NCCN: Low-grade astrocytomas are a diverse group of relatively uncommon malignancies, and outcomes depend on many factors. Of these malignancies, 70% are diffuse astrocytomas (fibrillary, protoplasmic, and gemistocytic types), which are poorly circumscribed, invasive, and gradually evolve into higher-grade astrocytomas. Gliomatosis cerebri is characterized by widespread dissemination of neoplastic astrocytes, often involving an entire cerebral hemisphere. The most common noninfiltrative astrocytomas are the pilocytic astrocytomas, which are circumscribed, often surgically resectable, and rarely transform; however, the NCCN algorithm does not encompass pilocytic astrocytomas because these tumors are curable by surgery alone. These are more common in the cerebellum of children but also occur in the cerebral cortex of adults. Many other rare low-grade astrocytomas also exist, such as the pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, and subependymoma.

Patients with infiltrative low-grade tumors usually present with seizures (66%), headache, and/or weakness. The median duration from onset of symptoms to diagnosis ranges from 6 to 17 months. The mean age at presentation for these tumors is 37 years. The most powerful predictor of survival is age. The average 10-year survival rate for children is 83%, whereas the median survival is only 5 years for those older than 40 years. Other important prognostic factors for survival include long duration of symptoms, excellent postoperative neurologic status, and diploid tumors with a low labeling index. These tumors typically are nonenhancing, lowattenuation lesions on CT scans and MRI scans. However, the imaging “diagnosis” of low-grade astrocytoma is incorrect about 25% of the time; the most common alternate diagnosis is anaplastic astrocytoma.

Although low-grade astrocytomas are commonly thought to be benign, most of these tumors behave aggressively despite surgery and RT. A low-grade astrocytoma can transform into a glioblastoma during a period of 5 to 10 years. The best management strategy for a patient with seizures and a probable low-grade astrocytoma has yet to be defined. Whenever possible, total removal should be attempted, because survival and recurrence-free intervals are superior when the tumors can be safely removed. Furthermore, a gross total removal could potentially delay or prevent malignant progression. Of course, for tumors that are infiltrative and involve eloquent areas, a total removal may not be feasible and an aggressive approach could result in neurologic deficits.

Surgery remains an important diagnostic and therapeutic modality for patients with low-grade astrocytomas. The primary surgical goal is to provide adequate tissue for a pathologic diagnosis and grading. Needle biopsies are often performed when lesions are in deep or critical regions of the brain. Biopsy results can be misleading, because gliomas often have varying degrees of cellularity, mitoses, or necrosis from one region to another; thus, small samples can provide a lower histologic grade.

The role of gross total surgical tumor excision in low-grade astrocytomas remains unresolved, although most of the available retrospective biomedical literature suggests a survival benefit from aggressive surgical resection. Because these tumors are relatively uncommon, published series generally include patients treated for decades, which introduces additional variables. In the past, for example, the completeness of surgical excision was based on the surgeon's report. This approach is relatively unreliable when compared with assessment by modern postoperative imaging studies. Furthermore, most patients also received RT, and thus the net effect of the surgical procedure on outcome is difficult to evaluate. Shaw and colleagues reviewed 126 patients with astrocytomas and mixed oligoastrocytomas. After gross total removal, patient survival rates were 52% at 5 years and 23% at 10 years. These survival rates were identical to those after subtotal removal or biopsy only. Most patients received postoperative RT, but a higher proportion in the subtotal removal group received this treatment. This experience suggests that if RT is applied, the degreeof surgical removal may be less important. Other studies have suggested prolonged survival in patients who underwent gross total resection, compared with those patients who underwent less radical excision. Berger and colleagues have shown an inverse correlation between the postsurgical residual tumor volume and the length of survival in patients with low-grade astrocytomas. Biological considerations also favor an attempt at a complete excision of an astrocytoma. First, the tumor may contain highergrade foci, which may not be reflected in a small specimen. Second, complete excision may decrease the risk of future dedifferentiation to a more malignant astrocytoma. Third, a large tumor burden is removed, which also may enhance the effect of RT. As a result of these considerations, the general recommendation for treating an astrocytoma is to first attempt as complete an excision of tumor as possible without compromising function.

No consensus exists regarding the proper timing of postoperative radiation in low-grade astrocytomas. Some oncologists advocate immediate RT, whereas others delay radiation until tumor progression is evident. In Shaw's study (1989), immediate RT did prolong survival in patients with these tumors. Also, higher doses seemed to be more effective; 5-year survival rates were 68%, 47%, and 21% for patients receiving a total dose of 53 Gy or higher, less than 53 Gy, and no radiation, respectively. However, others have reported no prolongation of survival in irradiated patients. A randomized trial of early versus delayed radiotherapy in adult patients was conducted by the European Organization for Research and Treatment of Cancer (EORTC). In this trial, patients with lowgrade gliomas were randomly assigned to either (1) 54 Gy postoperative radiation; or (2) no immediate therapy. With a median follow-up of 5 years, the 5-year disease-free survival was better with immediate postoperative radiation (44% versus 37%; = 0.02). However, the 5-year overall survival was the same (63% versus 66%) indicating that deferring the postoperative therapy can be an option for a selected group of patients. Further analysis of mature data is necessary before firm recommendations can be made based on this study. Although delaying radiation in young healthy patients without progressive neurologic decline can be controversial, there is a consensus to proceed with immediate postoperative radiation in older patients after a less-than-total resection, because their survival is as poor as patients with anaplastic astrocytoma. When radiation is given to patients with low-grade astrocytomas, it is administered with restricted margins. Whole-brain RT (WBRT) results in more treatment-related neurotoxicity than does localized RT in these patients, who are often young and may survive for years. A T2-weighted MRI scan is the best means for evaluating tumor extent. In general, contrast administration is not helpful, because these tumors enhance weakly or not at all. The target volume is defined by the tumor with a 2-cm margin. Every attempt should be made to decrease the radiation dose outside the target volume. Therefore, the use of only two parallel opposed portals is not recommended. A wedged pair beam is adequate for many lateral tumors. The dose outside the target can be further decreased by the use of multiple beams and three-dimensional planning, and their use is encouraged. Stereotactic RT and intensity-modulated beams are being studied at a few institutions, but their value is not known at present. The standard radiation dose for low-grade astrocytomas is 54 Gy, given at a rate of 1.8 Gy per day. The selection of 54 Gy as the standard dose is based on its relative safety when applied to a limited volume of the brain and on the lack of evidence for increased efficacy with higher doses. In a randomized trial conducted by the EORTC in patients with low-grade astrocytomas, no survival difference was observed when 45 Gy was compared with 59.4 Gy. With a median follow-up of 6 years, the 5-year disease-free survival and the 5-year overall survival were the same. Patients were randomly assigned to receive either (1) 50.4 Gy in 28 fractions, or (2) 64.8 Gy in 36 fractions in another combined NCCTG (North Central Cancer Treatment Group), RTOG, and ECOG (Eastern Cooperative Oncology Group) study. With a median follow-up of 6.3 years, the 5-year disease-free survival and the 5-year overall survival were again the same indicating that lower doses of RT are probably as effective as higher doses of radiation for low-grade gliomas. Enthusiasm for interstitial radiation or stereotactic radiosurgery in recurrent low-grade astrocytomas has decreased due to lack of evidence for efficacy.

Currently, chemotherapy is not used in the treatment of low-grade astrocytomas in which a maximal safe resection is feasible, but chemotherapy may be considered at recurrence. The RTOG recently conducted a clinical trial that allowed observation alone for completely resected low-grade gliomas in patients younger than 40 years and randomly assigned younger patients who were sub-totally resected and older patients who received any kind of resection to postoperative radiation to 54 Gy with or without PCV chemotherapy for 6 cycles. This study has completed the accrual, and the results are awaiting publication.

Treatment Algorithm.    When possible, maximal resection is recommended for low-grade astrocytomas, and the actual extent of resection should be documented with an immediate postoperative MRI scan within 72 hours after surgery. For patients undergoing complete excision, observation alone is reasonable after the surgical intervention. These tumors tend to behave more aggressively in patients older than 45 years; therefore, immediate RT may also be considered for patients in this age group who have had complete excision. Regular follow-up is essential for patients receiving observation alone after resection. Although surgery is generally recommended, serial observations are appropriate for selected patients.

Patients who only had a diagnostic biopsy or subtotal excision are more likely to be treated with immediate RT, especially if their symptoms are uncontrolled or progressive; chemotherapy (category 2B) is also an option. Because of concerns about the neurotoxicity of RT, patients with residual asymptomatic low-grade astrocytoma may be followed until their disease progresses. Observation is also reasonable in patients with diffuse low-grade astrocytoma, because neurotoxicity increases with the size of the RT port required to encompass the entire lesion. Chemotherapy (category 2B) and irradiation are other options. Patients should be followed using MRI every 3 to 6 months for 5 years and then less frequently. At the time of recurrence, surgery is considered for resectable lesions. This can be followed by radiation, if it was not previously administered, or by reirradiation, especially if progression-free survival is more than 2 years after prior RT, the new lesion is outside the target of previous RT, or the recurrence is small and geometrically favorable. Local recurrence can also be treated with local RT and/or chemotherapy.