Jaboin, Jerry J.

Kubicky, Charlotte D.

McClelland, Shearwood, III

Mitin, Timur

English

IUPUIScholarWorks

Journal of Radiosurgery and SBRT  Vol. 6  2019    77Jour. of Radiosurgery and SBRT, Vol. 6, pp. 77-79 © 2019 Old City Publishing, Inc.Reprints available directly from the publisher Published by license under the OCP Science imprint,Photocopying permitted by license only a member of the Old City Publishing Group.LetterLong-term stroke risk in meningioma patients treated with conventionally fractionated photon-based radiation therapyShearwood McClelland III, MD1,2, Timur Mitin, MD, PhD2, Charlotte D. Kubicky, MD, PhD2 and  Jerry J. Jaboin MD, PhD21Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN, USA2Department of Radiation Medicine, Oregon Health and Science University, Portland, OR, USACorrespondence to: Shearwood McClelland III, MD, Department of Radiation Oncology, Indiana University School of Medicine, 535 Barnhill Drive, RT 041, Indianapolis, IN 46202, USA; Email: drwood@post.harvard.edu;  Phone: +1 (503) 494-8756; Fax: +1 (503) 346-0237(Received: July 1, 2018; Accepted: September 18, 2018)Keywords: meningioma, fractionated radiotherapy, long-term stroke risk, proton-photon radiotherapy, photon radiotherapyConventionally fractionated radiotherapy (RT) has been a stalwart radiation-based treatment modality for intracranial meningioma for decades, providing excellent tumor control (1). Although the majority of patients receive conventional photon-based therapy, the physical properties of proton beam make this radiation modality very attractive, leading to a dramatic growth in the number of proton centers across the United States (2). The increasing popularity of protons over the past decade may lead to increased proton utilization in the management of benign conditions, where long-term survival is expected, such as meningioma (3). A recent randomized study of RT from the Massachu-setts General Hospital involving an 80%/20% proton/photon ratio during treatment for subtotally resected/recurrent benign meningioma patients found the risk of stroke was 20.5%, with the average stroke develop-ing 5.6 years after RT completion (4). This high rate is worrisome and puts the safety of external beam radia-tion therapy in the management of benign meningioma under question. However, before rejecting radiation therapy as a management for benign meningiomas, it is important to determine whether this high rate of stroke is also evident in patients treated with photon-based conventionally fractionated RT. This study was performed to address this void.Studies examining RT for meningioma were assessed using an extensive search of the PubMed data-base. Search terms used were “long-term”, “fraction-ated”, “radiotherapy”, and “meningioma”. To optimize stroke inclusion, only studies with mean/median clini-cal follow-up of at least six years were included in the final analysis in order to exceed the 5.6 year lag time between completion of RT and stroke development established by Sanford et al. (4). Additional inclusion criteria were: a) minimum of 30 patients, b) English language, c) exclusive RT patient population, d) exclu-sive meningioma population, e) comprehensive post-RT morbidity analysis, and f) non-duplicant patient pool. Proton therapies were excluded from the analysis. The stroke rate for each article was assessed either from being directly described in the manuscript, or from extrapolating post-RT complications from reported clinical examinations (i.e. hemiparesis/weakness, pitui-tary dysfunction following treatment of cavernous sinus lesions given the known course of the internal carotid Shearwood McClelland III et al.78    Journal of Radiosurgery and SBRT  Vol. 6  2019artery in that anatomic region) at last follow-up in order to rule out transient events. Results were then culled to determine an overall stroke rate. Six studies exam-ining RT for meningioma with long-term follow-up met inclusion criteria, providing a total of 303 patients as shown in Table 1 (5-10). Median/mean follow-up ranged from 78 to 168 months. Operative meningi-oma resection prior to fractionated RT occurred in 213 patients (70.3%). Mean total dose ranged from 45.1 Gy to 57.6 Gy; the mean dose per fraction ranged from 1.7 to 2.0 Gy (Table 1). Seventeen patients suffered a stroke following RT, for a stroke rate of 5.6% (Table 1); the vast majority of these strokes were deduced from reported clinical manifestations, most predominantly hemiparesis either caused or worsened by RT. All six studies used exclusively photons for RT. The results of our PubMed database search show a dramatically lower long-term stroke rate at 5.6% with photon-based therapy. This rate is in line with the normal expected rate of stroke for people ages 40-79 according to the American Heart Association (11). Therefore, it is possible that the high stroke rate seen in the randomized clinical trial may be related to the use of proton beam; another possibility, independent of technique, is the dose prescription in both arms of that study. Addition-ally, the Bragg peak phenomenon may have resulted in a higher radiobiological effect upon adjacent cerebral vessels thereby resulting in vascular damage. The retro-spective nature of this study and inability to determine the individual dosing, follow-up, treatment plans, and detailed clinical course (symptom onset, intervention, imaging findings, etc.) of the 17 patients who suffered post-photon RT stroke are limitations of this study. Another limitation is that the deductive approach used for identifying stroke could potentially overestimate or underestimate the true incidence of stroke follow-ing RT. Nevertheless, this information suggests that additional studies are greatly needed to determine the most effective and safe method of treating patients with benign meningiomas.In conclusion, the long-term stroke risk of RT using photons is 5.6%, in line with the expected rate of stroke development in a general population. Given that the results of Sanford et al. are based on an 80% proton-based therapy, it is pertinent to wonder whether the long-term stroke morbidity of 100% proton-based RT may be higher than their 20.5% rate. Further studies with sufficient follow-up will be required to definitively address this issue.ACKNOWLEDGEMENTSAuthors’ disclosure of potential conflicts of interestDr. Mitin receives research funding from Novocure, outside the submitted work. Other authors have nothing to disclose.Author contributionsConception and design: Shearwood McClelland III, Jerry J. JaboinData collection: Shearwood McClelland IIIData analysis and interpretation: Shearwood McClel-land III, Timur Mitin, Charlotte D. Kubicky, Jerry J. JaboinTable 1. Studies meeting inclusion criteria (minimum clinical follow-up = 72 months) for long-term stroke evaluation following fractionated radiotherapy (RT) for meningiomaReferenceNo. patientsFollow-up (months)Resection prior to RTRT as primary treatmentClinical evidence of strokeStroke incidence(%)Mean dose (Gy)Mean dose per fraction (Gy)RT modality5 61a 108 (median)61 0 7 11.5 57.5 1.7 Photon6 49 168 (median)34 15 3 6.1 45.1 2.0 Photon7 45 108 (mean)45 0 7 15.6 52.0 1.8 Photon8 38 89 (median)20 18 0 0 53.0 1.9 Photon9 57 78 (median)28 29 0 0 57.6 1.8 Photon10 53 83 (median)25 28 0 0 52.9 1.9 PhotonTotal 303 213 90 17 5.6aAssessable for late toxicity (of the 82 patients total in this study).Stroke risk in meningioma patients treated with photon-based radiation therapyJournal of Radiosurgery and SBRT  Vol. 6  2019    79Manuscript writing: Shearwood McClelland III, Timur Mitin, Jerry J. JaboinFinal approval of manuscript: Shearwood McClelland III, Timur Mitin, Charlotte D. Kubicky, Jerry J. JaboinREFERENCES1. Maire JP, Caudry M, Guérin J, et al. Fractionated radiation therapy in the treatment of intracranial meningiomas: local control, functional efficacy, and tolerance in 91 patients. Int J Radiat Oncol Biol Phys. 1995;33:315-321.2. Kerstiens J, Johnstone PA. Proton therapy expansion under current United States reimbursement models. Int J Radiat Oncol Biol Phys. 2014;89:235-240.3. Waddle MR, Sio TT, Van Houten HK, et al. Photon and proton radiation therapy utilization in a population of more than 100 million commercially insured patients. Int J Radiat Oncol Biol Phys. 2017;99:1078-1082.4. Sanford NN, Yeap BY, Larvie M, et al. Prospective, randomized study of radiation dose escalation with combined proton-photon therapy for benign meningiomas. Int J Radiat Oncol Biol Phys. 2017;99:787-796.5. Nutting C, Brada M, Brazil L, et al. Radiotherapy in the treatment of benign meningioma of the skull base. J Neurosurg. 1999;90:823-827.6. Cozzi R, Barausse M, Asnaghi D, Dallabonzana D, Lodrini S, Attanasio R. Failure of radiotherapy in acromegaly. Eur J Endocrinol. 2001;145:717-726.7. Mathiesen T, Kihlström L, Karlsson B, Lindquist C. Potential complications following radiotherapy for meningiomas. Surg Neurol. 2003;60:193-200.8. Metellus P, Regis J, Muracciole X, et al. Evaluation of fractionated radiotherapy and gamma knife radiosurgery in cavernous sinus meningiomas: treatment strategy. Neurosurgery. 2005;57:873-886.9. Milker-Zabel S, Zabel-du Bois A, Huber P, Schlegel W, Debus J. Fractionated stereotactic radiation therapy in the management of benign cavernous sinus meningiomas : long-term experience and review of the literature. Strahlenther Onkol. 2006;182:635-640.10. Metellus P, Batra S, Karkar S, et al. Fractionated conformal radiotherapy in the management of cavernous sinus meningiomas: long-term functional outcome and tumor control at a single institution. Int J Radiat Oncol Biol Phys. 2010;78:836-843.11. 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Long-term stroke risk in meningioma patients treated with conventionally fractionated photon-based radiation therapy

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Long-term stroke risk in meningioma patients treated with conventionally fractionated photon-based radiation therapy

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