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Standardized MRI assessment of high-grade glioma response: a
review of the essential elements and pitfalls of the RANO criteria
Dewen Yang
ICON Medical Imaging, 2800 Kelly Road, Warrington, PA 18976
Corresponding Author: Dewen Yang, MD, PhD, ICON Medical Imaging, 2800 Kelly Rd., Warrington, PA 18976 (dewen.yang@iconplc.com).
Accurately evaluating response in the treatment of high-grade gliomas presents considerable challenges. This review looks at the ad-
vancements made in response criteria while critically outlining remaining weaknesses, and directs our vision toward promising end-
points to come. The 2010 guidelines from the Response Assessment in Neuro-Oncology (RANO) working group have enhanced
interpretation of clinical trials involving novel treatments for high-grade glioma. Yet, while the criteria are considered clinically appli-
cable to high-grade glioma trials, as well as reasonably accurate and reproducible, RANO lacks sufficient detail for consistent imple-
mentation in certain aspects and leaves some issues from the original Macdonald guidelines unresolved. To provide the most accurate
assessment of response to therapeutic intervention currently possible, it is essential that trial oncologists and radiologists not only
have a solid understanding of RANO guidelines, but also proper insight into the inherent limitations of the criteria. With the expectation
of improved data collection as a standard, the author anticipates that the next high-grade glioma response criteria updates will in-
corporate advanced MRI methods and quantitative tumor volume measurements, availing a more accurate interpretation of response
in the future.
Keywords: clinical trials, high grade glioma, MRI, RANO criteria.
High-grade gliomas are the most common malignant, primary in-
tracranial neoplasms found in adults
1
and include WHO grade III
anaplastic glioma (comprised of anaplastic astrocytoma, mixed
anaplastic oligoastrocytoma, and anaplastic oligodendroglioma)
and WHO grade IV glioblastoma multiforme (GBM). Despite re-
cent advances in chemoradiation therapy and the development
of antiangiogenic agents for recurrent tumors, the prognosis for
patients with most types of high-grade gliomas is still very
poor. Patients diagnosed with anaplastic astrocytoma have a me-
dian survival of 14 to 36 months, while those with GBM have a
median survival of only 9 to 15 months.
2–4
In addition to the gold standard of overall survival, high-grade
glioma trials frequently measure imaging-related endpoints, pri-
marily progression-free survival and objective radiographic re-
sponse rate.
5–7
Endpoints based on imaging, which involve the
evaluation and measurement of tumor, can shorten trial lengths
and reduce drug development costs.
8
They are also suitable for
crossover study designs.
9
To standardize the assessment and re-
porting of results, objective evaluation of measurable and non-
measurable disease relies on the use of 4 categories to describe
response: complete response (CR), partial response (PR), stable
disease (SD [referred to as “no change” originally]), and progres-
sive disease (PD). These categories were introduced as the essen-
tial measurement of systemic cancer treatment response in the
WHO criteria.
10
In 1990, Macdonald et al published the first standard for high-
grade gloima, taking their cue from WHO by measuring the
maximal cross-sectional diameters of enhancing tumor, and re-
cording response using the WHO categories. The publication was
pivotal in introducing uniform criteria to assess post-therapeutic re-
sponse of high-grade glioma using computed tomography (CT).
11
The Macdonald criteria were later adapted to include gadolinium
(Gd)-contrast-enhanced MRI in addition to incorporating cortico-
steroid dose and clinical status into the response-grading scheme.
Gd contrast enhancement is nonspecific (for instance, it is
not useful in differentiating recurrent high-grade glioma from
radiation necrosis). The enhancement mainly captures the leak-
age of contrast across a disrupted blood-brain barrier. As a
result, increased enhancement after chemoradiation is not a
consistently reliable indication of actual progression.
12
In addi-
tion, efficacy measurements of novel treatments, such as anti-
angiogenic agents,
13
also emphasize the need to assess
nonenhancing components of tumors. Limitations of the Mac-
donald criteria include addressing only the contrast-enhancing
component of tumor and inadequate instruction for measuring
the enhancing lesion in the wall of cystic or surgical cavities, for
handling irregularly shaped tumors, and for assessing multifocal
tumors.
14 –16
Over time, the Macdonald criteria have become
associated with these significant limitations and with high inter-
reader variability.
Received 17 December 2014
#The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.
For permissions, please e-mail: journals.permissions@oup.com.
Neuro-Oncology Practice
Neuro-Oncology Practice 2015; 0, 1– 9, doi:10.1093/nop/npv023
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In 2010, the Response Assessment in Neuro-Oncology (RANO)
working group improved the guidelines for determining high-
grade glioma response to therapy considerably.
17
The RANO crite-
ria were promptly adopted for many high-grade glioma trials,
largely superseding the Macdonald criteria. Nevertheless, some
aspects of RANO lack the detail needed for consistent implemen-
tation. Explicitly, these include shortcomings in assessing pseudo-
progression,
18
the absence of measurement guidelines for
nonenhancing lesion,
19
and the hindrance of applying two-
dimensional (2D) measurements to complex three-dimensional
(3D) lesions that commonly surround postoperative cavities.
20
Particularly in multicenter trials, the resulting discordance in inter-
pretation and outright misinterpretation of disease progression
can lead to high inter-reader variability and reduced study
power. Due to these factors, trial neuro-oncologists and neurora-
diologists must not only comprehend the essentials of RANO cri-
teria, they must also comprehend the predictable operational
challenges.
The essential RANO guidelines
The RANO guidelines improved the Macdonald criteria in three
major areas: (i) by standardizing imaging definitions, including
measureable and nonmeasurable lesions and specifying the size
and number of enhancing T1 lesions; (ii) by interpreting pseudo-
progression and pseudoresponse; and (iii) by expanding radio-
graphic response to account for changes in T2 and FLAIR signal
abnormality, which is especially pertinent in assessing the effect
of antiangiogenic therapies.
Standardization of imaging definitions
Accurate assessment of change in tumor burden is the very basis
of imaging endpoints in clinical trials for predicting therapeutic ef-
fect on clinical outcome or survival. While using the same MRI
scanner across visits is highly preferred for accurate interpretation
of change, using the same magnet strength is absolutely manda-
tory.
17
Consistency in imaging parameters at each time point ac-
quisition, e.g. Gd dose, is also essential for accurate interpretation.
Although measurements may be recorded in any viewing plane,
the axial plane is most typical; and again, consistency is a prereq-
uisite for accuracy.
Perhaps the most valuable component of RANO isthe clarifica-
tion on evaluating contrast-enhancing measureable and non-
measurable disease, including the number of lesions. RANO
defines measurable lesions as those bi-dimensionally contrast-
enhancing lesions with clearly defined margins that have 2 per-
pendicular diameters, each at least 10 mm in diameter. These
requirements deter likely variation in measuring smaller lesions
(resulting from slice selection and volume averages). Further-
more, a slice thickness of ≤5 mm (without gap) is recommended.
In the event that thicker slices are acquired, the size of a measur-
able lesion at baseline should be 2 times the slice thickness. When
there are multiple measurable lesions, a minimum of the 2 larg-
est lesions should be measured, with a maximum of 5 measured
lesions.
Although enhancing tumor frequently rims all or part of the
periphery of a cyst or surgical cavity, in general, only a nodular
component ≥10 mm in diameter can be considered measureable
in RANO; the cystic or surgical cavity should not be measured in
determining response (Fig. 1). Lesions are defined as nonmea-
sureable when either or both maximal perpendicular diameters
are ,10 mm (e.g. 11×9mmor9×9 mm). The nonmeasurable
definition also applies to masses with poorly defined margins,
predominantly cystic or necrotic lesions, and leptomeningeal
tumors. Nonenhancing lesions seen on FLAIR or T2 imaging
that decisively represent tumor should also be considered non-
measureable (Fig. 2). Since patients with remaining nonmeasur-
able tumor can only achieve SD as a best radiographic outcome,
measurable disease is customarily required for patient study eli-
gibility when response rate is the primary endpoint of the trial.
Conversely, when determination of progression is the primary in-
terest, such as for progression-free survival or duration of tumor
control, measurable disease is not a criterion for enrollment.
The surgical goal is typically to remove the enhancing portion
of the tumor; however, nonspecific enhancement frequently de-
velops in the wall of the surgical cavity within 48 to 72 hours after
a surgical intervention and can remain for weeks thereafter.
21,22
Fig. 1. Measureable lesion selection and measurements using RANO. Only the enhancing and nodular component, measuring ≥10 mm in diameter
bi-dimensionally, should be considered measureable (A and B). The cystic component or surgical cavity should not be measured (C) unless the nodular
component measures ≥10 mm in diameter (note: the nodular enhancement has 1.9×0.9 cm in the diameters).
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To avoid interpreting postoperative changes as residual enhanc-
ing disease, RANO recommends that unenhanced and enhanced
baseline MRI scans should be obtained within 24 to 48 hours after
surgery and no later than 72 hours following surgery. Unen-
hanced T1-weighted images are helpful in distinguishing residual
disease from postoperative blood products that appear as
hyperintense areas (Supplementary Material, Fig. S1). In addition
to the immediate postoperative pre- and post-Gd-enhanced
T1-weighted images, a diffusion-weighted imaging (DWI) se-
quence, also acquired immediately following surgery, is particu-
larly useful in distinguishing areas of infarction from residual
tumor along the surgical cavity (Supplementary Material, Fig. S2).
Notably in 2006, Ulmer et al found that cerebral infarcts demon-
strated enhancement in 43% of cases on follow-up MRI scans
and could mimic tumor progression.
23
Definition of radiographic response
Fig. 3illustrates a typical tumor-response evaluation paradigm.
When initiating assessment for objective response or progression,
the baseline tumor burden must be estimated on screening scans
to compare subsequent measurements. One or more lesions that
qualify as measurable and that lend themselves to reproducible
and repeated measurement should be selected as targets, from
Fig. 2. Nonmeasureable lesions are those ,10 mm in diameter either uni- or bi-dimensionally measured (A). Lesions (arrows) with margins that are not
clearly defined and that blend in with brain tissue (B and C), a cystic lesion (D), leptomeningeal dissemination (E, arrow), and nonenhancing lesions on
FLAIR and T2 imaging (F) should also be characterized as nonmeasureable lesions.
Fig. 3. The paradigm of evaluating tumor response. PFS, progression-free survival; ORR, objective response rate.
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the largest to the smallest in the case of multiple lesions. The sum
of the products of diameters (SPD) for all target lesions should be
calculated and reported as the baseline measurement (Supple-
mentary Material, Fig. S3). Any other lesions should be identified
as nontarget lesions, and should also be documented at baseline.
At each subsequent visit, the lesions identified as measureable
at baseline must be continuously monitored and measured using
the same methods (the quantitative evaluation of target lesions).
Also at each follow-up visit, the reviewer evaluates nontarget le-
sions qualitatively, identifies any new lesions, and monitors corti-
costeroid dosage. The RANO criteriaalsoincorporateclinical
factors in support of MRI interpretation as follows:
†CR: complete disappearance of all enhancing lesions for at
least 4 weeks; no new lesions; stable or improved nonenhanc-
ing (T2/FLAIR) tumor lesion; off corticosteroids or on physiologic
replacement dose only; and stable or improved clinically.
†PR: ≥50% decrease in SPD of all target lesions compared with
baseline measurement for at least 4 weeks; no progression of
nonmeasurable disease; no new lesions; stable or improved
nonenhancing (T2/FLAIR) tumor lesion without higher dose of
corticosteroids compared with baseline scan; stable or reduced
corticosteroid dose, and stable or improved clinically.
†PD: ≥25% increase in SPD of all target lesions compared with
the smallest tumor measurement (nadir) at either baseline or
best response; significant increase in nonenhancing (T2/FLAIR)
tumor lesion without lower dose of corticosteroids; any new
lesion; clear progression of nonmeasurable disease; or clear
clinical deterioration due to tumor, not due to decrease in cor-
ticosteroid dose.
†SD: not qualify as CR, PD, or PR; stable nonenhancing (T2/FLAIR)
tumor lesion without higher dose of corticosteroids compared
with baseline scan and clinically stable status.
To achieve a rating of response or stability (CR, PR, SD), RANO re-
quires improvement or stability of neurological symptoms. In the
absence of a confirmatory scan at least 4 weeks later, CR or PR
should only be considered SD. Furthermore, patients who have
nonmeasurable enhancing disease that significantly increases
in size (.5 mm increase in maximal diameter or ≥25% increase
in SPD) should be considered to have progressed. If there is any
doubt as to whether a lesion has progressed, the patient may
continue on treatment until subsequent evaluation proves PD.
In such a case, the date of PD should reflect the time point that
first prompted suspicion. Moreover, RANO guidelines define clini-
cal deterioration as follows: change in the Karnofsky Performance
Status (KPS) from ≥90 to ≤70, or at least a decline of 20 points
from 80, or lasting at least 7 days at ≤50; or Eastern Cooperative
Oncology Group and WHO performance scores from ≤1to2,or
from 2 to 3 unless the neurologic deterioration is attributable to
comorbid events or changes in corticosteroid dose.
Pseudoprogression and pseudoresponse
Pseudoprogression is defined as new enhancement or an increase
in the size of a contrast-enhancing tumor that shows subsequent
improvement or stabilization without further treatment, and
thereby refutes true PD. The phenomenon generally occurs after
completion of radiochemotherapy or radiotherapy, and frequent-
ly in patients with a methylated methyl-guanine methyl transfer-
ase (MGMT)genepromoter.
24
Such patients typically have a
longer median overall survival than those without MGMT promot-
er methylation.
25,26
Pseudoprogression results primarily from the
effects of irradiation, which can include an inflammatory compo-
nent; edema; and abnormal vessel permeability, although the
pathophysiology of pseudoprogression is not entirely clear.
27,28
The incidence is considerable, with recent reports estimating
pseudoprogression in 31% to 48% of GBM patients.
18,24
Since
pseudoprogression is most prevalent within the first 12 weeks fol-
lowing radiotherapy (Fig. 4), RANO suggests that true PD can only
be determined when there is pathologic confirmation of PD or if
the majority of new enhancement is outside of the radiation field
(i.e. beyond the 80% isodose line). Patients for whom pseudo-
progression cannot be differentiated from true PD should not be
permitted to enroll in trials that evaluate tumor recurrence. If
pseudoprogression is suspected, therapy should continue as
long as the patient remains clinically stable.
Pseudoresponse on the other hand, is a rapid decrease in
contrast-enhancing tumor without true antitumor effect. This
occurs after the administration of biologic therapies that target
vascular endothelial growth factor (VEGF) pathways, such as bev-
acizumab (anti-VEGF antibody) and cediranib (VEGF receptor tyro-
sine kinase inhibitor). Such agents alter the permeability of the
blood-brain barrier in such a way that simulates improvement
of enhancing tumor on MRI. Over time however, worsening dis-
ease is typically noted by changes on T2-weighted and FLAIR im-
ages, which suggest progressive infiltrative disease – even in the
absence of postcontrast enhancement on T1-weighted images
(Fig. 5). As a result, radiologic responses in studies with antiangio-
genic agents should be interpreted with caution. Consequently,
RANO criteria suggest that radiologic responses persist for at
least 4 weeks before they are considered true response.
The challenges of the RANO criteria and
future needs
The RANO criteria are an evolving set of guidelines and are widely
considered to be clinically applicable and reasonably reproducible,
i.e. accurate for use in interpreting high-grade glioma treatment
results. However, a number of aspects still need to be fully ad-
dressed in future updates. This is especially true in relation to
early phases of clinical trials where study sponsors look to con-
serve every bit of statistical power. The standardization of image
acquisition protocols across multicenter high-grade glioma trials is
of foremost importance. RANO should include recommendations
on consistent use of field strength, sequence parameters, and
contrast agent dose and timing to reduce unnecessary variability.
As GBMs often demonstrate heterogeneous enhancement
with areas of cystic degeneration and necrosis, guidance in the
task of quantifying primary cystic GBMs should also be addressed
more clearly. Of particular concern is the method for determining
whether the enhancing wall is thick enough or the cystic compo-
nent small enough to be included in measurements (Fig. 6). The
challenge is even greater when evaluating those patients who
have undergone recent tumor resection. This factor also repre-
sents a source of variability between readers that underlines
the need for consensus and further clarification in an updated
publication.
Also of notable concern is the need for guidance in the area of
discerning PR from SD when previously measurable lesions reduce
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to a size that is no longer measurable. While some instances of
reduction are clearly interpretable (e.g. a 1.5×1.5-cm enhancing
lesion becomes a 0.8×0.8-cm enhancing nodule), other instanc-
es are more ambiguous and beg clarification (e.g. a 1.1×1.1-cm
enhancing measurable lesion becomes a 0.8×0.8-cm, thin-wall
cystic lesion that is too difficult to measure, or a 5×5-cm clearly
enhancing lesion becomes only faintly enhancing and likely
,5 cm in any dimension, yet not clearly distinguishable).
Although further studies are needed to validate such ap-
proaches, ongoing investigation is revealing methods that may
reduce errors in evaluating enhancement and improve accuracy
in response assessment,
29
e.g. incorporating contrast enhance-
ment with T1 subtraction. In fact, reports from the Jumpstarting
Brain Tumor Drug Development Coalition workshop, conducted in
close collaboration with the FDA in early 2014, predicted that
future revisions may include T1 subtraction maps, in addition to
volumetric imaging and other advanced techniques such as per-
fusion and diffusion MRI—again, contingent upon validation.
30
Certainly, the rapid increase of novel immunotherapies ushers
in new challenges that also require careful consideration of re-
vised response criteria. As immunotherapies capitalize on a pa-
tient’s own immune system to counter disease, often the body
reacts with the appearance of new lesions or transient increases
in existing lesions before reduction or resolution of disease. This
phenomenon has lead to the development of immune-related re-
sponse criteria for melanoma.
31
Similarly, the growing number of
immunotherapy trials for high-grade gliomas are also showing
these complex radiographic effects, which also pose significant
challenges in differentiating immune-related pseudoprogression
from true progression.
32
Incorporating the necessary consider-
ations into the RANO criteria (ideas currently referred to as
iRANO) should improve response assessment and clarify clinical
guidelines for patients undergoing immunotherapy trials for high-
grade gliomas.
RANO’s use of conventional 2D measurements (carried over
from Macdonald and WHO) has proven largely inadequate for ac-
curately characterizing the growth of certain complex geometric
shapes not uncommon in high-grade glioma. A recent study con-
cluded that to properly evaluate small gliomas (,20 mm in
diameter) exact replication of MRI scanning conditions was re-
quired; furthermore, when slice thickness was ≥3 mm (regardless
of head positioning), bi-dimensional measurements were plainly
inadequate in evaluating tumor growth rates.
33
In recent years, studies have demonstrated that 3D volume
segmentation proved more reliable than 2D for tumor measure-
ment while reducing variability.
20,33,34
Three-dimensional tumor
measurement has been found to be predictive of survival and
progression-free survival in recurrent high-grade glioma using
Gd-enhanced T1-weighted images,
35
T1 subtraction map,
29
and
DWI.
36
In fact, for determining tumor volume of postoperative
recurrence, software based semautomated tumor volume esti-
mations were more effective than manual measurements,
Fig. 4. A pseudoprogression case after chemoradiotherapy. An axial, Gd-contrast-enhanced T1-weighted image before chemoradiotherapy (A); 4 and
12 weeks after radiotherapy and concomitant temozolomide showing increased enhancement (B and C), raising the possibility of progressive disease;
after additional 18, 28, 43, 50, 64 weeks of treatment (D – H) with adjuvant temozolomide after radiotherapy, showing a steady decrease in the
Gd-enhancing lesion –typical pseudoprogression.
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rated as more reliable, more reproducible, and faster.
37
Another
study demonstrated that in terms of quantifying residual and
recurrent glioblastomas alike, not only was semi-automatic
volumetric segmentation faster than the manual technique, it
was also more reliable and reproducible compared with the one-
dimensional and 2D measurements.
38
Fig. 6. Measurement of tumor with less predominant cystic components (A) or with irregular, enhancing thick wall (D) is a particularly difficult
challenge. Different measurements, such as measurements of enhancing portions (B and E) or the entire lesion (C and F), can be a source of
variability even among highly experienced RANO readers.
Fig. 5. Progressive disease suggested by changes on FLAIR images. Serial MR imaging after left parietal lobe GBM resection for a patient treated with
anti-VEGF therapy and temozolomide chemotherapy. Small, high-intensity spots are seen on FLAIR imaging (A) at cycle 2; a new high-intensity area
(arrow) is found in the left splenium of the corpus callosum on FLAIR imaging (B) at cycle 4 and significantly worsens on FLAIR imaging (C) at cycle 6; No
enhancement is detected on Gd-enhanced T1-weighted images (D–F).
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Of course, a term such as “semiautomated algorithms” broad-
ly describes a class of software with varying degrees of automa-
tion; consequently, semiautomatic volumetric methods must be
clarified and standardized to be incorporated into the high-grade
glioma response criteria recommendations. Nevertheless, the vol-
umetric approach is superior in circumventing areas of necrosis,
cystic cavities, and surgical cavities, and also estimates tumor
size more accurately than conventional 2D methods.
38,39
The
high-grade glioma case in Figure 6D is a perfect example in
which applying volumetric measurement more accurately esti-
mates tumor volume.
In terms of grading the involvement of a nonenhancing lesion
on FLAIR and T2 imaging, no standard thresholds for the deter-
mination of PR or PD have been established to date. The resulting
gap in the standard guidance can lead to a high discordance rate
in radiographic interpretation between observers. Although var-
iations in FLAIR and T2 images can mean greater difficultly in
measurement than enhancing tumor, this factor alone does
not justify excluding measurements of nonenhancing tumor in
all situations.
40
While there is concern over the lack of signal spe-
cificity (e.g. edema versus tumor), T2/FLAIR images benefit inter-
pretation by distinguishing decreased vasogenic edema from
vascular normalization. Furthermore, reduced T2/FLAIR signal
is also associated with decreased morbidity, improved clinical
status, and reduced steroid dosing, regardless of whether a
patient is experiencing a pseudoresponse or true response to
antiangiogenic agents.
41–43
Therefore, the ability to quantify
unequivocal tumor progression of nonenhancing FLAIR/T2
lesionsisjustifiedandguidelinesformeasurementshouldbe
addressed.
Furthermore, since many anaplastic gliomas do not enhance,
eliminating the measurement of nonenhancing tumor thwarts
the assessment of drug response in grade III tumor trials.
19
Follow-up of T2 and FLAIR imaging with DWI can justly provide
a superior means of discerning the presence of tumor.
44
Likewise,
adding DWI to the immediate postoperative MRI scan can act as
an independent predictor for 6-month progression-free sur-
vival,
45
a common primary endpoint in phase II trials, which rep-
resents clinically meaningful benefit in the rapidly progressing
GBM.
46
The RANO paper on low-grade glioma
47
has proposed
using FLAIR and T2 imaging as key tumor response evaluation se-
quences. Similar evaluation should be included for the next RANO
update in high-grade glioma, particularly for nonenhancing grade
III tumor.
Although the consideration of pseudoprogression was intro-
duced in the first RANO publication, pseudoprogression continues
to pose particular challenges for patient management and for ef-
ficacy assessment in high-grade glioma trials. When wrongly in-
terpreted as treatment failure, pseudoprogression can affect
clinical therapeutic decision, possibly resulting in premature dis-
continuation of effective adjuvant therapy. Conversely, failure to
exclude patients with pseudoprogression from studies will result
in falsely high objective radiographic response rate. In addition,
eliminating patients from drug trials who progress within 3
months of the completion of radiation therapy may exclude the
most malignant tumors, resulting in selection bias.
19
For instance,
although the RANO working group recommended that pseudo-
progression should be considered inside the 80% isodose line of
radiotherapy, precise radiation field information is rarely available
to independent observers.
Pseudoprogression is not uncommon in the 3 to 6 month post-
radiation timeframe, and the prolonged effect of chemoradiation
necrosis can manifest months to even years after treatment.
12
In
fact, a recent study reported that among 27 patients, almost
30% of pseudoprogression occurred more than 12 weeks after
chemoradiotherapy.
18
This raises doubts as to the value of the
12-week time limit implemented in the RANO criteria. Therefore,
further guidelines are needed. In our central imaging review prac-
tice, pseudoprogression is assumed when growth of an existing
lesion or appearance of a new lesion occurs within 12 weeks of
completion of radiation therapy and the lesion later stabilizes or
shrinks at continued follow-up imaging.
Nevertheless, conventional MRI signs have limited utility in di-
agnosing pseudoprogression in patients with recently treated
GBMs and worsening enhancing lesions.
48
Although further
study validation is required, advanced imaging techniques such
as PET/CT, perfusion MRI, and MRS have shown intriguing potential
in differentiating pseudoprogression from true progression.
18,49–51
While the sensitivity and specificity of such methods are not yet
perfected, these techniques are often used as standard high-
grade glioma imaging protocol at many medical and academic
centers. The best choice for differentiating pseudoprogression
may be an optimum combination of multiple imaging methods,
e.g. MRS combined with DWI.
52
Indeed, the experts from RANO
working group have themselves recently listed volumetric, perfu-
sion MRI, MRS, DWI, and PET as auxiliary or secondary endpoints in
clinical high-grade glioma trials.
8
Since the ability to differentiate
pseudoprogression from true PD can affect clinical decisions re-
garding whether to continue patients on their current therapies
or begin alternative treatment, improvement of these standards
and introduction of additional modalities is crucial.
Summary
RANO is essentially a 2D anatomical assessment of tumor bur-
den that includes nonenhancing tumor into the determination
of overall tumor burden. Especially in the setting of antiangio-
genic therapies, measurements of response and progression ac-
cording to RANO are the best surrogate imaging endpoints
available for high-grade glioma multicenter trials at this time.
Nonetheless, the adequate assessment of response and time-
to-progression is an evolving matter in the high-grade glioma
arena; and, while concerns regarding the use of change-in-
tumor-size endpoints persist, advances in neuroimaging tech-
niques continue. Not only is it essential that trial oncologists
and radiologists have a solid understanding of the RANO guide-
lines, they must also have proper insight into their limitations in
generating an accurate assessment of response to therapeutic
intervention. The author anticipates that with sufficient data col-
lection, the next high-grade glioma response criteria updates will
incorporate the advanced MRI methods discussed within this re-
view, including quantitative tumor volume measurements,
which will improve accuracy in the future interpretation of re-
sponse to treatments.
Supplementary Material
Supplementary material is available online at Neuro-Oncology
(http://neuro-oncology.oxfordjournals.org/).
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Acknowledgments
The author thanks Dr. David Raunig, Dr. James Conklin, and Dr. Gregory
Goldmacher for their useful suggestions and encouragement. The
author also thanks Elizabeth Robson, MS for her kind editorial support.
Disclosure
The author is an employee of the Medical Imaging division of ICON plc, a
global CRO.
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