Keywords low-grade glioma - IDH - oligodendroglioma - proton beam therapy - PCV
Introduction
Low-grade glioma generally refers to the two most common histologic subtypes of the
World Health Organization (WHO) grade II gliomas: diffuse astrocytoma and oligodendroglioma
(ODG).[1 ] They have a protracted natural history, which in most instances, terminates with
transformation into high-grade gliomas. Treatment options for these tumors have ranged
from observation to a biopsy for histological confirmation to aggressive radical resections
followed by adjuvant radiotherapy (RT) with or without additional chemotherapy.[2 ] Based on the increasing knowledge and emerging data, 2016 WHO brain tumor classification
uses molecular information to establish a brain tumor diagnoses. Gliomas with isocitrate
dehydrogenase (IDH) 1 and 2 mutation and lp/19q co-deletion with the histological
pattern of ODGs form the most favorable prognosis.[3 ] Modern highly conformal RT techniques have been shown to minimize RT doses to the
normal brain significantly as compared with conventional RT, without compromising
RT doses essential for durable tumor control. However, the recent RT techniques have
mitigated several of the long-term challenges, issues such as neurocognitive decline
continue to exist.[4 ]
[5 ] Proton beam therapy (PBT) has emerged peerless in terms of precision, safety, and
efficacy due to its unique physical characteristics of minimal exit dose that has
an unequivocal dosimetric superiority over high-end photon/standard X-ray beam therapy
and is particularly advantageous in low-intermediate grade gliomas because of their
very high probability of long-term cures.[6 ] We would like to report our preliminary experience of two cases of favorable low-intermediate
grade ODG treated at our facility, showing excellent radiological response.
Case Reports
Case 1
A 45-year-old male was evaluated for seizures in September 2018. His magnetic resonance
imaging (MRI) showed a diffuse lesion in the right medial temporal, right occipital,
and posterior parietal lobe involving the splenium of the corpus callosum. He underwent
right parieto-occipital navigation-guided burhole biopsy of the occipital lobe lesion
in November 2018. The histopathology report was suggestive of infiltrative glioma
grade IL. The molecular markers were IDH mutation, lpl9q codeletion, and telomerase
reverse transcriptase mutation that were positive. Because of age >40 years and some
features of a high-grade component on radiology, he was advised concurrent radiation
with PBT to dose 54 GyE in 30 fractions at 1.8 GyE per fraction along with concurrent
temozolomide ([Fig. 1 ]). Baseline quality of life (QOL) questionnaire was assessed; he tolerated treatment
well with no interruptions. Response assessment scan after 4 weeks showed a very good
response, with a nearly 50% reduction in the disease burden ([Fig. 2A ]).
Fig. 1 Representative images of proton pencil-beam therapy plan showing dose-wash in axial,
sagittal, and coronal view. Planning is based on Monte Carlo optimization algorithms.
Fig. 2 (A ) Axial fluid-attenuated inversion-recovery image pre- (image on the left) and post-proton
beam therapy (image on the right) of a case of low-grade glioma showing a very good
response to proton beam therapy; (B ) axial fluid-attenuated inversion-recovery image pre- (image on the left) and post-proton
beam therapy (image on the right) of a case of low-grade glioma showing an excellent
response.
Case 2
A 31-year-old male was evaluated for generalized tonic–clonic seizures in 2011. His
MRI brain revealed a large hyperintense area in the anterior occipital and post-temporal
lobe. He underwent left temporoparietal craniotomy and resection of the lesion. Histopathology
was reported as ODG WHO grade II (lpl9q-codeleted). He was kept on a regular follow-up
with 6 months MRI. Serial imaging revealed a gradual increase in the size of the left
temporal lobe lesion. He also had occasional episodes of generalized tonic–clonic
seizure. The last MRI brain in July 2018 showed infiltrative lesion measuring 5 ×
3.8 × 5.56 cm in the left posterior temporal lobe with ill-defined patchy enhancement
consistent with disease progression. His case was discussed in the neuro-oncology
tumor board meeting. Due to young age group and favorable histology, it was decided
to offer him adjuvant PBT to a dose of 55.8 GyE in 31 fractions at 1.8 GyE per fraction
along with concurrent temozolomide. Baseline QOL questionnaire was assessed; he tolerated
treatment well with no interruptions. Response assessment scan after 4 weeks showed
a very good response, with a nearly 50% reduction in the disease burden ([Fig. 2B ]).
Discussion
The management of low-grade gliomas is an evolving and often controversial topic.
With a long-term survival rate that exceeds 90%, therapy selection involves careful
consideration of minimizing late toxicity from the surgery, chemotherapy, and irradiation.
Surgery, radiation therapy, and chemotherapy may be used as individual therapies or
in combination, offering different therapeutic response depending on the clinical
setting. IDH mutation has a predictive value for response to chemotherapy in gliomas.
Extended follow-up of a large randomized controlled trial (RTOG 9402) that compared
procarbazine/lomustine/vincristine (PCV) chemotherapy in combination with RT to RT
alone demonstrated a survival advantage of the combination in IDH-mutant anaplastic
gliomas.[7 ] Alkylating chemotherapy using the PCV regimen initially and temozolomide more recently
have assumed a firm place in the treatment of patients with low-grade gliomas.[8 ]
Prospective and retrospective studies indicate that radiation therapy offers effective,
long-term disease control, but perceptions of radiation toxicity have produced limited
enthusiasm surrounding its use, particularly in younger adults.[6 ]
[9 ]
[10 ] Several studies have attempted to reduce the effect of late radiation toxicity by
using advanced radiation techniques to reduce the dose administered to normal tissues.
and by the use of advanced radiation techniques.[10 ] PBT, by the modern pencil beam technique with image guidance, is particularly promising
because it allows for reductions in the low and intermediate radiation dose to normal
tissue outside of the target volume, which is shown by various dosimetric studies.[9 ] Radiation side effects such as neurocognitive impairment, neurologic deficits, neurovascular
compromise, neuroendocrine deficiency, and second malignancies can be significantly
reduced by reducing the radiation dose to critical organs such as the hippocampus,
cochlea, and hypothalamic–pituitary axis. A Phase II Randomized Trial of Proton versus
Photon Therapy (IMRT) for cognitive preservation in patients with IDH mutant, low-to-intermediate
grade gliomas (NRG-BN005) is currently ongoing and should give us better insights
in the future.
We report our preliminary experience of two cases of favorable low-intermediate grade
glioma treated with modern contemporary PBT showing excellent radiological response.
Neurocognitive assessment, QOL, and response assessment are prospectively captured
and will be published once we have a longer follow-up.
Conclusion
PBT due to its unprecedented precision for more focused targeting of tumors, less
damage to healthy tissue around the tumor and lesser chance of intellectual impairment,
vascular complications, and secondary cancers can be the treatment of choice in low-intermediate
grade glioma and is likely to emerge as the standard of care in the management of
these tumors.
