Jean Régis and Constantin Tuleasca
Daniele Starnoni, Roy Thomas Daniel, Constantin Tuleasca, Mercy George, Marc Levivier, and Mahmoud Messerer
During the last decade, the primary objective for large vestibular schwannoma (VS) management has progressively shifted, from tumor excision to nerve preservation by using a combined microsurgical and radiosurgical approach. The aim of this study was to provide a systematic review and meta-analysis of the available literature regarding the combined strategy of subtotal resection (STR) followed by stereotactic radiosurgery (SRS) for large VSs.
The authors performed a systematic review and meta-analysis in compliance with the PRISMA guidelines for article identification and inclusion using the PubMed, Embase, and Cochrane databases. Established inclusion criteria were used to screen all identified relevant articles published before September 2017 without backward date limit.
The authors included 9 studies (248 patients). With a weighted mean follow-up of 46 months (range 28–68.8 months), the pooled rate of overall tumor control was 93.9% (95% CI 91.0%–96.8%). Salvage treatment (second STR and/or SRS) was necessary in only 13 (5.24%) of 18 patients who experienced initial treatment failure. According to the House-Brackmann (HB) grading scale, functional facial nerve preservation (HB grade I–II) was achieved in 96.1% of patients (95% CI 93.7%–98.5%). Serviceable hearing after the combined approach was preserved in 59.9% (95% CI 36.5%–83.2%).
A combined approach of STR followed by SRS was shown to have excellent clinical and functional outcomes while still achieving a tumor control rate comparable to that obtained with a total resection. Longer-term follow-up and larger patient cohorts are necessary to fully evaluate the rate of tumor control achieved with this approach.
Constantin Tuleasca, Iulia Peciu-Florianu, Henri-Arthur Leroy, Maximilien Vermandel, Mohamed Faouzi, and Nicolas Reyns
Arteriovenous malformations (AVMs) present no pathologic tissue, and radiation dose is confined in a clear targeted volume. The authors retrospectively evaluated the role of the biologically effective dose (BED) after Gamma Knife radiosurgery (GKRS) for brain AVMs.
A total of 149 consecutive cases of unruptured AVMs treated by upfront GKRS in Lille University Hospital, France, were included. The mean length of follow-up was 52.9 months (median 48, range 12–154 months). The primary outcome was obliteration, and the secondary outcome was complication appearance. The marginal dose was 24 Gy in a vast majority of cases (n = 115, 77.2%; range 18–25 Gy). The mean BED was 220.1 Gy2.47 (median 229.9, range 106.7–246.8 Gy2.47). The mean beam-on time was 32.3 minutes (median 30.8, range 9–138.7 minutes). In the present series, the mean radiation dose rate was 2.259 Gy/min (median 2.176, range 1.313–3.665 Gy/min). The Virginia score was 0 in 29 (19.5%), 1 in 61 (40.9%), 2 in 41 (27.5%), 3 in 18 (12.1%), and 4 in 0 (0%) patients, respectively. The mean Pollock-Flickinger score was 1.11 (median 1.52, range 0.4–2.9). Univariate (for obliteration and complication appearance) and multivariate (for obliteration only) analyses were performed.
A total of 104 AVMs (69.8%) were obliterated at the last follow-up. The strongest predictor for obliteration was BED (p = 0.03). A radiosurgical obliteration score is proposed, derived from a fitted multivariable model: (0.018 × BED) + (1.58 × V12) + (−0.013689 × beam-on time) + (0.021 × age) − 4.38. The area under the receiver operating characteristic curve was 0.7438; after internal validation using bootstrap methods, it was 0.7088. No statistically significant relationship between radiation dose rate and obliteration was found (p = 0.29). Twenty-eight (18.8%) patients developed complications after GKRS; 20 (13.4%) of these patients had transient adverse radiological effects (perilesional edema developed). Predictors for complication appearance were higher prescription isodose volume (p = 0.005) and 12-Gy isodose line volume (V12; p = 0.001), higher Pollock-Flickinger (p = 0.02) and Virginia scores (p = 0.003), and lower beam-on time (p = 0.03).
The BED was the strongest predictor of obliteration of unruptured AVMs after upfront GKRS. A radiosurgical score comprising the BED is proposed. The V12 appears as a predictor for both efficacy and toxicity. Beam-on time was illustrated as statistically significant for both obliteration and complication appearance. The radiation dose rate did not influence obliteration in the current analysis. The exact BED threshold remains to be established by further studies.
Veronica L. Chiang, Samuel T. Chao, Constantin Tuleasca, Matthew C. Foote, Cheng-chia Lee, David Mathieu, Hany Soliman, and Arjun Sahgal
In order to determine what areas of research are a clinical priority, a small group of young Gamma Knife investigators was invited to attend a workshop discussion at the 19th International Leksell Gamma Knife Society Meeting. Two areas of interest and the need for future radiosurgical research involving multiple institutions were identified by the young investigators working group: 1) the development of additional imaging sequences to guide the understanding, treatment, and outcome tracking of diseases such as tremor, radiation necrosis, and AVM; and 2) trials to clarify the role of hypofractionation versus single-fraction radiosurgery in the treatment of large lesions such as brain metastases, postoperative cavities, and meningiomas.
Constantin Tuleasca, Romain Carron, Noémie Resseguier, Anne Donnet, Philippe Roussel, Jean Gaudart, Marc Levivier, and Jean Régis
The goal of this study was to establish whether clear patterns of initial pain freedom could be identified when treating patients with classic trigeminal neuralgia (TN) by using Gamma Knife surgery (GKS). The authors compared hypesthesia and pain recurrence rates to see if statistically significant differences could be found.
Between July 1992 and November 2010, 737 patients presenting with TN underwent GKS and prospective evaluation at Timone University Hospital in Marseille, France. In this study the authors analyzed the cases of 497 of these patients, who participated in follow-up longer than 1 year, did not have megadolichobasilar artery– or multiple sclerosis–related TN, and underwent GKS only once; in other words, the focus was on cases of classic TN with a single radiosurgical treatment. Radiosurgery was performed with a Leksell Gamma Knife (model B, C, or Perfexion) using both MR and CT imaging targeting. A single 4-mm isocenter was positioned in the cisternal portion of the trigeminal nerve at a median distance of 7.8 mm (range 4.5–14 mm) anterior to the emergence of the nerve. A median maximum dose of 85 Gy (range 70–90 Gy) was delivered. Using empirical methods and assisted by a chart with clear cut-off periods of pain free distribution, the authors were able to divide patients who experienced freedom from pain into 3 separate groups: patients who became pain free within the first 48 hours post-GKS; those who became pain free between 48 hours and 30 days post-GKS; and those who became pain free more than 30 days after GKS.
The median age in the 497 patients was 68.3 years (range 28.1–93.2 years). The median follow-up period was 43.75 months (range 12–174.41 months). Four hundred fifty-four patients (91.34%) were initially pain free within a median time of 10 days (range 1–459 days) after GKS. One hundred sixty-nine patients (37.2%) became pain free within the first 48 hours (Group PF≤ 48 hours), 194 patients (42.8%) between posttreatment Day 3 and Day 30 (Group PF(>48 hours, ≤ 30 days)), and 91 patients (20%) after 30 days post-GKS (Group PF>30 days). Differences in postoperative hypesthesia were found: in Group PF≤ 48 hours 18 patients (13.7%) developed postoperative hypesthesia, compared with 30 patients (19%) in Group PF(>48 hours, ≤ 30 days) and 22 patients (30.6%) in Group PF>30 days (p = 0.014). One hundred fifty-seven patients (34.4%) who initially became free from pain experienced a recurrence of pain with a median delay of 24 months (range 0.62–150.06 months). There were no statistically significant differences between the patient groups with respect to pain recurrence: 66 patients (39%) in Group PF≤ 48 hours experienced pain recurrence, compared with 71 patients (36.6%) in Group PF(>48 hours, ≤ 30 days) and 27 patients (29.7%) in Group PF>30 days (p = 0.515).
A substantial number of patients (169 cases, 37.2%) became pain free within the first 48 hours. The rate of hypesthesia was higher in patients who became pain free more than 30 days after GKS, with a statistically significant difference between patient groups (p = 0.014).
Jean Régis, Constantin Tuleasca, Noémie Resseguier, Romain Carron, Anne Donnet, Jean Gaudart, and Marc Levivier
Gamma Knife surgery (GKS) is one of the surgical alternatives for the treatment of drug-resistant trigeminal neuralgia (TN). This study aims to evaluate the safety and efficacy of GKS in a large population of patients with TN with very long-term clinical follow-up.
Between July 1992 and November 2010, 737 patients presenting with TN were treated using GKS. Data were collected prospectively and were further retrospectively evaluated at Timone University Hospital. The frequency and severity of pain, as well as trigeminal nerve function, were evaluated before GKS and regularly thereafter. Radiosurgery using the Gamma Knife (model B, C, 4C, or Perfexion) was performed with the help of both MR and CT targeting. A single 4-mm isocenter was positioned in the cisternal portion of the trigeminal nerve at a median distance of 7.6 mm (range 4–14 mm) anterior to the emergence of the nerve (retrogasserian target). A median maximum dose of 85 Gy (range 70–90 Gy) was prescribed.
The safety and efficacy are reported for 497 patients with medically refractory classical TN who were never previously treated by GKS and had a follow-up of at least 1 year. The median age in this series was 68.3 years (range 28.1–93.2 years). The median follow-up period was 43.8 months (range 12–174.4 months). Overall, 456 patients (91.75%) were initially pain free in a median time of 10 days (range 1–180 days). Their actuarial probabilities of remaining pain free without medication at 3, 5, 7, and 10 years were 71.8%, 64.9%, 59.7%, and 45.3%, respectively. One hundred fifty-seven patients (34.4%) who were initially pain free experienced at least 1 recurrence, with a median delay of onset of 24 months (range 0.6–150.1 months). However, the actuarial rate of maintaining pain relief without further surgery was 67.8% at 10 years. The hypesthesia actuarial rate at 5 years was 20.4% and at 7 years reached 21.1%, but remained stable until 14 years with a median delay of onset of 12 months (range 1–65 months). Very bothersome facial hypesthesia was reported in only 3 patients (0.6%).
Retrogasserian GKS proved to be safe and effective in the long term and in a very large number of patients. Even if the probability of long-lasting effects may be modest compared with microvascular decompression, the rarity of complications prompts discussion of using GKS as the pragmatic surgical first- or second-intention alternative for classical TN. However, a randomized trial, or at least a case-matched control study, would be required to compare with microvascular decompression.
Constantin Tuleasca, Laura Negretti, Mohamed Faouzi, Vera Magaddino, Thierry Gevaert, Erik von Elm, and Marc Levivier
The authors present a retrospective analysis of a single-center experience with treatment of brain metastases using Gamma Knife (GK) and linear accelerator (LINAC)–based radiosurgery and compare the results.
From July 2010 to July 2012, 63 patients with brain metastases were treated with radiosurgery. Among them, 28 (with 83 lesions) were treated with a GK unit and 35 (with 47 lesions) with a LINAC. The primary outcome was local progression–free survival (LPFS), evaluated on a per-lesion basis. The secondary outcome was overall survival (OS), evaluated per patient. Statistical analysis included standard tests and Cox regression with shared-frailty models to account for the within-patient correlation.
The mean follow-up period was 11.7 months (median 7.9 months, range 1.7–32 months) for GK and 18.1 months (median 17 months, range 7.5–28.7 months) for LINAC. The median number of lesions per patient was 2.5 (range 1–9) in the GK group and 1 (range 1–3) in the LINAC group (p < 0.01, 2-sample t-test). There were more radioresistant lesions (e.g., melanoma) and more lesions located in functional areas in the GK group. Additional technical reasons for choosing GK instead of LINAC were limitations of LINAC movements, especially if lesions were located in the lower posterior fossa or multiple lesions were close to highly functional areas (e.g., the brainstem), precluding optimal dosimetry with LINAC. The median marginal dose was 24 Gy with GK and 20 Gy with LINAC (p < 0.01, 2-sample t-test). For GK, the actuarial LPFS rate at 3, 6, 9, 12, and 17 months was 96.96%, 96.96%, 96.96%, 88.1%, and 81.5%, remaining stable until 32 months. For LINAC the rate at 3, 6, 12, 17, 24, and 33 months was 91.5%, 91.5%, 91.5%, 79.9%, 55.5%, and 17.1% (log-rank p = 0.03). In the Cox regression with shared-frailty model, the risk of local progression in the LINAC group was almost twice that of the GK group (HR 1.92, p > 0.05). The mean OS was 16.0 months (95% CI 11.2–20.9 months) in the GK group, compared with 20.9 months (95% CI 16.4–25.3 months) in the LINAC group. Univariate and multivariate analysis showed that a lower graded prognostic assessment (GPA) score, noncontrolled systemic status at last radiological assessment, and older age were associated with lower OS; after adjustment of these covariables by Cox regression, the OS was similar in the 2 groups.
In this retrospective study comparing GK and LINAC-based radiosurgery for brain metastases, patients with more severe disease were treated by GK, including those harboring lesions of greater number, of radioresistant type, or in highly functional areas. The risk of local progression for the LINAC group was almost twice that in the GK group, although the difference was not statistically significant. Importantly, the OS rates were similar for the 2 groups, although GK was used in patients with more complex brain metastatic disease and with no other therapeutic alternative.
Constantin Tuleasca, Yohan Ducos, Marc Levivier, Fabrice Parker, and Nozar Aghakhani
Constantin Tuleasca, David Patin, and Marc Levivier
Constantin Tuleasca, Mercy George, Mohamed Faouzi, Luis Schiappacasse, Henri-Arthur Leroy, Michele Zeverino, Roy Thomas Daniel, Raphael Maire, and Marc Levivier
Vestibular schwannomas (VSs) represent a common indication of Gamma Knife surgery (GKS). While most studies focus on the long-term morbidity and adverse radiation effects (AREs), none describe the acute clinical AREs that might appear on a short-term basis. These types of events are investigated, and their incidence, type, and outcomes are reported in the present paper.
The included patients were treated between July 2010 and March 2016, underwent at least 6 months of follow-up, and presented with a disabling symptom during the first 6 months after GKS that affected their quality of life. The timing of appearance, as well as the type of main symptom and outcome, were noted. The prescribed dose was 12 Gy at the margin.
Thirty-five (22%) of 159 patients who fulfilled the inclusion criteria had acute clinical AREs. The mean followup period was 30 months (range 6–49.2 months). The mean time of appearance was 37.9 days (median 31 days; range 3–110 days). In patients with de novo symptoms, the more frequent symptoms were vertigo (n = 4; 11.4%) and gait disturbance (n = 3; 8.6%). The exacerbation of a preexisting symptom was more frequently related to hearing loss (n = 10; 28.6%), followed by gait disturbance (n = 7; 20%) and vertigo (n = 3, 8.6%). In the univariate logistic regression analysis, the following factors were statistically significant: age (p = 0.002; odds ratio [OR] 0.96), hearing at baseline by Gardner-Robertson (GR) class (p = 0.006; OR 0.21), pure tone average at baseline (p = 0.006; OR 0.97), and Koos grade at baseline (with Koos Grade I used as a reference) (for Koos Grade II, OR 0.17 and p = 0.002; for Koos Grade III, OR 0.42 and p = 0.05). The following were not statistically significant but showed a tendency toward significance: the number of isocenters (p = 0.06; OR 0.94) and the maximal dose received by the cochlea (p = 0.07; OR 0.74). Fractional polynomial regression analysis showed a nonlinear relationship between the outcome and the radiation dose rate (minimum reached at a cutoff of 2.5 Gy/minute) and the maximal vestibular dose (maximum reached at a cutoff of 8 Gy), but the small sample size precludes a detailed analysis of the former. The clinical acute AREs disappeared in 32 (91.4%) patients during the first 6 months after appearance. Permanent and somewhat disabling morbidity was found in 3 cases (1.9% from the whole series): 1 each with complete hearing loss (GR Class I before and V after), hemifacial spasm (persistent but alleviated), and dysgeusia.
Acute effects after radiosurgery for VS are not rare. They concern predominantly de novo vertigo and gait disturbance and the exacerbation of preexistent hearing loss. In de novo vestibular symptoms, a vestibular dose of more than 8 Gy is thought to play a role. In most cases, none of these effects are permanent, and they will ultimately improve or disappear with steroid therapy. Permanent AREs remain very rare.