2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

CONCEPTS IN BRAIN TUMOR IMAGING
tumor or any new tumor on CT or MRI scans, or neurologically
worse, and steroids stable or increased.” 31 Although
these were the best available criteria for nearly 20 years,
their focus on enhancing tumor limited their usefulness
because low-grade diffuse gliomas typically lack an enhancing
component and high-grade gliomas often contain nonenhancing
elements. Furthermore, processes other than tumor
frequently influence the extent of contrast enhancement.
Examples include treatment-induced inflammation or
necrosis, postoperative changes, seizures, and infarction.
Medications may also affect contrast enhancement. Corticosteroids,
for example, perhaps the most commonly used class
of medication in neuro-oncology, are known to reduce contrast
enhancement in a large portion of patients with gliomas.
32
False Positives
A number of phenomena may lead to an inaccurate diagnosis
of tumor recurrence on posttreatment MRI scans.
Since publication of a large, randomized trial in 2005,
standard-of-care therapy for GBM includes involved-field
radiation therapy with concurrent and adjuvant temozolomide.
33 Most neuro-oncologists obtain an initial posttreatment
MRI scan 4 weeks following the radiation therapy
phase. In approximately 20% to 30% of cases, this MRI
meets the criteria for progressive disease, but without
further treatment other than adjuvant temozolomide, subsequent
follow-up scans show lesion shrinkage or stability.
34,35 This has been termed pseudoprogression and is
among the most common causes of misdiagnosed tumor
recurrence.
Knowledge of this phenomenon has changed practice for
many neuro-oncologists, who now accept the first postradiation
MRI scan as a new baseline; so long as a patient is
not highly symptomatic from apparent progression, a
reasonable approach is to proceed with one-to-three cycles
of adjuvant temozolomide before deciding whether the
changes reflect pseudoprogression or true progression. In
general, pseudoprogression that is related to radiation
therapy occurs within 3 months following treatment, but
cases have been described as late as 6 months following
treatment. For patients who develop severe or symptomatic
worsening in this window of time, surgery may be
required. Although the pathologic substrate of pseudoprogression
remains to be determined with certainty, in one
article seven patients underwent surgical resection for pseudoprogression
and subsequent histopathology showed only
necrosis. 36
Given an increasing recognition of pseudoprogression in
the temozolomide treatment era and the knowledge that
temozolomide has radiosensitizing properties, many have
suggested that combining temozolomide with radiation therapy
increases the risk of pseudoprogression compared with
radiation therapy alone. 36 However, the rates of pseudoprogression
reported in recent studies 34,35 are similar to the
rates reported before the widespread use of temozolomide. 37
Another potentially important risk factor for pseudoprogression
is the DNA repair gene O 6 -methylguanine-DNA methyltransferase
(MGMT) promoter methylation. Recent data
demonstrate that MGMT promoter methylation status is
predictive of response to temozolomide and a favorable
prognosis in patients with GBM. 38 This finding is intuitive
because MGMT is an endogenous DNA repair enzyme that
mediates resistance to alkylating chemotherapeutics like
temozolomide. In a study of 103 patients newly diagnosed
with GBM, pseudoprogression was diagnosed in 32 (31%)
patients. Ninety-one percent of subjects whose tumors had
methylated MGMT promoters developed pseudoprogression
as compared with 41% of patients whose tumors had unmethylated
MGMT promoters, and the difference was statistically
significant. 35 Also of interest is that overall
survival was higher in patients whose tumors developed
pseudoprogression. The findings suggest that pseudoprogression
may occur when concurrent radiation therapy and
temozolomide are particularly active against residual tumor,
although this remains to be confirmed in prospective
studies.
Pseudoprogression is problematic from the perspective of
clinical trial end points in addition to the clinical challenges
it creates. Accrual of patients whose tumors spontaneously
“respond” falsely elevates response rates and prolongs
progression-free survival in clinical trials for recurrent disease.
For this reason, the recently adopted RANO criteria
(Table 1) stipulate that progression cannot be diagnosed
within the first 12 weeks after radiation therapy unless the
majority of new enhancement is outside the radiation field
or there is histopathologic confirmation of tumor progression.
6
Treatments other than radiation therapy are less common
causes of misdiagnosed progression. It is well known, for
example, that enhancement at the margin of an operative
cavity often develops 48 to 72 hours after surgery and may
persist for weeks or months. In some cases, perioperative
infarction may result in new enhancement that is visually
indistinguishable from tumor recurrence. In a study of 50
GBM resections, diffusion-weighted MRI sequences showed
restricted diffusion consistent with infarction in 35 (70%)
cases. Of these, 15 (43%) showed enhancement that might
have been confused with recurrent disease. 39 Finally, local
therapies may provoke MRI changes that are suspicious for
recurrence. Examples include carmustine wafers and experimental
therapies administered by direct intracerebral injection
or convection-enhanced delivery.
False Negatives
As noted above, the Macdonald criteria were not designed
to assess nonenhancing tumors. This is problematic because
the majority of low-grade gliomas and an important minority
of high-grade gliomas do not enhance, particularly in
older adults. 40 Furthermore, nonenhancing elements are
present in almost all enhancing high-grade gliomas. Another
challenge in assessing nonenhancing tumor is that
these abnormalities typically appear hyperintense on T2- or
FLAIR sequences and cannot be readily distinguished from
edema, gliosis, toxic leukoencephalopathy, microangiopathy,
or radiation-induced white matter disease.
Unfortunately, the widespread use of antiangiogenic
therapy has only compounded the problem. The prototypic
antiangiogenic agent is bevacizumab, a humanized monoclonal
antibody against VEGF that received accelerated
United States Food and Drug Administration approval
for recurrent high-grade glioma in 2009. Although bevacizumab
is responsible for high radiographic response rates
and marked prolongation of progression-free survival, 41,42
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