Original ArticleEstablishment of a Therapeutic Ratio for Gamma Knife Radiosurgery of Trigeminal Neuralgia: The Critical Importance of Biologically Effective Dose Versus Physical Dose
Introduction
Gamma knife (GK) radiosurgery is an effective treatment of trigeminal neuralgia (TN) that has been advocated in numerous patient series, including the reporting of long- and very long-term results.1, 2, 3, 4 The results of a prospective clinical trial established the minimum effective dose for TN of 70 Gy for GK treatment.5 Recently, the International Stereotactic Radiosurgery Society review paper reported the maximum dose to be 90 Gy.2 Several other factors could also play a role in the safety and efficacy of stereotactic radiosurgery (SRS) for classic TN. The time required to deliver any given SRS treatment, using a GK, varies significantly. For example, the total treatment time of SRS for TN, which, by virtue of the use of a single isocenter, is likely to give the smallest variation possible, by a factor of ∼4. However, in cases in which multiple isocenters have been used, this can vary by a factor of up to 10.
Multiple factors can lead to this variability. Historically, the decay of the cobalt-60 sources, with a half-life of 5.26 years, has been considered a major factor. For comparable treatment plans, the beam-on time will become progressively longer with time such that, by one half-life, the beam-on time would double. However, the introduction of progressive plugging/sector blocking would have the same effect. In addition, collimator factors and individual patient geometry will also affect the beam-on time. Time gaps in treatment can be scheduled or unscheduled, although this is less likely in the case of the treatment of TN because the treatments will be most frequently given as a single continuous exposure. Thus, clearly, for a given prescription dose, the source activity, degree of beam or sector blocking, and patient geometry will be the only factors that will influence the duration of the total treatment time for TN.
The GK calibration dose rate (CDR) has recently been indicated to play a role in the safety and efficacy of SRS for TN.6,7 In addition, Lee et al.8 suggested that treatment with a CDR of >2 Gy/minute will produce earlier and more long-lasting pain relief, with a lower recurrence rate compared with treatment with a CDR of <2 Gy/minute in a series of 133 patients treated with the same prescription dose of 80 Gy.
The retrospective analysis of SRS data has frequently resulted in confounding results. For the cranial nerves, the morbidity was reported to be greater for patients treated in shorter times with new sources compared with those treated in longer times with older sources, an effect reported to be related to the CDR.9 In contrast, a multivariate analysis of the complications associated with the treatment of arteriovenous malformations found no such correlation,10 although many more treatment variables exist for patients treated for closure of arteriovenous malformations. However, it was also suggested, in the same report, that a smaller number of isocenters might increase the efficacy of a given prescription dose.10 Clearly, the use of fewer isocenters will result in fewer repositioning gaps, which, with the older models of GK, would have also greatly reduced the overall treatment time.
The CDR, a physical measurement in a standard phantom, is not the same as the dose rate in the tissue of an individual patient. This is because this “in-patient” parameter depends, not only on the activity of the sources (CDR), but also on the collimators used, the individual patient geometry, and the degree of plugging or sector blocking, which will vary for a fixed CDR. The dose rate in an individual patient, at the prescription isodose, will depend on the prescription dose and the total treatment time, both of which vary.
It has long been recognized that the biological effectiveness of a given physical radiation dose in tissue will decline as a function of increasing exposure time. This was classically illustrated by cell survival studies in which different doses were delivered at fixed dose rates.11 However, in a recent study, a range of doses were delivered over the same times.12 This more directly mimics the SRS situation where the target is irradiated simultaneously at different dose rates (e.g., the dose rate at the 50% isodose is half that at the 100% isodose) because treatment to all areas is given in a fixed time. The effect of a range of doses was shown to be progressively reduced with increasing exposure times. Thus, the doses needed to be increased to maintain the same level of effect (cell survival). Comparable effects have been seen in central nervous system (CNS) tissue.13
The importance of these two variables, treatment time and dose, can only be evaluated appropriately 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.14,15 The purpose of the present study was to evaluate whether this parameter would be of help in the evaluation of the safety and efficacy of SRS for TN. This was investigated in a large historical cohort of patients treated using the GK for classical TN. Due to the variety of radiation doses used in this cohort of cases, the use of minimal and/or extensive use of plugging or sector blocking, the effect of large variations in BED could be investigated. This was expressed in terms of three measures of safety and efficacy: pain free incidence (acutely, at 30 days), maintenance of pain relief at 1 and 2 years, and the overall incidence of hypoesthesia. The bias associated with confounding factors was also considered.
Section snippets
Study Type
A retrospective analysis has been carried out on a historical cohort of cases presenting with intractable classical TN, treated between 1997 and 2010 using GK-based SRS (Elekta Instrument AB, Stockholm, Sweden).
Patient Population
Previously, clinical parameters were carefully studied for a cohort of 497 patients with more than 1 year of follow-up.3,16,17 In order to analyze a more homogeneous cohort of TN cases, in strict relation to the radiation treatment, cases related to compression of the megadolichobasilar
Re-evaluation of Prescribed Physical Dose and Calculation of BED
The original planned physical doses prescribed for the present cohort of patients were 70 to 90 Gy. Re-evaluation of these physical doses, because of the adoption of the change in the 4 mm collimator factor, resulted in a revised dose range of 76.1 to 97.9 Gy. The number of patients treated with the different prescription doses are presented in Table 1. Relatively few patients had been were treated with a prescription dose of 75 Gy or 76.1 Gy; thus, the physical dose–effect relationships could
Discussion
The results from the re-evaluation of the physical dose in the present investigation suggest the need for caution in the interpretation of the results from other analyses of the physical dose, in particular, patients treated in the period before the 4 mm collimator factor had changed from 0.80 to 0.87.21 Studies involving the U and B GK Models might have underreported the physical dose prescribed. In the present study, the revised variation in the prescription dose was 30% (range, 75–97.9 Gy).
Conclusions
The key strength of the present study was the consideration of the major variables present in any treatment, rather than just a single variable (e.g., CDR or physical dose). The study limitations were those commonly associated with any retrospective study of this type, including the potential bias, although, as indicated, efforts were made to minimize these.
Consequently, the present results indicate that the safety and efficacy of SRS for TN might be best be achieved by prescribing a specific
Acknowledgments
Constantin Tuleasca gratefully acknowledges receipt of a Young Researcher in Clinical Research Award (Jeune Chercheur en Recherche Clinique) from the University of Lausanne, Faculty of Biology and Medicine, and the Lausanne University Hospital. The authors also thank Dr. John Lee for providing the treatment times associated with the cases included within their series to allow the BED values to be calculated and not simply estimated from the CDR data provided in their original report.8
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Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.