbid events
 Any new lesion
 Clear clinical deterioration not attributable to other causes apart
from the tumor or changes in corticosteroid dose
*Increase in corticosteroids alone will not be taken into account in determining
progression in the absence of persistent clinical deterioration.

33
PD is diagnosed when tumor increases
25% from nadir, not necessarily baseline
Nadir = the lowest SPPD
value from any timepoint
tumor area
350

300

250 25%
PD
200

150 tumor area

100

50

0
baseline cycle 1 cycle 2 cycle 3 cyclce 4
Summary of the RANO Response Criteria

CR PR SD PD
T1 gadolinium
<50% ↓ but
enhancing none ≥50% ↓ ≥25% ↑a
<25% ↑
disease
T2/FLAIR stable or ↓ stable or ↓ stable or ↓ ↑a
New lesions none None None presenta
Corticosteroids none stable or ↓ stable or ↓ NAb
Clinical status stable or ↑ stable or ↑ stable or ↑ ↓a
Requirement
All All All Anya
for response

aProgression occurs when this criterion is present.

bIncrease in corticosteroids alone will not be taken into account in determining

progression in absence of persistent clinical deterioration.

Wen et al, J Clin Oncol 2010;28:1963-72
Overall Assessment Post-Baseline
Only in conjunction with clear
neurological signs and
symptoms deterioration
baseline Cycle 1 Cycle 2 Cycle3 Cycle 4
Clinical
-- SD SD SD PD PD
assessment

MRI -- SD SD SD PD
assessment

Steroid dose
Imaging

BL TP2 TP3 TP4 PD

TP5 PD

BL: Baseline; TP: Timepoint

36
Overall Assessment Post-Baseline

baseline Cycle 1 Cycle 2 Cycle3 Cycle 4

Clinical
-- SD SD SD PD
assessment

MRI -- SD SD PD PD
assessment

Steroid dose
Imaging

BL TP2 TP3 TP4 PDTP5

BL: Baseline; TP: Timepoint

37
Some details

 Failure to return for evaluation as a result of death or deteriorating

condition is to be considered progression.
• For progression: ideally, the change should be significant (5mm
increase in maximal diameter or 25% increase in sum of the products of
perpendicular diameters of enhancing lesions)
 If in doubt about PD (‘equivocal PD’) , RANO allows continuation of
treatment
 If the next scan confirms PD then the date of PD is backdated to
the date of the scan with equivocal PD
Re-operated patients in studies with OS,
PFS endpoints

 Patient may have been operated for recurrence.

 If operated protocol may stipulate that:
 Residual and measurable disease after surgery is not required but
surgery must have confirmed the recurrence
 If so: required:
 a post-surgery MRI must be available within 48 hours following
surgery: defines target (if present)
 an MRI scan has to be done within 2 weeks prior to randomization
 surgery completed at least 2 weeks before randomization and
patients should have fully recovered as assessed by investigators.

39
RANO is about communication

 Objective of outcome
scoring is to a
understand and
commmunicate the
imaging findings….

Brueghel, the elder. Babel’s Tower