To the Editor:
We have read with great interest the recent article by Smith et al,1 discussing treatment outcomes and potential radiation dose rate (RDR) effects following single fraction stereotactic radiosurgery (SRS) by Gamma Knife (GK) for vestibular schwannomas (VSs). The serviceable hearing preservation rate was 72.2% among cases with baseline Gardner–Roberston class I/II hearing and post-treatment audiological evaluations. The authors conclude that GKRS provided effective tumor control independently of RDR. However, patients with lower dose rates (<2.675 Gy/min) experienced significantly better freedom from post-treatment hearing loss and facial nerve dysfunction.
There are several aspects, which caught our attention and would deserve further explanation.
First, this is a second study1 discussing the potentially important aspect of the RDR in hearing preservation after single fraction SRS for VSs, after a previous analysis of its influence on immediate acute and subacute effects (during the first 6 mo after SRS) by the team in Lausanne.2 Indeed, while the former focused on short-term impact2 of the RDR, here the authors concentrate on long-term effects, providing an important and very noteworthy and detailed analysis.1 Interestingly, Smith et al1 provide a cut-off of less than < 2.675 Gy/min for better long-term hearing preservation. This value is quite similar to what the team in Lausanne suggested for the appearance of acute and subacute clinical adverse radiation events (ARE) after GK, with a cut-off of 2.5 Gy/min. In fact, there was a tendency for such outcomes to appear during the first 6 mo after SRS for a continuing increase of RDR after 2.5 Gy/min. Importantly, these ARE were transient in vast majority of cases.2
Secondly and most important, as an historical aspect, RDR has been initially studied for functional disorders, in particular in trigeminal neuralgia (TN).3,4 However, it should be further underlined that beam on time (ie, GK treatment time) might be more relevant than RDR. The authors actually state in the introduction section that RDR describes the rate of radiation dose delivery, as defined as the amount of radiation absorbed by tissues per unit time. Moreover, it is now generally recognized that the time engaged to deliver a given SRS treatment dose using the GK varies meaningfully. For a single isocenter, like in the case of TN, treatment time nevertheless varies by a factor of 4. For the case of VSs, meningiomas etc, using multiple isocenters, this may vary up by a factor of 10. The decay of the Cobalt-60 sources, with a half-life of 5.26 yr, contribute to this as a major aspect. The RDR at the prescription isodose in an individual patient depends on the prescription dose and the treatment time, both of which vary. Hence, the importance of further incorporating both of them (ie prescribed dose and treatment time) using the concept of biologically effective dose (BED), where the impact of the changes in treatment time can be taken into account for the different doses prescribed.5 This methodology was initially proposed by Millar and Canney (1993)6,7 and its application to GK was first described by Hopewell et al (2012).8 This approach is much complicated in multi-isocentric plans, as compared to mono-isocentric ones, like in TN. The actual effects of BED in the context of the GK are largely undiscovered. In any case, BED has a direct relationship with beam on time, while the RDR does not.
We do believe that BED and not RDR will be the key toward a better understanding of GK effects and its treatment outcomes. Most probably, by modulating this parameter, we will achieve better outcomes in the near future. This Pandora box has been opened at the International Stereotactic Radiosurgery Society Congress in Monteux in 2017, when some preliminary data revealed a major BED impact (stronger than the prescription dose) on TN outcomes (especially toxicity and long-term efficacy).9 In our opinion, it will continue to increase our understanding during the next decades and will provide us with an improved care for our patients.
We congratulate the authors for a very nice study. We consider that an outcome analysis would need to include, in the future, a direct evaluation of the BED effects in single fraction GK on VS, further to be expanded on other pathologies. We believe that modern SRS would relate to a desired radiobiological effect, in which BED is going to play a key role. In this context, it will ultimately become a core parameter incorporated in the treatment planning, allowing for better efficacy, while decreasing toxicity.
Dr Tuleasca gratefully acknowledges receipt of a “Young Researcher in Clinical Research Grant” (Jeune Chercheur en Recherche Clinique) from the University of Lausanne (UNIL), Faculty of Biology and Medicine (FBM) and the Lausanne University Hospital (CHUV). The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.
1. Smith DR, Saadatmand HJ, Wu CC, et al. Treatment outcomes and dose rate effects following gamma knife stereotactic radiosurgery for vestibular schwannomas. Neurosurgery. 2019;85(6):E1084-E1094.
2. Tuleasca C, George M, Faouzi M, et al. Acute clinical adverse radiation effects after Gamma Knife surgery for vestibular schwannomas. J Neurosurg. 2016;125(Suppl 1):73-82.
3. Arai Y, Kano H, Lunsford LD, et al. Does the Gamma Knife dose rate affect outcomes in radiosurgery for trigeminal neuralgia? J Neurosurg. 2010;113(Suppl):168-171.
4. Lee JY, Sandhu S, Miller D, Solberg T, Dorsey JF, Alonso-Basanta M. Higher dose rate Gamma Knife radiosurgery may provide earlier and longer-lasting pain relief for patients with trigeminal neuralgia. J Neurosurg. 2015;123(4):961-968.
5. Hopewell JW, Millar WT, Lindquist C, Nordstrom H, Lidberg P, Garding J. Application of the concept of biologically effective dose (BED) to patients with vestibular schwannomas treated by radiosurgery. J Radiosurg SBRT. 2013;2(4):257-271.
6. Millar WT, Canney PA. Derivation and application of equations describing the effects of fractionated protracted irradiation, based on multiple and incomplete repair processes. Part 2. Analysis of mouse lung data. Int J Radiat Biol. 1993;64(3):293-303.
7. Millar WT, Canney PA. Derivation and application of equations describing the effects of fractionated protracted irradiation, based on multiple and incomplete repair processes. Part I. Derivation of equations. Int J Radiat Biol. 1993;64(3):275-291.
8. Hopewell JW, Millar WT, Lindquist C. Radiobiological principles: their application to gamma knife therapy. Prog Neurol Surg. 2012;25:39-54.
9. Tuleasca C, Paddick I, Hopewell JW, et al. Establishment of a therapeutic ratio for Gamma Knife Radiosurgery of trigeminal neuralgia: The critical importance of biologically effective dose (BED) versus physical dose. World Neurosurg. 2019;S1878-8750(19)32636-1 (doi:10.1016/j.wneu.2019.10.021).