The Rationale for Early Adjuvant Radiotherapy After Gross Total Resection of Atypical Meningioma

Whether to treat World Health Organization (WHO) grade 2 atypical meningiomas with early adjuvant radiotherapy after gross total resection (GTR) or to observe closely and salvage with surgery or radiotherapy at the time of recurrence is an enduring controversy. Two randomized phase 3 clinical trials (NRG-BN003 and European Organization for Research and Treatment of Cancer (EORTC) 1308/Radiation versus Observation following Surgical Resection of Atypical Meningioma (ROAM)) have been launched to address this specific controversy.1 Completion of these prospective clinical trials, maturation and analysis of their data, and retrospective incorporation of molecular biomarkers that predict meningioma outcomes and radiotherapy responses will require several more years, and in the meantime, the controversy persists.2 We need to make decisions for patients who face this dilemma in real time. A practical near-term but short-duration solution, and one that recognizes the equipoise inherent to the treatment of atypical meningiomas after GTR, is to encourage enrollment on NRG-BN003 itself. EORTC 1308/ROAM has completed accrual and is expected to read out at the end of 2026, and NRG-BN003 has nearly completed accrual. Nevertheless, patients and providers often find randomization between observation and radiotherapy discomforting and instead look to individualize their decisions based on retrospective data, despite the lack of causal inference that can be drawn. Multiple retrospective studies show approximately 50% long-term recurrence after GTR alone for atypical meningioma, even after Simpson grade 1 resection.3-6 These observations have led some to take their chances with a proverbial “flip of a coin”, fueled, in-part, by poorly evidenced speculation that early adjuvant radiotherapy can be safely omitted in favor of salvage radiotherapy or salvage re-resection without compromising clinical outcomes. On the other hand, the rationale in support of early adjuvant radiotherapy for atypical meningioma after GTR is based on data showing (1) that salvage re-resection can be associated with significant toxicity,7,8 (2) that recurrent atypical meningiomas acquire aggressive genomic and molecular alterations that underlie poor clinical outcomes,9,10 and (3) that patients with recurrent atypical meningiomas rarely achieve durable tumor control after salvage treatments, and often end up in a continuous downward spiral of recurrences, reinterventions, and decline in quality of life, performance status, and neurological function.11-16 Five retrospective series reporting a total of 1118 patients with lengthy clinical follow-up (median 53 months-25 years) suggest that there are few (maybe no) long-term survivors after recurrence of atypical meningioma.11-15 One of these series with 25 years of follow-up reported a mean overall survival of 6 years from recurrent atypical meningioma despite salvage treatment,14 an overall survival that is similar to unfavorable astrocytoma.17 The NRG/Radiation Therapy Oncology Group (RTOG)-0539 phase 2 clinical trial identified a key observation underscoring the dismal prognosis of patients with recurrent atypical meningioma. Specifically, for initially unirradiated atypical meningiomas enrolled on the trial that were irradiated at recurrence, the 5-year progression of 70.0% was considerably worse than the 30% rate observed among patients with newly diagnosed WHO grade 3 anaplastic meningiomas who were treated with early adjuvant radiotherapy on NRG/RTOG 0539.16 This large difference indicates that the natural history of atypical meningiomas at recurrence is characterized by significant acceleration of biological aggressivity and therapeutic resistance, suggesting that waiting for recurrence could mean waiting for a far worse disease to emerge. The same prospective study also showed greater local control with adjuvant radiotherapy for atypical meningioma after GTR than with observation for WHO grade 1 meningioma after subtotal resection, underscoring the therapeutic efficacy of radiotherapy before the tumor-acquiring biological aggressivity, a hand-in-glove phenomenon that tracks with recurrence.18,19 Thus, the available retrospective and prospective clinical data demonstrate that recurrent atypical meningiomas are biologically more aggressive and resistant to salvage therapies than newly diagnosed atypical meningiomas, putatively implying that the concept of “wait-and-watch with salvage at relapse” may create a scenario where the success of salvage therapy is limited. Hence, it is reasonable to propose that early adjuvant radiotherapy should be considered as nonequivalent to salvage radiotherapy, as radiotherapy can improve long-term clinical outcomes if used expeditiously at initial diagnosis, but not at relapse. In support of this hypothesis, a meta-analysis found that patients who receive early adjuvant radiotherapy after GTR of atypical meningioma have superior local control compared with observation.20 With these data in mind, both European Association of Neuro-Oncology (EANO) and National Comprehensive Cancer Network (NCCN) guidelines recommend consideration of adjuvant radiotherapy for atypical meningioma after GTR,21,22 but in practice, the decision to offer this treatment can be influenced by a variety of histological, molecular, or imaging features that have not been tested in clinical trials. Adjuvant radiotherapy may be more applicable for an atypical meningioma with 18 mitoses per 10 high-powered fields,23 hypermitotic or proliferative DNA methylation profile,24-26 high gene expression risk score,27,28 or abundant copy number alterations.29,30 Conversely, postoperative observation may be more applicable for an atypical meningioma with Simpson grade 1 resection that is brain invasive but has otherwise benign histology,2 Ki-67 labeling index of 7% or less,31 Merlin-intact or immune-enriched DNA methylation profile, low gene expression risk score, few or no copy number alterations, short somatic variant that is associated with favorable clinical outcomes,32 or negative DOTATATE PET imaging study.33-36 Somatostatin receptor–based imaging such as DOTATATE positron emission tomography (PET) has emerged as a useful tool for assessing extent of resection and has other potential benefits such as differentiating tumor-related dural enhancement from reactive “dural tail” enhancement. DOTATATE PET imaging is therefore being incorporated into radiotherapy planning and response assessment for meningioma in real time,37-40 but this emerging imaging modality has not been broadly applied in clinical practice for patients with meningiomas and is untested in clinical trials. Thus, evolving understanding of histological, molecular, and imaging features underlying meningioma outcomes needs to be balanced against retrospective and prospective clinical data suggesting that recurrent atypical meningiomas may be incurable with current treatments,11-16 likely due to evolution of genomic and molecular features that are supported by analyses of patient-matched newly diagnosed and recurrent tumor samples.9,10 We propose that these factors are best balanced within a multidisciplinary care team including neurological surgeons, radiation oncologists, neuro-oncologists, neuropathologists, neuroradiologists, advanced practice providers, and clinical research coordinators. Considering all these nuances, tumor board review should be considered for all patients with atypical meningioma after GTR. Equally nuanced is the topic of the optimal adjuvant radiotherapy modality for atypical meningioma after GTR. Single-fraction radiosurgery may, for many reasons, at first glance seem preferable but that may not in fact be the case after more detailed analyses.41,42 Most neurosurgeons who are involved in the care of patients with meningioma need to remember that radiosurgery is not the only form of radiotherapy for these tumors and that radiosurgery may undertreat the volume at risk. This volume includes the dural attachment of the original tumor, which may not have been surgically excised, plus a margin to account for microscopic spread. The available clinical data, which are admittedly limited to retrospective series, show that radiosurgery is an excellent option for imaging-defined and WHO grade 1 meningiomas,43-45 but single-fraction radiosurgery seems suboptimal for atypical and anaplastic meningiomas because of higher risks of in-field and marginal recurrences.46-54 One series found 2-year in-field control of 50% and 5- to 6-year intracranial control of only 30%,46 whereas another reported 3-year progression-free survival of 23% after single-fraction radiosurgery for atypical meningioma.47 These data imply that beyond the need for local control, which single-fraction radiosurgery may be able to provide for atypical meningioma, marginal and regional control, which single-fraction radiosurgery cannot achieve, is also necessary. Indeed, single-fraction radiosurgery for atypical meningioma after GTR does not seem to have the same benefits as conventionally fractionated radiotherapy,48 likely due to higher rates of marginal recurrence because of smaller target margins with single-fraction treatment. This hypothesis is being tested as a secondary objective in the pilot Adjuvant Hypofractionated Stereotactic Radiosurgery for Intermediate-risk Meningioma clinical trial (SRS-AIM) study of adjuvant 5-fraction radiosurgery for intermediate-risk meningiomas, which includes atypical meningiomas after GTR, where anisotropic dural radiosurgery margins up to 1.5 cm are being added, as is performed with conventionally fractionated treatments, so long as dose constraints can be met (NCT06557512). Establishing the efficacy of this therapeutic strategy will likely require larger clinical trials in the future. Phase 2 studies of 5-fraction adjuvant radiotherapy without a dural margin for recurrent or residual atypical meningiomas,55 or large WHO grade 1 meningiomas,56 show no Grade 3 or higher toxicity at a median follow-up of 28 months and reveal any toxicity in only 11.7% of patients with 5-year minimum follow-up, respectively. These studies demonstrate 5-year in-field control of 97% for large WHO grade 1 meningiomas56 and 3-year in-field control of 86% for recurrent or residual atypical meningiomas.55 However, when considering both in-field and marginal recurrences, the 3-year progression-free survival for recurrent or residual atypical meningiomas was only 47% after 5-fraction adjuvant radiosurgery without a dural margin.55 These retrospective and prospective clinical data suggest that if adjuvant radiotherapy (or fractionated radiosurgery) is used for atypical meningioma after GTR, an appropriate dural margin expansion may need to be added, with care, to the target volume. Thus, in cases where the dura cannot be excised and only coagulated, there may be an increased risk of recurrence if the entire volume (including original dural attachments) is not treated with radiotherapy, irrespective of whether a target of residual tumor is present. It should also be mentioned that there is no prospective randomized data to support the use of a radiosurgery boost after conventionally fractionated radiotherapy for meningioma, and although such strategies are being investigated for gross residual high-risk meningiomas, there may be associated adverse side effects that need to be evaluated on a patient-by-patient basis.57-59 Owing to the important clinical and biological data articulated here, we currently favor consideration of early adjuvant radiotherapy after GTR of atypical meningioma outside of the context of a clinical trial. Off protocol, radiotherapy doses from 54 to 59.4 Gy in 30 to 33 fractions, targeted to the resection cavity plus a 1.5-cm dural margin (and perhaps a 3 mm intraparenchymal margin for brain-invasive meningiomas60) are reasonable per the completed NRG/RTOG-0539 clinical trial and the nearly completed NRG-BN003 clinical trial. These recommendations may require modification once the NRG-BN003, EORTC 1308/ROAM, and SRS-AIM clinical trials are complete, and some institutions or providers may still follow a risk-adapted approach until results from these clinical trials are available, particular regarding balancing the anticipated benefits of early adjuvant radiotherapy with the anticipated toxicities of treatment. These recommendations may also require modification if molecular biomarkers that predict clinical outcomes in retrospective research samples or post hoc clinical trial samples are tested in prospective studies or using samples from NRG-BN003, EORTC 1308/ROAM, or SRS-AIM.2 Moreover, evolving medical therapies (such as rational small molecules, radionuclides, and emerging biologics), which are being tested for recurrent meningiomas in single-institution and cooperative group clinical trials,61 could dramatically change the landscape of treatment options for patients. We do not yet know if such therapies could be used in sequence with radiotherapy (or surgery) for atypical meningioma after GTR, or meningiomas more broadly, and we encourage caution and treatment on protocol for all experimental treatments.