A management dilemma: adjuvant radiotherapy after gross total resection of atypical meningioma

Weber et al. recently published initial results of a prospective phase II trial of patients with grade II and III meningiomas treated with adjuvant radiotherapy (RT) after subtotal or gross total resection (GTR) (1). This initial publication of EORTC 22042 reports outcomes of the 56 enrolled patients with grade II meningiomas who underwent GTR followed by adjuvant RT, and shows favorable 3-year progression free survival (PFS) with moderate toxicity. Together with RTOG 0539 intermediate risk cohort (2), these two trials provide the only prospective data on outcomes of adjuvant RT for atypical meningiomas. Despite meeting the primary endpoints for both of the aforementioned trials, adjuvant RT remains controversial in the management of gross totally resected grade II meningiomas.

The short-term efficacy of radiotherapy has now been demonstrated prospectively in each of these two recent trials. Both EORTC and RTOG studies show favorable results of their primary endpoint, with 3-year PFS rates of 88.7% and 93.8%, respectively. These results are in concordance with multiple retrospective reports showing 3-year local control rates after GTR and adjuvant RT of 96% to 100% (2). The importance of locoregional control should not be underestimated, as each trial had a small number of patients with fatal local progression, 2 in EORTC and 1 in RTOG. Subsequent long term outcomes will be important to determine if control remains durable in this cohort of patients.

Although adjuvant RT has shown promising efficacy, its toxicity is not negligible based on this study, which reports a 19.6% rate of acute grade 3+ side effects, 14.3% late grade 3+ side effects, and 32.1% incidence of late grade 2 side effects. Since these results were not further characterized by the relationship to RT, the reported side effects likely overestimate the true toxicity profile. The authors estimate that 50% of serious events were likely related to RT. In contrast, RTOG 0539 did categorize toxicity based on relation to RT. 15.4% of patients experienced grade 3+ adverse effects; however, none were felt to be possibly related to RT. There were, however, a sizeable number of grade 2 toxicities, with a 25.5% rate of events considered at least possibly related to RT. Potential explanations for higher toxicity in the EORTC trial include the increased dose of 60 vs. 54 Gy and the decreased use of IMRT (53.6% compared to 84.6%). Previous studies using modern radiotherapy techniques have shown rates of grade 3 toxicity of 2–4% (3-5).

Acknowledging that adjuvant radiotherapy carries a risk of adverse effects, the side effects of additional therapy must be weighed against the risk of recurrence with observation alone. Multiple retrospective reports of observation after gross total resection have shown 3-year PFS rates of 57% to 90%, with the majority near 70%; most, but not all, have shown significant improvement with the addition of adjuvant radiotherapy, and it appears this benefit is sustained over longer periods of follow up (2,5-9). These outcomes will be prospectively confirmed by EORTC 1308 and NRG BN003, both phase III trials randomizing patients with gross totally resected grade II meningiomas to adjuvant radiotherapy versus observation (10,11).

Though recurrence rates seem convincingly lower with adjuvant RT, effective salvage therapy could obviate the need for upfront treatment. However, even for perfectly compliant patients, this approach is not without risk. Allowing for recurrence may predispose patients to future relapse, as recurrence itself has been associated with increased risk of local failure (5). The increased tumor volume of even small macroscopic recurrences may potentially decrease the efficacy of salvage RT. Long-term results of the EORTC and NRG trials will be required to adequately compare close observation and adjuvant RT. In addition to PFS, outcomes evaluating toxicity, neurocognitive function, and quality of life will help guide future decision making.

To better select patients for observation versus adjuvant radiotherapy, additional histopathologic and genetic factors may be useful in risk stratifying patients. Bone and brain invasion, Ki-67 proliferation rate, and TERT promoter mutations have all been independently associated with increased risk of disease recurrence (12-14). In addition to risk stratification, specific mutations may prove to be actionable targets for systemic therapies; targeted therapies against AKT, SMO, NF2, BAP1, mTOR, and PD-1 are currently under investigation (15-17). Targeted systemic therapies will be particularly important for grade II and III meningiomas, which are more likely to recur despite aggressive treatment and exhaust all focal therapeutic options.

Management of gross totally resected atypical meningioma remains a controversial and important area of research. Two recent prospective trials have shown favorable short term control with moderate toxicity after adjuvant radiotherapy. We await long term outcomes of these studies as well as the results of the randomized trials NRG BN003 and EORTC 0138 to fully ascertain the benefit of adjuvant radiotherapy versus observation. Additional histopathologic and genetic factors are likely to further influence patient selection in the foreseeable future. Targeted therapies may eventually prove to be another therapeutic option for refractory disease.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned and reviewed by the Section Editor Xian-Xin Qiu (Shanghai Proton and Heavy Ion Center (SPHIC), a.k.a. the Proton and Heavy Ion Center of Fudan University Shanghai Cancer Center (FUSCC), Shanghai, China).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2018.10.07). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Weber DC, Ares C, Villa S, et al. Adjuvant postoperative high-dose radiotherapy for atypical and malignant meningioma: A phase-II parallel non-randomized and observation study (EORTC 22042-26042). Radiother Oncol 2018;128:260-5. [Crossref] [PubMed]
2. Rogers L, Zhang P, Vogelbaum MA, et al. Intermediate-risk meningioma: initial outcomes from NRG Oncology RTOG 0539. J Neurosurg 2018;129:35-47. [Crossref] [PubMed]
3. Debus J, Wuendrich M, Pirzkall A, et al. High efficacy of fractionated stereotactic radiotherapy of large base-of-skull meningiomas: long-term results. J Clin Oncol 2001;19:3547-53. [Crossref] [PubMed]
4. Goldsmith BJ, Wara WM, Wilson CB, et al. Postoperative irradiation for subtotally resected meningiomas. A retrospective analysis of 140 patients treated from 1967 to 1990. J Neurosurg 1994;80:195-201. [Crossref] [PubMed]
5. Rogers L, Mehta M. Role of radiation therapy in treating intracranial meningiomas. Neurosurg Focus 2007;23:E4. [Crossref] [PubMed]
6. Aghi MK, Carter BS, Cosgrove GR, et al. Long-term recurrence rates of atypical meningiomas after gross total resection with or without postoperative adjuvant radiation. Neurosurgery 2009;64:56-60; discussion 60. [Crossref] [PubMed]
7. Komotar RJ, Iorgulescu JB, Raper DM, et al. The role of radiotherapy following gross-total resection of atypical meningiomas. J Neurosurg 2012;117:679-86. [Crossref] [PubMed]
8. Park HJ, Kang HC, Kim IH, et al. The role of adjuvant radiotherapy in atypical meningioma. J Neurooncol 2013;115:241-7. [Crossref] [PubMed]
9. Goyal LK, Suh JH, Mohan DS, et al. Local control and overall survival in atypical meningioma: A retrospective study. Int J Radiat Oncol Biol Phys 2000;46:57-61. [Crossref] [PubMed]
10. Observation or Radiation Therapy in Treating Patients With Newly Diagnosed Grade II Meningioma That Has Been Completely Removed by Surgery2018. Available online: https://clinicaltrials.gov/ct2/show/NCT03180268
11. Jenkinson MD, Javadpour M, Haylock BJ, et al. The ROAM/EORTC-1308 trial: Radiation versus Observation following surgical resection of Atypical Meningioma: study protocol for a randomised controlled trial. Trials 2015;16:519. [Crossref] [PubMed]
12. Kim D, Niemierko A, Hwang WL, et al. Histopathological prognostic factors of recurrence following definitive therapy for atypical and malignant meningiomas. J Neurosurg 2018;128:1123-32. [Crossref] [PubMed]
13. Sahm F, Schrimpf D, Olar A, et al. TERT Promoter Mutations and Risk of Recurrence in Meningioma. J Natl Cancer Inst 2015;108:djv377. [Crossref] [PubMed]
14. Yuzawa S, Nishihara H, Tanaka S. Genetic landscape of meningioma. Brain Tumor Pathol 2016;33:237-47. [Crossref] [PubMed]
15. Vismodegib and FAK Inhibitor GSK2256098 in Treating Patients With Progressive Meningiomas. Available online: https://clinicaltrials.gov/ct2/show/NCT02523014
16. Gupta S, Bi WL, Dunn IF. Medical management of meningioma in the era of precision medicine. Neurosurg Focus 2018;44:E3. [Crossref] [PubMed]
17. Preusser M, Brastianos PK, Mawrin C. Advances in meningioma genetics: novel therapeutic opportunities. Nat Rev Neurol 2018;14:106-15. [Crossref] [PubMed]