11 Natural History and Management Options of Low-Grade Glioma

Rebecca J. Limb, Cristian Gragnaniello, and Leon T. Lai

Abstract

This chapter aims to summarize the most up-to-date literature on the clinical management of low-grade glioma, including the impact of surgical resection and adjuvant therapies on patient survival. In recent years, emerging evidence has somewhat modified practice worldwide, and with the advent of detailed molecular characterization, predicting tumor behavior may allow better prognosis and better guidance for therapy.

Low-grade gliomas (LGGs) are World Health Organization (WHO) grade II glial series tumors and represent a heterogenous group of neoplasms with astrocytic, oligodendroglial, ependymal, or mixed cellular histology. Worldwide incidence in adults is estimated to be 0.26 to 0.75 per 100,0003 and they account for approximately 15% of all brain tumors.¹ There is a slight male predominance and a biphasic age distribution with the first peak occurring during childhood (ages 6–12 years) and a second peak in adulthood (between the third and fifth decades). The median age of presentation in adults is 35 years.

With growing use of neuroimaging, incidental LGGs are increasingly being diagnosed, which poses significant management dilemmas for these asymptomatic patients. Symptomatic LGGs often present with partial or generalized seizures. It is thought that these tumors produce factors that either mimic glutamate or increase the circulating levels of glutamate, which is neuroexcitatory acting via alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NDMA) receptors. Most LGGs, and in particular diffuse astrocytoma (DA) and oligodendroglioma (OG), show a predilection for the supratentorial compartments, namely (in decreasing order of frequency) frontal, temporal, insula, parietal, and occipital lobes.

The prognosis for LGG is generally favorable compared to their high-grade counterpart, although in recent years a growing body of evidence suggests these pathologies are part of a continuous genetic and molecular spectrum, as opposed to separate disease entities (Fig. 11.1). Long-term survival for LGGs ranges from 5 to 13 years depending on the histological and molecular tumor profile.²

11.2 Selected Papers on the Natural History of LGG

●Smits A, Jakola AS. Clinical presentation, natural history, and prognosis of diffuse low-grade gliomas. Neurosurg Clin N Am 2019;30(1):35–42⁴

●Opoku-Darko M, Eagles ME, Cadieux M, Isaacs AM, Kelly JJP. Natural history and growth patterns of incidentally discovered diffusely infiltrating low-grade gliomas: a volumetric study. World Neurosurg 2019;132:e133–e139

●Gui C, Kosteniuk SE, Lau JC, Megyesi JF. Tumor growth dynamics in serially-imaged low-grade glioma patients. J Neurooncol 2018;139(1):167–175

●Potts MB, Smith JS, Molinaro AM, Berger MS. Natural history and surgical management of incidentally discovered low-grade gliomas. J Neurosurg 2012;116(2):365–372

11.3 Natural History of Low-Grade Glioma

The natural history of LGG is not well characterized in the literature, in part owing to the lack of long-term observational studies and the propensity for treatment bias. Contemporary evidence suggests LGGs display an asymptomatic (silent) phase, during which time the tumor may grow slowly at an estimated rate of 2 to 4 mm/y.5^{,​ 7} This may then be followed by a symptomatic phase, characterized by seizures in 70 to 90%,⁵ and finally, a progressive phase during which the tumor may grow exponentially.^{6,​ 7} At this point, increasing mass effect may be the main driver of neurological signs and symptoms, requiring surgical intervention to alleviate. The time periods between these stages are usually measured in years or months but are difficult to predict.⁵ Clinically silent tumors are more likely to be of lower volume, located in less eloquent areas, and therefore have a better prognosis following treatment.⁸

Increasingly, molecular rather than histological characteristics are becoming valuable in predicting LGG behavior³:

●Isocitrate dehydrogenase 1 (IDH-1 and IDH-2) enzyme gene mutation absence, that is, “negative” status in LGG (the so-called wild-type variant) confers more aggressive clinical behavior and rapid tumor progression.

●In OG, the presence of chromosomal co-deletion of 1p/19q along with IDH-1 mutant (positive) status is associated with a less aggressive clinical course.

●Other molecular markers, such as ATRX mutation, TERT (upregulating) promoter mutation, TP53 mutation, and MGMT methylation status, are not required for diagnosis but are adjuncts in predicting clinical behavior. ATRX and TP53 inactivating mutations are found in the majority of LGGs, but their role in prognostication is complex and appears to be more relevant in combination with other molecular subtypes, for example, IDH mutations. Similarly, TERT promoter mutations in combination with IDH-negative (wild-type) status confer a worse prognosis in LGGs. MGMT methylation is associated with improved tumor response to temozolomide (TMZ) chemotherapy, but its role in LGG prognostication is currently less clear than in high-grade gliomas (HGGs).³²

Median long-term survival ranges from 10 to 15 years for grade 2 OG, and 6 to 8 years for DA (although this is heavily influenced by IDH-1 mutation status, and some estimates state median survival to be as high as 10 years in the presence of an IDH-1 mutation).

11.4 Rate of Progression to High-Grade Glioma

Rates of progression to HGG are difficult to quantify, as available observational data are confounded by the effect of treatment bias (Table 11.1). However, malignant progression following treatment is heterogeneously reported and can be as high as 72% over a median follow-up of 8 years.⁹ A more recent study reported a 17% transformation rate among 486 LGG patients over a median 5-year follow-up. However, treatment modalities were variable, ranging from observation only to radiotherapy alone, chemotherapy alone (TMZ), and a combination of postoperative radiotherapy and chemotherapy. Factors associated with malignant transformation (MT) were male sex, tumor size  > 5 cm, IDH-1 negative mutation status, IDH-1 mutation positive but 1p19q noncodeleted, and TMZ therapy.¹⁰ Interestingly, few laboratory studies have correlated TMZ with increased rate of MT in LGG. This is thought to relate to hypermutation causing “selection pressure” on LGG cells, thereby enhancing the ability of more aggressive mutations to arise.¹¹ For this reason, TMZ chemotherapy in some centers is increasingly being reserved for tumors that have already undergone MT, and other chemotherapeutic agents (e.g., vincristine, nimustine, procarbazine, lomustine, or CCNU) are more favored for the treatment of “lower-risk” LGG tumors with a favorable molecular profile.^{1,​ 2} However, some centers still advocate the use of TMZ as a preferred first-line agent.¹² The role of greater extent of resection (EOR) on malignant progression-free survival (MPFS) has also been extensively studied in recent years, and found overall to be associated with delayed time to malignant progression, as well as longer progression-free survival (PFS) and overall survival (OS).^{13,​ 14,​ 16,​ 17,​ 19,​ 20,​ 21,​ 23,​ 25,​ 26}

Table 11.1 Summary of the literature on factors affecting malignant transformation in LGG ^{10,​ 13,​ 15,​ 16,​ 17,​ 18,​ 20,​ 21,​ 22,​ 23,​ 24,​ 26}

11.5 Selected Papers on the Treatment Outcomes of LGGs

●Ghaffari-Rafi A, Samandouras G. Effect of treatment modalities on progression-free survival and overall survival in molecularly subtyped WHO grade II diffuse gliomas: a systematic review. World Neurosurg 2020;133:366–380.e2

Close radiological surveillance, with 6-monthly magnetic resonance imaging (MRI) scans for the first few years, may be acceptable when a tumor is small, asymptomatic, and is located in an eloquent area. Such lesions are increasingly being discovered incidentally on neuroimaging. This management strategy is supported by some authors, and surgery is deferred until the patient experiences symptoms or has imaging findings suggestive of growth or high-grade transformation.12 In the case of a low-risk lesion (e.g., suspected tectal plate glioma) that has demonstrated radiological and clinical stability for more than a few years, an extended surveillance MRI scan interval of once every 1 to 2 years is appropriate.

11.6.2 Radical Surgical Resection

Studies published over the last several decades have demonstrated that in LGGs, significant improvements in OS, PFS, and delays in MT can be achieved with maximal safe resection (Table 1.3).^{1,​ 13,​ 14,​ 16,​ 17,​ 19,​ 20,​ 21,​ 23,​ 24,​ 25,​ 26,​ 36} In 2012, a landmark JAMA study demonstrated that maximal safe resection versus biopsy alone conferred a significant improvement in OS for LGGs.²⁶ A recent meta-analysis also demonstrated that GTR versus STR was associated with a significant survival benefit at 2, 5, and 10 years. However, the authors highlighted that the strength of this recommendation must be tempered by the low quality of the existing evidence (Fig. 11.2).¹ A large case series published in 2020 of LGGs undergoing maximal safe resection indicated significantly greater EOR for incidental tumors, which translated into significantly improved OS.³⁶ In the cases where the lesion is easily surgically accessible and noneloquent, GTR should be considered. Surgical adjuncts that are becoming standard of care to maximize safe resection include electrocorticography (ECOG) to perform asleep motor mapping or awake surgery with speech and/or motor mapping. This requires specialized anesthetic and surgical teams, the availability of which is not universal worldwide. Other important adjuncts to maximize surgical resection include intraoperative imaging such as intraoperative MRI (iMRI) or ultrasound (Table 11.3). One of the obvious disadvantages with iMRI is safety concerns, necessitating procedures that can add hours to a surgical case. In recent years, the technology surrounding navigated intraoperative ultrasound probes has advanced significantly, which circumvents any safety issues and allows real-time images via a hand-held device that is easy for the surgeon to use. It may be therefore that intraoperative ultrasound will replace intraoperative MRI as a tool to maximize EOR in the future.

Table 11.2 Summary of the literature on the relationship between EOR and survival in LGG^{10,​ 13,​ 15,​ 16,​ 17,​ 18,​ 20,​ 21,​ 22,​ 23,​ 24,​ 26}

Table 11.3 Summary of evidence-based surgical adjuncts maximizing EOR^{33,​ 34,​ 35}

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