14 Hospital Physician Board Review Manual www.turner-white.com
efit from TMZ.50 The MGMT repair enzyme is one
mechanism by which tumor cells repair DNA dam-
age from alkylating agents such as TMZ. MGMT
promoter methylation suggests decreased avail-
ability of this enzyme and alkylating chemotherapy
may be more likely to lead to cell death.
Overexpression, amplification, or mutations of
the epidermal growth factor receptor (EGFR)
are common in glioblastoma.51 Several EGFR
inhibitors have been approved for other malignancies, but unfortunately clinical trials have failed to
demonstrate a benefit in malignant glioma.52 One
interesting mutation results in a constitutively active receptor, the EGFRvIII. The co-expression of
EGFRvIII and phosphatase and tensin homolog
(PTEN) seems to predict sensitivity of recurrent
GBM to EGFR inhibitors.53 While found in other
cancers, EFGRvIII is not found in normal human
tissue. The unique protein structure is the target of
a cancer vaccine in clinical trials for glioblastoma.54
Other novel experimental therapies include small-molecule targeted agents, oncolytic viruses,55,56
and dendritic-cell immunotherapies.57
Discovered in 2008, mutations of the isoci-trate dehydrogenase glycolytic enzyme (IDH1 and
IDH2) are commonly found in low-grade and secondary high-grade gliomas.58 These mutations
appear to occur early in the development of gliomas and change the function of IDH to produce
2-hydroxyglutarate, a potential oncometabolite.
When compared with wild-type IDH, the presence
of IDH1 and IDH2 mutations is associated with improved prognosis in glioma.
Significant work is being performed using mi-
croarray technology and sophisticated analysis to
identify gene expression patterns that may have
prognostic signficance.59,60 One such analysis
stratified tumors into 3 groups: proneural, mesen-
chymal, and proliferative,59 with tumors exhibiting
the proneural signature correlated with improved
prognosis. It was noted that at recurrence, tumors
tended to exhibit more of the mesenchymal pat-
tern, which was correlated with a poorer prognosis.
Four weeks after the patient completed
concurrent chemoradiation, an MRI of
the brain was obtained. This revealed increased
contrast enhancement and surrounding edema.
The patient was clinically unchanged. Surgical
re-operation was deemed risky. The patient was
continued on adjuvant TMZ with a shorter interval of MRI tumor surveillance (4-week intervals).
By the third scan following chemoradiation, there
was marked reduction in the size of the contrast-enhancing lesion, measuring approximately 50%
of the pre-radiation size. The early MRI changes
were attributed to a transient post-treatment phenomenon known as pseudoprogression. MRI surveillance was changed to 8-week intervals (after
every 2 cycles of TMZ).
It is becoming increasingly evident that patients
may experience transient radiological “
progression” early after the completion of chemoradiation
with TMZ. This phenomenon has been labeled
pseudoprogression.61–63 Patients may remain clinically stable in many of these cases. Up to half of
all radiologic progression following chemoradiation may in fact fall under this category. The most
significant consideration in a patient with possible
pseudoprogression is whether to continue adjuvant TMZ, as a proportion of such patients have