Low grade gliomas are slow growing tumors that are divided into pilocytic and non-pilocytic tumors. They account for about 20% and 10% of gliomas and primary intracranial tumors in adults. These are WHO Grade I and II tumors and are managed as described below. Pilocytic astrocytomas are WHO Grade I and are amenable to resection which is usually curative. With complete resection > 90% are cured and no further treatment is necessary. Incomplete resection is also associated with a high rate of long term survival with OS10 at 70% — 80%. The benefit of post-operative Radiation therapy (PORT) is unclear.
Non-pilocytic WHO Grade II tumors are more diffusely infiltrating and may arise from astrocytic, oligodendrocytic or mixed cell lines. these generally present in the 3rd or 4th decade of life and are rarely seen in patients < 19 years old or in patients > 65. CT imaging demonstrates an ill-defined, diffuse, non-enhancing low-density region, often in the frontal or temporal lobes. Calcifications are common in oligodendrogliomas MRI is more sensitive with non-enhancing, hypointense T1 lesions and hyperintense T2 lesions. The tumor always extends beyond the imaging observed abnormality volume.
Histopathologically there is increased cellularity compared to normal brain parenchyma. There is mild-moderate nuclear pleomorphism, and no evidence of mitotic activity, vascular proliferation or necrosis. Reactive gliosis is difficult to distinguish from neoplastic disease. Gemistotcytic subtypes behave more like malignant gliomas while fibrillary and protoplasmic subtypes carry no prognostic information.
1p19q co-deleted oligodendrogliomas are associated with improved survival independent of other factors, including age. Patients with loss of 1p19q had an overall median survival of 14.9 years compared with 4.7 years for those without loss of 1p19q. IDH1 mutations may also predict better outcomes in low grade gliomas, but does not predict chemotherapy response. PTEN methylation has been associated with poorer prognosis and a higher rate of malignant transformations. Temozolomide in patients 1p del appears to be more effective and had a significant improved response to chemotherapy (p < .004) .
Patients with ≤ 2 factors were considered lower risk with median survival of 7.7 years, and patients with ≥ 3 factors were high risk with a median survival of 3.2 years.
Clinical workup includes an H&P, MRI and at least a biopsy if a resection is not possible. MRI should be T2/FLAIR sequences (hypodense) and T1/Gad sequences.
The clinical course is variable but in general early intervention is indicated for increasing symptoms, radiographic progression and high risk features suggestive of transformation to high grade gliomas. Maximum safe surgical resection is important, both to insure correct diagnosis and for therapeutic benefit. In patient < 40 with R0 resection, observation with serial imaging and H&P is reasonable. For less than total resection (R1/R2) or in those with high risk features, adjuvant radiation is indicated. Radiation is typically delivered to 50 Gy in 1.8 Gy fractions. Chemotherapy may have a roll in 1p19q co-deleted lesions.
Surgery is an important integral part of the treatment. The goal and timing are debated, but most patients undergo surgery at the time of diagnosis. Surgery is unlikely to achieve a negative margin due to the diffusely infiltrating nature of Grade II gliomas. Most studies have found that sub-total resection (> 90% resection) is associated with improved outcome. Surgical resection alone is unlikely to be curative. RTOG 9802 examined surgery and found a PFS5 was 48%. Review of post-op MRI demonstrated crude recurrence rates of:
There is no apparent role for chemotherapy in the treatment of low grade gliomas. TMZ has been shown ot have activity in Phase II trials in newly diagnosed and recurrent LGG and trials are underway in both the US and EU.
Patients considered favorable by the scoring system above are observed. This was tested in an EORTC trial 22845/van den Bent. 334 patients were randomized to PORT v. RT at recurrence in the post-operative setting. Treatment was 54 Gy. A significant improvement in median PFS was found with early radiation but there was no difference in median survival. Only 65% of the patients in the delayed radiation group received radiation at progression. Malignant transformation occurred in 65% - 72%. The study concluded that delayed radiation does not jeopardize survival.
For post-operative radiation, dose has been investigated by two Phase III trials, the EORTC22844 and NCCTG/RTOG/ECOG trials. The EORTC trial randomized 45 Gy in 5 weeks or 59.4 Gy in 6.6 weeks. The NCCTG trial randomized 50.4 Gy to 64.8 Gy. OS, PFS were similar with both doses and groups. The EORTC showed OS 54% v. 59%, PFS 47% v. 50%. The NCCTG group randomized 50.4 Gy v. 64.8 Gy. The OS at 2 and 5 years was 94% and 72%, at lower dose radiation and for higher dose radiation the PFS was 85% and 64%. Grade 3 neurotoxicity doubled in the higher dose to 5% from 2.5%. Lower dose radiation to 50.4 Gy is the standard of care.
Treatment volumes are local, with a margin of GTV+2 cm. If FLAIR is used, the CTV is FLAIR+0.8-1 cm.
Surgical management is not possible as this disease has diffuse involvement of multiple parts of the brain, sparing neurons and nurmal structures. On MRI there is diffuse increased T2 and FLAIR signal, and low or absent signal in T1. MDACC treated patients under 40 wtih RT and demonstrated transient imaging improvement in 87% and clinical improvement in 70% Patients < 40 and non-glioplastoma histology did better and had significantly improved OS.
Adult brainstem gliomas, unlike the pediatric counterpart is rare. There are several distinct types:
There are also non-neoplastic processes that can mimic a brainstem glioma: neurofibromatosis, demyelinating disease, arterio-venous malformation, abscess and encephalitis.
Diffuse pontine gliomas are difficult to diagnose and treat. Biopsy is not possible due to the substantial risk of mortality and morbitidy. Diagnosis is based solely on clinical presentation of rapid onset of neurologic signs, of multiple cranial nerve palsies, (VI and VII), hemiparesis, and ataxia. These signs in combination with MRI imaging of diffuse enlargement and poorly marginated T2 signal involving > 50% of the pons, suggest diffuse pontine glioma. Most intrinsic pontine gliomas are non-enhancing. If there is focal enhancement, the disease is more likely to be a JPA, rather than a high grade glioma and these lesions should be biopsied.
Prompt initiation of corticosteroids may be necessary to manage neurologic symptoms until treatment is started. Patients with hydrocephalus may require a VP shunt. The approach is dependent on the type of brainstem glioma as determined by both clinical presentation and by imaging. If the lesion is operable, surgery is the first choice. Otherwise, radiation should be delivered using volumes and doses for low grade gliomas (50.4 Gy GTV+2 cm).
Involved field radiation therapy is the primary treatment for diffuse infiltrating pontine gliomas. The GTV is the T2 or FLAIR MRI enhancement. CTV is the GTV plus 1 - 1.5 cm margin. The PTV is the final expansion of between 0.3 and 0.5 cm + the CTV (which equals the GTV + ~ 2 cm). The treatment volume can be reduced for anatomic barriers to spread. Final radiation doses should be 55.8 to 60 Gy at 2.0 or 1.8 Gy/day.
In a word: dismal. Patients without anaplasia do significantly better with longer term survivals of up to 7 years. Chemotherapy has no established role, radiation offers short term relief, and surgery is impossible. Overall survival is 45% to 66% at 2 - 6 years which may be more favorable in adults than children, where most data on brainstem gliomas exists. Adults appear to have a more favorable mix of tumor histologies than pediatric cases. Significant favorable prognostic factors are:
Unfavorable indicators:
Nearly all of the patients with unfavorable characteristics were ultimately found to have anaplasia. In this group median survival was 11.2 months, similar to pediatric survival rates.
Treatment is indicated in patients with favorable types (exophytic → surgery, if feasible, slow onset/progression of symptoms > 3 months, older, non-enhancing).
Surgery is indicated with favorable tumor types but is neither feasible nor achievable in diffuse intrinsic pontine disease. For intrinsic disease, radiotherapy is the standard of care. Dose escalation strategies have not demonstrated any advantage over conventional radiation of 55 - 60 Gy.