Update: Low grade glioma treatment

Choosing the best treatment strategy for each patient with a diffuse low grade glioma, in other words optimizing the oncologic and functional balance, implies not only a full knowledge of the natural history of this chronic disease, but also an understanding of the adaptation of the brain in response to growth and spread of the glioma1).

The ideal management of suspected low-grade gliomas (LGGs) has historically been controversial in neurosurgery and neurooncology 2) 3) 4).

The management of low-grade glioma (LGG) still remains controversial because the effectiveness of early and extensive resection is unclear, and the use of radiation therapy or chemotherapy is not well-defined.

Surgery

Despite the lack of randomized controlled trials hampering the performance of appropriate metaanalysis, the increasing amount of evidence pointed toward an aggressive surgical strategy.

Although a large amount of data supports resection for symptomatic diffuse low-grade glioma (LGG), the therapeutic strategy regarding incidental LGG (ILGG) is still a matter of debate. Indeed, early “preventive” surgery has recently been proposed in asymptomatic patients with LGG, after showing that the extent of resection was larger than in symptomatic patients with LGG. However, the quality of life should be preserved by avoiding both neurological deficit and epilepsy 5).

The largest study in patients with low-grade gliomas, performed by Capelle et al. 6) , showed a strong impact of the extent of resection EOR on survival, especially when a radiological complete resection was obtained.

Although non-controlled series have a potential selection bias, similar results were found in a study with an unusual geographic and medical constellation that essentially eliminated the selection bias: two hospitals in Norway, each taking exclusive care of a large, stable population, followed different strategies for patients with low-grade glioma. One of the hospitals favoured a biopsy followed by a “wait-and-see” strategy, delaying further therapy until malignant progression while the other hospital preferred to perform maximal safe resection whenever possible. Outcome comparison between the two hospitals revealed that patients of the surgery-preferring hospital had a significantly better survival rate, suggesting that a proactive and aggressive treatment plan improves survival of low-grade glioma patients. Moreover, the rate of malignant transformation was twice as high in the “wait-and-see” cohort. Taken together, these findings support a proactive and radical surgical approach for low-grade gliomas rather than a “wait-and-see” strategy 7).

This surgery has to be performed with the appropriate armamentarium, which is the availability of intraoperative stimulation mapping, especially for those lesions occurring in cortical and subcortical eloquent sites.

According to the recently published guidelines, surgical treatment has been increasingly recognized as the initial therapeutic act of choice for patients diagnosed with a presumed low grade glioma, given that total resection can improve seizure control, progression free survival and overall survival, while reducing the risk of malignant transformation and preserving patients’ functional status 8).


Treatment options include observation, surgery, radiation, chemotherapy, or a combined approach, and management is individualized based on tumor location, histology, molecular profile, and patient characteristics. Moreover, in this type of brain tumor with a relatively good prognosis and prolonged survival, the potential benefits of treatment must be carefully weighed against potential treatment-related risks 9).

Patients with clinically and radiographically suspected LGG have two initial surgical options, biopsy or resection. Biopsy can provide a histological diagnosis with minimal risk but does not offer a direct treatment. Resection may have additional benefits such as increasing survival and delaying recurrence, but is associated with a higher risk for surgical morbidity. There remains controversy about the role of biopsy versus resection and the relative clinical outcomes for the management of LGG.

Evidence suggests that a greater extent of resection (EOR) extends malignant progression-free survival among patients with low-grade gliomas (LGGs). These studies, however, rely on the combined analysis of oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas-3 histological subtypes with distinct genetic and molecular compositions 10).

The following electronic databases were searched in 2012 for the first version of the review: Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 11), MEDLINE (1950 to November week 3 2012), Embase (1980 to Week 46 2012). For this updated version, the following electronic databases were searched: Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 5), MEDLINE (Nov 2012 to June week 3 2016), Embase (Nov 2012 to 2016 week 26). All relevant articles were identified on PubMed and by using the ‘related articles’ feature.

Jiang et al. also searched unpublished and grey literature including ISRCTN-metaRegister of Controled Trials, Physicians Data Query and ClinicalTrials.gov for ongoing trials.

Jiang et al. planned to include patients of any age with a suspected intracranial LGG receiving biopsy or resection within a randomized clinical trial (RCT) or controlled clinical trial (CCT). Patients with prior resections, radiation therapy, or chemotherapy for LGG were excluded. Outcome measures included overall survival (OS), progression-free survival (PFS), functionally independent survival (FIS), adverse events, symptom control, and quality of life (QoL).

A total of 1375 updated citations were searched and critically analyzed for relevance. This was undertaken independently by two review authors. The original electronic database searches yielded a total of 2764 citations. In total, 4139 citations have been critically analyzed for this updated review.

No new RCTs of biopsy or resection for LGG were identified. No additional ineligible non-randomized studies (NRS) were included in this updated review. Twenty other ineligible studies were previously retrieved for further analysis despite not meeting the pre-specified criteria. Ten studies were retrospective or were literature reviews. Three studies were prospective, however they were limited to tumor recurrence and volumetric analysis and extent of resection. One study was a population-based parallel cohort in Norway, but not an RCT. Four studies were RCTs, however patients were randomized with respect to varying radiotherapy regimens to assess timing and dose of radiation. One RCT was on high-grade gliomas (HGGs) and not LGG. Finally, one RCT evaluated diffusion tensor imaging (DTI)-based neuro-navigation for surgical resection.

Since the last version of this review, no new studies have been identified for inclusion and currently there are no RCTs or CCTs available on which to base definitive clinical decisions. Therefore, physicians must approach each case individually and weigh the risks and benefits of each intervention until further evidence is available. Some retrospective studies and non-randomized prospective studies do seem to suggest improved OS and seizure control correlating to higher extent of resection. Future research could focus on RCTs to determine outcomes benefits for biopsy versus resection 11).


Based on results of three randomized clinical trials (RCT), radiotherapy (RT) may be deferred in patients with low risk low grade glioma (defined as age <40 years and having undergone a complete resection), although combined chemoradiotherapy has never been prospectively evaluated in the low-risk population. The recent RTOG 9802 RCT established a new standard of care in high-risk patients (defined as age >40 years or incomplete resection) by demonstrating a nearly twofold improvement in overall survival with the addition of PCV (procarbazine, CCNU, vincristine) chemotherapy following RT as compared to RT alone. Chemotherapy alone as a treatment of LGG may result in less toxicity than RT; however, this has only been prospectively studied once (EORTC 22033) in high-risk patients. A challenge remains to define when an aggressive treatment improves survival without impacting quality of life (QoL) or neurocognitive function and when an effective treatment can be delayed in order to preserve QoL without impacting survival. Current WHO histopathological classification is poorly predictive of outcome in patients with LGG. The integration of molecular biomarkers with histology will lead to an improved classification that more accurately reflects underlying tumor biology, prognosis, and hopefully best therapy 12).

Chemotherapy

Radiotherapy

Radiation therapy has been proven effective in increasing time to progression in LGG, and emerging data support a role for combined modality therapy incorporating chemotherapy.

Postoperative Radiotherapy

Early radiation therapy was associated with the following adverse effects: skin reactions, otitis media, mild headache, nausea, and vomiting. People with LGG who undergo early radiotherapy showed an increase in time to progression compared with people who were observed and had radiotherapy at the time of progression. There was no significant difference in overall survival between people who had early versus delayed radiotherapy; however, this finding may be due to the effectiveness of rescue therapy with radiation in the control arm. People who underwent early radiation had better seizure control at one year than people who underwent delayed radiation. There were no cases of radiation-induced malignant transformation of LGG. However, it remains unclear whether there are differences in memory, executive function, cognitive function, or quality of life between the two groups since these measures were not evaluated 13).

1)

Duffau H. Diffuse low-grade gliomas and neuroplasticity. Diagn Interv Imaging. 2014 Sep 10. pii: S2211-5684(14)00220-4. doi: 10.1016/j.diii.2014.08.001. [Epub ahead of print] PubMed PMID: 25218490.
2)

Keles GE, Lamborn KR, Berger MS: Low-grade hemispheric gliomas in adults: a critical review of extent of resection as a factor influencing outcome. J Neurosurg 95:735–745, 2001
3)

Lang FF, Gilbert MR: Diffusely infiltrative low-grade gliomas in adults. J Clin Oncol 24:1236–1245, 2006
4)

Wessels PH, Weber WE, Raven G, Ramaekers FC, Hopman AH, Twijnstra A: Supratentorial grade II astrocytoma: biological features and clinical course. Lancet Neurol 2:395–403, 2003
5)

de Oliveira Lima GL, Duffau H. Is there a risk of seizures in “preventive” awake surgery for incidental diffuse low-grade gliomas? J Neurosurg. 2015 Jun;122(6):1397-405. doi: 10.3171/2014.9.JNS141396. Epub 2015 Feb 27. PubMed PMID: 25723301.
6)

Capelle L, Fontaine, D, Mandonnet E, Taillandier L, Golmard JL, Bauchet L, et al. Spontaneous and therapeutic prognostic factors in adult hemispheric World Health Organization Grade II gliomas: a series of 1097 cases. J Neurosurg. 2013;118(6):1157–68.
7)

Jakola A, Mymel KS, Kloster R, Torp SH, Lindal S, Unsgard G. Comparison of a strategy favoring early surgical resection vs a strategy favoring watchful waiting in low-grade gliomas. JAMA. 2012;308(18):1881–8.
8)

Riva M, Bello L. Low-grade glioma management: a contemporary surgical approach. Curr Opin Oncol. 2014 Nov;26(6):615-21. doi: 10.1097/CCO.0000000000000120. PubMed PMID: 25279963.
9)

Forst DA, Nahed BV, Loeffler JS, Batchelor TT. Low-Grade Gliomas. Oncologist. 2014 Mar 24. [Epub ahead of print] PubMed PMID: 24664484.
10)

Snyder LA, Wolf AB, Oppenlander ME, Bina R, Wilson JR, Ashby L, Brachman D, Coons SW, Spetzler RF, Sanai N. The impact of extent of resection on malignant transformation of pure oligodendrogliomas. J Neurosurg. 2014 Feb;120(2):309-14. doi: 10.3171/2013.10.JNS13368. Epub 2013 Dec 6. PubMed PMID: 24313617.
11)

Jiang B, Chaichana K, Veeravagu A, Chang SD, Black KL, Patil CG. Biopsy versus resection for the management of low-grade gliomas. Cochrane Database Syst Rev. 2017 Apr 27;4:CD009319. doi: 10.1002/14651858.CD009319.pub3. [Epub ahead of print] Review. PubMed PMID: 28447767.
12)

Le Rhun E, Taillibert S, Chamberlain MC. Current Management of Adult Diffuse Infiltrative Low Grade Gliomas. Curr Neurol Neurosci Rep. 2016 Feb;16(2):15. doi: 10.1007/s11910-015-0615-4. PubMed PMID: 26750130.
13)

Sarmiento JM, Venteicher AS, Patil CG. Early versus delayed postoperative radiotherapy for treatment of low-grade gliomas. Cochrane Database Syst Rev. 2015 Jun 29;6:CD009229. doi: 10.1002/14651858.CD009229.pub2. PubMed PMID: 26118544; PubMed Central PMCID: PMC4506130.

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