Low-Grade Astrocytoma Treatment & Management

Updated: Dec 21, 2017
  • Author: George I Jallo, MD; Chief Editor: Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS  more...
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Treatment

Medical Care

From the history, physical, and radiologic appearance of a tumor on CT scan or MRI, a presumptive diagnosis of a low-grade glioma can be made. The primary care physician should coordinate care with a neurologist, neurosurgeon, and oncologist. The initial treatment steps depend on patient presentation. [9]

One of the classic presenting symptoms in this group of lesions is seizures, as mentioned before. Seizures occur in more than 90% of patients. This is more pronounced in oligodendrogliomas, but still very common in low grade astrocytomas as well. [47] If the patient presents with seizures, first-line therapy is to start the patient on valproic acid, levetiracetam (Keppra), phenytoin (Dilantin), or carbamazepine (Tegretol). Treating the seizures quickly after presentation will reduce the occurrence of seizures in the following 1–2 years after starting the treatment, which does not affect QOL (quality of life) nor results in severe complications, as compared to deferred treatment. [48]

If the patient presents with headache and has significant edema surrounding the tumor, dexamethasone (Decadron) therapy is appropriate in doses ranging from 2-4 mg every 6 hours. With dexamethasone, antiulcer medications (ie, antacid, H2 blocker) usually are prescribed. Corticosteroid therapy may also improve symptoms in patients who have low-grade astrocytomas of the spinal cord. However, treatment with steroids will not solve the primary problem and should be used only for symptom relief as it is not a definitive treatment of the tumor.

If hydrocephalus is observed on CT scan or MRI and the patient is symptomatic, surgical placement of a ventricular drainage device or an endoscopic third ventriculostomy (ETV) may be appropriate. Either an external ventricular drain or a ventriculoperitoneal shunt may be inserted. The exact procedure depends on any further plans for surgery, with the common agreement to avoid installation of permanent shunts unless there is no other option.

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Surgical Care

Aside from the initial measures noted in Medical Care, the cornerstone of therapy for most low-grade gliomas is surgery. [10, 11, 12] Maximum safe resection is the goal of surgical treatment. Positive impact on PFS (progression-free survival), OS (overall survival) and QOL (quality of life) is achieved when complete or even sub-total resections are performed. Residual tumor volume correlates with potential malignant transformation. Hence, multiple reoperations are feasible and sometimes necessary in order to achieve gross total resection, which is known to correlate with best clinical and prognostic results. Nonetheless, even subtotal resection is of benefit if the tumor can be removed safely. Ultimately, histologic diagnosis should be sought for all patients via biopsy or resection if possible.

Tumors in certain locations may be inoperable. Sometimes with the use of advanced imaging neuroplasticity is proven (relocation of specific local brain functions), which allows multiple and sequential resections in previously unresectable eloquent areas. The use of intraoperative electrostimulation mapping during surgeries has been shown to maximize safe resection especially around eloquent areas of the brain. This mapping is useful in understanding the correlation to important white matter fibers (eg, pyramidal tracts), as well as awake craniotomy for cortical mapping of eloquent areas (eg, speech-related areas) provides higher extent of resection and less permanent postoperative deficits.

Surgery is also the primary mode of treatment for low-grade astrocytomas of the spinal cord. Depending on the appearance of the tumor at surgery, a gross total resection, subtotal resection, or only biopsy may be possible. However, resection may lead to symptomatic and objective improvement in these patients. Furthermore, in low-grade astrocytomas, long-term readmission (>10 y) and even cure are frequent in both children and adults.

The extent of resection is measured differently for high-grade glioma, low-grade glioma, and pediatric gliomas. For classic enhancing tumors (high-grade gliomas and some of the pediatric gliomas like pilocytic astrocytomas) the extent of resection is determined by the remnant of enhancing tumor left after resection. For low-grade non-enhancing gliomas, like diffuse low-grade astrocytoma, the identification of the tumor volume relies primarily on the identification of T2/ FLAIR abnormalities. [49, 51] As a result, gross total resection (GTR), defined as the complete radiographic resection of regions of T2/FLAIR hyperintensity in nonenhancing lesions.

Intraoperative 5-ALA fluorescence can be used to help achieve a greater extent of resection. [52] Fluorescence-guided resection has shown great potential for maximizing EOR because it permits real-time intraoperative identification of residual tumor tissue. [49] Preoperative administration of 5-ALA results in preferential accumulation of fluorescent protoporphyrin IX (PpIX) in malignant tissues compared with normal brain. [49] A study published by Sanai et al [13] showed that intraoperative confocal microscopy can help visualize cellular 5-ALA–induced tumor fluorescence within low-grade gliomas and at the brain-tumor interface.

The use of intraoperative imaging to guide the resection of gliomas in general has provided surgeons with a new tool to improve the extent of resection. [14] Today, two important tools are the intraoperative ultrasound (iUS) and intraoperative MRI (iMRI). iUS offers valuable real-time information about the location, size, vascular relationships, and adjacent structures of brain tumors. [53, 54] In some systems, there is a way to incorporate iUS with preoperative imaging (merging real-time iUS imaging with the navigation imaging), so the surgeon can evaluate how much he took out and identify tumor margins that were left behind. [53, 54, 55] iMRI is a more complex solution that can provide real-time imaging and is important especially with low-grade astrocytomas when it is hard to understand tumor margins from surrounding healthy brain tissue. One problem with this technology is its high cost and limited availability. It also extends operating times, which could be a downside for patients with high anesthetic risk.

Intraoperative neurophysiological monitoring has been used increasingly in the last few years. [15, 16] (See Intraoperative Neurophysiological Monitoring.) This is a preferred technique to remove lesions close to, or involving, eloquent (functionally important) regions of the brain. The goal of such monitoring is to identify changes in brain and spinal cord function prior to irreversible damage. Intraoperative monitoring also has been effective in localizing anatomical structures, which helps guide the surgeon during dissection.

One of the electrophysiological modalities is intraoperative cortical mapping, which can help to achieve a greater extent of resection. The mapping is often done with small electrodes that stimulate certain areas of the brain and evoke particular responses. This technique is often used in combination with awake craniotomy.

In awake craniotomy, the patient is awake during parts of the procedure. With the patient awake, it is possible to test regions of the brain before they are incised or removed, and patient’s function is tested continuously throughout the operation.

See Brain Cancer Treatment Protocols for summarized information.

In spinal surgeries for resection of low-grade astrocytomas, the monitoring usually includes sensory-evoked potentials, motor-evoked potentials, and the use of direct wave (D-waves), which allows for monitoring the propagation of cortical stimulation along the white matter fibers of the spinal cord.

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Consultations

Patients in whom a low-grade astrocytoma is suspected should be evaluated primarily by a neurosurgeon. The best treatment modality is through a multidiscipline approach with a team structured with neurosurgeon, neurooncologist, neuropathology, neurologist, neuropsychology, and neuroradiology. The neurosurgeon will guide the diagnostic evaluation preferably after maximally safe resection of the tumor. After surgery the team will decide on the best approach to treat the patient; either continue follow-up only (eg, after GTR of pilocytic astrocytoma), adjuvant oncological treatment, and sometimes re-do surgery for tumor remnant.

Patients who present with seizures usually will receive first treatment by the neurosurgeon. Further treatment and the decision of weaning the antiepileptic drugs usually will be managed by a neurologist.

Other consults should be considered only in individual circumstances (eg, psychiatry in patients with concomitant psychoaffective disorders).

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Diet

There are no special dietary restrictions for patients with brain tumors although patients with pre-existing medical conditions which warrant dietary modifications must continue to abide by their previous regimens to avoid potential complications (e.g. episodes of hypo/hyperglicemia in diabetic patients).

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Activity

In general, no restrictions are placed on activity of patients with low-grade glioma. However, patients' activity may relate to their overall neurologic status. The presence of seizures may prevent the patient from driving. Neurologic deficits such as hemiparesis may improve after treatment. Physical therapy is often beneficial.

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Role of Adjuvant Therapy

Adjuvant therapy is usually recommended in patients presenting with bad prognostic factors. These factors are summarized in Table 3. Many of these factors are also predictive of bad response to treatment. Currently, we lack prospective long-term studies that will reveal the long-term benefit in overall survival and quality of life as result of the treatment. We also lack the data regarding the change in the cognitive and neuropsychology status of the patient as a result of the treatment. Another unsold issue is with recurrent disease. Some advocate repeat surgery before changing oncological regimen. Some will choose the treatment in relation to risk factors; low-risk patients will be sent for surgery and then possible radiotherapy, while high-risk patients that initially were treated already with radiotherapy and chemotherapy are ultimately rescued with other chemotherapy regimens with or without repeat resection. [56, 71] Several trials were published in regard to these questions. The results from the RTOG 9802 randomized trial [56, 58]  showed that low-risk LGG patients (those who had complete resection by postoperative imaging and are less than 40 years old) exhibited a 93% 5-year survival rate and a 5-year PFS (progression-free survival) of 48% without any adjuvant therapy. These results were very similar to those obtained by another important trial, EORTC 22845, which tested the patients for postoperative radiotherapy alone (either immediately after surgery or in progression) and found PFS in 5 years of 44% in the group that received immediate post-surgical radiation therapy. One important unsettled debate regarding the routine use of radiotherapy is the fact that most of the LGG patients are young and survive longer, hence may show more than usual the cognitive deterioration related to radiation therapy focused on the brain. As a result, today's paradigm is to treat with radiotherapy patients that have the highest probability of progression (age older than 40 years, preoperative tumor size larger than 5 cm, partial resection, astrocytic histology, lack of co-deletion and lack of IDH mutation) or had progressed after good resection and chemotherapy. [44]

The use of chemotherapy in LGG has been studied widely and still is. In summary, for high-risk patients, the addition of PCV to radiation therapy markedly improves PFS, doubles OS, and seems to preserve cognitive function. [56] The use of temozolomide (alone or concomitant) instead or before PCV is still under research, but it seems at least comparable in terms of QOL and survival, and became the standard of care in some centers that prefer its less toxic side effects.

In the pediatric population, children have excellent outcomes with prolonged survival, especially when a gross total resection (GTR) of the tumor is achieved. Yet, in cases subtotal resection is achieved or no resection is possible but biopsy, sometimes there is a need for multiple treatment regimens in order to halt progression of tumor growth. [61, 62, 63] The mortality in children tend to occur either from tumor-related case (tumor progression, malignant transformation) or toxicity-related morbidity from the treatments. Tumor progression in the pediatric population sometimes relates to the fact that the anatomical location tends to be different from their adult counterpart, with more deep-seated midline location like thalamic tumors, brainstem tumors, and so on. In recent years, these tumors were found to harbor H3K27M and MAPK pathway mutations, which are known today to be a bad prognostic factors with biological behavior of high-grade tumors rather than low-grade tumors. This understanding shifts the treatment paradigm toward more active and aggressive measures. 

Targated therapy 

In recent years, a lot of data has been published in regards to molecular biology and genomics of low-grade gliomas in the adult as well as pediatric population. Aberrant signaling in pathways like RAS/MAPK or the PI3K/Akt/mTOR network, have been identified in low-grade gliomas, and clinical trials are ongoing to target this pathway as a therapeutic approach. [64] In addition, ongoing studies are evaluating inhibitors of IDH. [65] The ability to image levels of the oncometabolite 2-hydroxyglutarate is an exciting area of research to develop noninvasive robust biomarkers of treatment response and clinical outcome in IDH-mutated tumors. [66] BRAF V600E mutations are found in pediatric low-grade gliomas and in circumscribed low-grade gliomas such as pleomorphic xanthoastrocytoma (PXA) and extra-cerebellar pilocytic astrocytoma, or epithelioid glioblastomas (E–GBM), a rare variant of GBM. [67] In tumors that harbor the V600E mutation, treatment with BRAF inhibitors was shown to make significant cytoreduction while under treatment. In the pediatric population, it was shown that when the V600E mutation is present, treatment with conventional chemotherapy leads to worse prognosis in comparison to BRAF inhibitors. [68]

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