Editor’s Note: To read another perspective on treatment of low-grade glioma, read “Counterpoint: Conservative Treatment for an Incidentally Found Supratentorial Low-grade Glioma.”

The management of patients with low-grade gliomas (LGG) continues to evolve and must be based on multiple factors. At the forefront of this decision-making process is the role of surgery as a component of the initial management strategy. The advantages of taking an aggressive approach, such as maximal resection, includes providing much-needed tissue to provide a molecular profile of the tumor, which, in turn, will allow for a more accurate prognosis. Emerging data from The Cancer Genome Atlas (TCGA) study on LGGs and from a combined University of California, San Francisco (UCSF)/Mayo SPORE analysis reveals strong prognostic relevance to the genotype of the LGG involving such markers as 1p, 19q co-deletion, IDH-1 mutation and a TERT promoter mutation. However, an accurate profile of the tumor is often not possible with just a small biopsy due to sampling errors, thus making the argument to provide more tissue to go beyond a histological diagnosis (1, 2). Since most patients present with seizures, their quality of life is often affected due to the epilepsy and the medication required to minimize the effects of the seizures. At best, seizure control with antiepileptic drugs remains less than optimal (3).

Achieving Gross Total Resection, Safely
The single most important factor in controlling seizures in patients with LGGs is gross total resection of the tumor (4, 5). Yet, the ultimate reason to resect a LGG remains its significant effect on patient outcome in terms of progression free — and overall — survival (PFS; OS). A critical reason for this positive effect of resection on outcome resides in the impact it makes on reducing the risk of malignant transformation. We know that in every case of a LGG, excluding glioneuronal tumors, such as dysembryoplastic neuroepithelial tumor (DNET), ganglioglioma, the lesion will grow and its biology is often reflected in the growth velocity (6).

Another reason to not wait and observe the lesion is the inability of any imaging modality to confirm without adequate tissue sampling that the glioma is low-grade, as up to 30 to 40 percent of non-enhancing, so-called LGGs may have anaplastic components. Three large retrospective studies on extent of resection and outcome confirm, based on volumetric assessment, that an aggressive tumor removal will significantly influence both PFS and OS. (7, 8, 9) The only prospective study performed on LGG extent of resection comes from the Norwegian comparative analysis of favoring early surgical resection versus a strategy to wait and watch (10). In this setting with the primary endpoint of OS and a mean follow-up of seven years, a huge survival advantage was seen for the resection group when adjusted for all prognostic factors. In addition, they demonstrated that there was a significant reduction in malignant transformation for those patients who were resected versus observed. This has also been demonstrated in the UCSF analysis (8).

Yet, if we are going to advocate to aggressively remove LGGs, it must be done safely. The only way to preserve function to the greatest degree possible is with intraoperative brain-mapping. Indeed, in a large meta-analysis recently published, the reduction in operative morbidity utilizing these surgical methods was 50-percent greater than in those patients who had their LGG removed without stimulation-mapping (11).

Studies Support an Aggressive Approach
So where does this leave us with incidentally discovered LGGs, which is becoming more prevalent during the age of surveillance scans and for individuals who receive an imaging study for various symptoms or signs not related to the finding of an incidental lesion? There have been two retrospective studies performed that addressed this issue, and, in both circumstances, there was a clear advantage in OS for individuals who had their gliomas resected when incidentally discovered versus patients who had the tumor removed following a symptomatic presentation referable to the lesion. (12, 13). In both studies, the volume of the tumor was smaller in the incidental versus symptomatic group, and we know that extent of resection is greater when the lesion is smaller (14, 15), thus another strong argument against “wait and see” approach.

Neurosurgeons around the world must now recognize that the advantages significantly outweigh the risks with regard to a more aggressive resection with all gliomas. We can no longer observe these tumors when they are discovered either symptomatically or incidentally. We have the tools to operate and resect gliomas safely with mapping. We are at the front line with regard to managing patients when an incidentally discovered glioma is found, and it is our responsibility to provide a maximal safe resection to that individual when presented with this occurrence.

Mitchel S. Berger, MD, FAANS, is chair of the department of neurological surgery at University of California, San Francisco (UCSF) and the Berthold and Belle N. Guggenhime Professor. A past president of the American Association of Neurological Surgeons, Dr. Berger also is the director of the Brain Tumor Research Center at UCSF. The author reported no conflicts for disclosure.

References

1. Brat DJ, Verhaak RGW, Aldape KD, et al. Comprehensive, Integrative Genomic Analysis of Diffuse Lower Grade Gliomas. Accepted: N Engl J Med.

2. Jenkins B, Rice T, Walsh K, Berger MS, et al. TERT, IDH and 1p/19q Alterations Define Five Clinically Relevant Glioma Groups. Submitted: N Engl J Med.

3. Ruda R et al. Seizures in low-grade gliomas: natural history, pathogenesis, and outcome after treatments. Neuro-Oncology 14: 55-64, 2012.

4. Englot DJ, Berger MS, Barbaro NM, Chang EF. Predictors of seizure freedom after surgical resection of supratentorial low-grade gliomas: A review. J Neurosurg 2011;115:240-244.

5. Chang EF, Keles GE, Potts MB, Lamborn KR, Chang SM, Barbaro NM, Berger MS. Seizure characteristics and control following surgical resection in 332 patients with low-grade glioma. J Neurosurg 2008;108:227-235.

6. Pallud J et al. Velocity of tumor spontaneous expansion predicts long-term outcomes for diffuse low-grade gliomas. Neuro Oncol. 2013 May; 15(5): 595–606.

7. Smith JS, Chang EF, Lamborn KR, Chang SM, Prados MD, Cha S, Tihan T, VandenBerg S, McDermott MW, Berger MS. The role of extent of resection in the long-term outcome of low-grade hemispheric gliomas. J Clinical Oncol 2008;26:1338-1345.

8. Pallud J, Audureau E, Blonski M, Sanai N, et al. Epileptic seizures in diffuse low-grade gliomas in adults. Brain. 2014 Feb;137(Pt 2):449-62.

9. Ius T, Isola M, Budai R, Pauletto G, et al: Low-grade glioma surgery in eloquent areas: volumetric analysis of extent of resection and its impact on overall survival. J Neurosurg. 2012 Dec;117(6):1039-52.

10. Jakola AS, Myrmel KS, Kloster R, Torp SH, Lindal S, Unsgård G, Solheim O. Comparison of a strategy favoring early surgical resection vs a strategy favoring watchful waiting in low-grade gliomas. JAMA. 2012 Nov 14;308(18):1881-8.

11. De Witt Hammer PC, Gil Robles S, Zwinderman AH, Duffau H, Berger MS. Impact of intraoperative stimulation brain mapping on glioma surgery outcome: a meta-analysis. J Clin Oncol 2012;30:2559-2565.

12. Potts MB, Smith JS, Molinaro AM, Berger MS. Natural history and surgical management of incidentally discovered low-grade gliomas. J Neurosurg. 2012 Feb;116(2):365-72.

13. Pallud J, Fontaine D, Duffau H, Mandonnet E, Sanai N, Taillandier L, et al.: Natural history of incidental World Health Organization grade II gliomas. Ann Neurol 68:727–733, 2010.

14. Ius T, Isola M, Budai R, Pauletto G, et al. Low-grade glioma surgery in eloquent areas: volumetric analysis of extent of resection and its impact on overall survival. A single-institution experience in 190 patients: clinical article. J Neurosurg. 2012 Dec;117(6):1039-52.

15. Snyder LA, Wolf AB, Oppenlander ME, Bina R, et al. The impact of extent of resection on malignant transformation of pure oligodendrogliomas. J Neurosurg. 2014 Feb;120(2):309-14.