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Shinji Matsuda, Toru Serizawa, Osamu Nagano and Junichi Ono

Object

Gamma Knife surgery (GKS) is an effective treatment for intractable trigeminal neuralgia (TN). The authors compared results using two major GKS target points, the dorsal root entry zone and the retrogasserian portion, in a series of patients with intractable TN.

Methods

One hundred patients with medically refractory TN underwent GKS between August 1998 and December 2007. Thirty-seven were men, and 63 were women. The median age at GKS was 74 years. With a single isocenter and use of a 4mm collimator, 51 patients received 80 Gy at the proximal trigeminal nerve (posterior group) and 7 patients received 80 Gy, 1 patient received 85 Gy, and 41 patients received 90 Gy at the retrogasserian portion (anterior group). Follow-up was obtained by clinic visits every 3–6 months after GKS. Data on pain control, complications, and pain recurrence were recorded. The relationships between pain control status, complications, recurrence, and the target portions (anterior vs posterior) were analyzed.

Results

The median duration of follow-up was 30 months (range 3–88 months). Initially, 87 patients achieved pain-free status and 64 achieved complete remission. At the final follow-up visit, 68 patients were still in pain-free status and 42 were in complete remission. Recurrence of facial pain occurred in 15 patients. Forty-one patients developed some degree of trigeminal dysfunction. The rate of initial complete remission was higher in the posterior group than in the anterior group (p = 0.003). More complications were observed in the anterior group than in the posterior group (p = 0.009).

Conclusions

The posterior targeting group had better pain control and a lower complication rate. The authors recommend the posterior targeting method and use of 80 Gy for treatment of TN with GKS.

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Toru Serizawa, Yoshinori Higuchi, Osamu Nagano, Tatsuo Hirai, Junichi Ono, Naokatsu Saeki and Akifumi Miyakawa

Object

The authors conducted validity testing of the 5 major reported indices for radiosurgically treated brain metastases— the original Radiation Therapy Oncology Group's Recursive Partitioning Analysis (RPA), the Score Index for Radiosurgery in Brain Metastases (SIR), the Basic Score for Brain Metastases (BSBM), the Graded Prognostic Assessment (GPA), and the subclassification of RPA Class II proposed by Yamamoto—in nearly 2500 cases treated with Gamma Knife surgery (GKS), focusing on the preservation of neurological function as well as the traditional endpoint of overall survival.

Methods

The authors analyzed data from 2445 cases treated with GKS by the first author (T.S.), the primary surgeon. The patient group consisted of 1716 patients treated between January 1998 and March 2008 (the Chiba series) and 729 patients treated between April 2008 and December 2011 (the Tokyo series). The interval from the date of GKS until the date of the patient's death (overall survival) and impaired activities of daily living (qualitative survival) were calculated using the Kaplan-Meier method, while the absolute risk for two adjacent classes of each grading system and both hazard ratios and 95% confidence intervals were estimated using the Cox proportional hazards model.

Results

For overall survival, there were highly statistically significant differences between each two adjacent patient groups characterized by class or score (all p values < 0.001), except for GPA Scores 3.5–4.0 and 3.0. The SIR showed the best statistical results for predicting preservation of neurological function. Although no other grading systems yielded statistically significant differences in qualitative survival, the BSBM and the modified RPA appeared to be better than the original RPA and GPA.

Conclusions

The modified RPA subclassification, proposed by Yamamoto, is well balanced in scoring simplicity with respect to case number distribution and statistical results for overall survival. However, a new or revised grading system is necessary for predicting qualitative survival and for selecting the optimal treatment for patients with brain metastasis treated by GKS.

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Shinji Matsuda, Osamu Nagano, Toru Serizawa, Yoshinori Higuchi and Junichi Ono

Object

Gamma Knife surgery (GKS) is an effective treatment option for intractable trigeminal neuralgia (TN). The incidence of trigeminal nerve dysfunction, such as facial numbness or dysesthesia, has been reported to be higher than previously published, and the degree and prognosis of trigeminal nerve dysfunction has not been well evaluated. The authors evaluated the incidence, timing, degree, and outcome of trigeminal nerve dysfunction after GKS for TN.

Methods

One hundred four patients with medically refractory TN were treated by GKS. Thirty-nine patients were men and 65 were women; their median age at GKS was 74 years. Using a single isocenter and a 4-mm collimator, 80 or 90 Gy was directed to the trigeminal nerve root. Follow-up data were obtained at clinical examinations every 3–6 months after GKS. Each patient's pain-control status and degree of trigeminal nerve dysfunction were recorded. The incidence, timing, and degree of dysfunction (assessed using the Barrow Neurological Institute facial numbness scale [BNI-N]) and the prognosis and factors related to trigeminal nerve dysfunction were analyzed.

Results

The median duration of follow-up in these patients was 37 months (range 6–121 months). At the final clinical visit, a pain-free status was still observed in 71 patients (68.3%). In 51 patients (49.0%), new or increased trigeminal nerve dysfunction developed at a median of 10.5 months (range 4–68 months) after GKS. In 24 patients (23.1%), this dysfunction was categorized as BNI-N Score II, in 20 patients (19.2%) as BNI-N Score III, and in 7 patients (6.7%) as BNI-N Score IV. Among those patients, 18 patients, including 3 patients with BNI-N Score IV, experienced improvement in nerve dysfunction between 24 and 108 months after GKS (median 52.5 months). At the final clinical visit, 43 patients (41.3%) reported having some trigeminal nerve dysfunction: in 26 patients (25.0%) this was categorized as BNI-N Score II, in 13 patients (12.5%) as BNI-N Score III, and in 4 patients (3.8%) as BNI-N Score IV. The only independent factor that was correlated to all trigeminal nerve dysfunction and also specifically to bothersome trigeminal nerve dysfunction was pain-free status at the final clinic visit.

Conclusions

The incidence of trigeminal nerve dysfunction after GKS for TN was 49%. The severity of the dysfunction improved in one-third of the afflicted patients, even in those with severe dysesthesia at long-term follow-up. A strong relationship between TN and good pain control was identified.

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Toru Serizawa, Yoshinori Higuchi, Junichi Ono, Shinji Matsuda, Osamu Nagano, Yasuo Iwadate and Naokatsu Saeki

Object

The authors analyzed the effectiveness of Gamma Knife surgery (GKS) for metastatic brain tumors without adjuvant prophylactic whole-brain radiotherapy (WBRT). Salvage GKS was performed as the sole treatment for new distant lesions.

Methods

Among 1127 patients in whom new brain metastases had been diagnosed, 97 who met one or more of the following three criteria were excluded from the study: any surgically inaccessible huge (≥ 35 mm) lesion; tumor number and size requiring an internal skull dose exceeding 10 J; or symptomatic carcinomatous meningitis. Thus, 1030 consecutive patients formed the basis for this study. Huge tumors were totally removed, whereas smaller lesions were treated with GKS. No adjuvant WBRT was given prior to GKS, and new distant lesions were appropriately retreated with GKS. Overall, neurological and new lesion–free survival curves were calculated and the prognostic values of covariates were obtained. In total, 1853 separate GKS sessions were required to treat 10,163 lesions.The patients' median overall survival period was 8.6 months. Neurological survival and new lesion–free rates at 1 year were 89.1 and 49.3%, respectively. In a multivariate analysis, the significant factors for poor prognosis were the development of more than four new brain metastases and active extracranial disease.

Conclusions

In meeting the goal of preventing neurological death and maintaining activities of daily living for patients with brain metastases, GKS alone provides excellent palliation without prophylactic WBRT. New distant lesions were quite well controlled with GKS salvage treatment alone.

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Toru Serizawa, Masaaki Yamamoto, Yoshinori Higuchi, Yasunori Sato, Takashi Shuto, Atsuya Akabane, Hidefumi Jokura, Shoji Yomo, Osamu Nagano, Jun Kawagishi and Kazuhiro Yamanaka

OBJECTIVE

The Japanese Leksell Gamma Knife (JLGK)0901 study proved the efficacy of Gamma Knife radiosurgery (GKRS) in patients with 5–10 brain metastases (BMs) as compared to those with 2–4, showing noninferiority in overall survival and other secondary endpoints. However, the difference in local tumor progression between patients with 2–4 and those with 5–10 BMs has not been sufficiently examined for this data set. Thus, the authors reappraised this issue, employing the updated JLGK0901 data set with detailed observation via enhanced MRI. They applied sophisticated statistical methods to analyze the data.

METHODS

This was a prospective observational study of 1194 patients harboring 1–10 BMs treated with GKRS alone. Patients were categorized into groups A (single BM, 455 cases), B (2–4 BMs, 531 cases), and C (5–10 BMs, 208 cases). Local tumor progression was defined as a 20% increase in the maximum diameter of the enhanced lesion as compared to its smallest documented maximum diameter on enhanced MRI. The authors compared cumulative incidence differences determined by competing risk analysis and also conducted propensity score matching.

RESULTS

Local tumor progression was observed in 212 patients (17.8% overall, groups A/B/C: 93/89/30 patients). Cumulative incidences of local tumor progression in groups A, B, and C were 15.2%, 10.6%, and 8.7% at 1 year after GKRS; 20.1%, 16.9%, and 13.5% at 3 years; and 21.4%, 17.4%, and not available at 5 years, respectively. There were no significant differences in local tumor progression between groups B and C. Local tumor progression was classified as tumor recurrence in 139 patients (groups A/B/C: 68/53/18 patients), radiation necrosis in 67 (24/31/12), and mixed/undetermined lesions in 6 (1/5/0). There were no significant differences in tumor recurrence or radiation necrosis between groups B and C. Multivariate analysis using the Fine-Gray proportional hazards model revealed age < 65 years, neurological symptoms, tumor volume ≥ 1 cm3, and prescription dose < 22 Gy to be significant poor prognostic factors for local tumor progression. In the subset of 558 case-matched patients (186 in each group), there were no significant differences between groups B and C in local tumor progression, nor in tumor recurrence or radiation necrosis.

CONCLUSIONS

Local tumor progression incidences did not differ between groups B and C. This study proved that tumor progression after GKRS without whole-brain radiation therapy for patients with 5–10 BMs was satisfactorily treated with the doses prescribed according to the JLGK0901 study protocol and that results were not inferior to those in patients with a single or 2–4 BMs.

Clinical trial registration no.: UMIN000001812 (umin.ac.jp)

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Masaaki Yamamoto, Yoshinori Higuchi, Toru Serizawa, Takuya Kawabe, Osamu Nagano, Yasunori Sato, Takao Koiso, Shinya Watanabe, Hitoshi Aiyama and Hidetoshi Kasuya

OBJECTIVE

The results of 3-stage Gamma Knife treatment (3-st-GK-Tx) for relatively large brain metastases have previously been reported for a series of patients in Chiba, Japan (referred to in this study as the C-series). In the current study, the authors reappraised, using a competing risk analysis, the efficacy and safety of 3-st-GK-Tx by comparing their experience with that of the C-series.

METHODS

This was a retrospective cohort study. Among 1767 patients undergoing GK radiosurgery for brain metastases at Mito Gamma House during the 2005–2015 period, 78 (34 female, 44 male; mean age 65 years, range 35–86 years) whose largest tumor was > 10 cm3, treated with 3-st-GK-Tx, were studied (referred to in this study as the M-series). The target volumes were covered with a 50% isodose gradient and irradiated with a peripheral dose of 10 Gy at each procedure. The interval between procedures was 2 weeks. Because competing risk analysis had not been employed in the published C-series, the authors reanalyzed the previously published data using this method.

RESULTS

The overall median survival time after 3-st-GK-Tx was 8.3 months (95% CI 5.6–12.0 months) in the M-series and 8.6 months (95% CI 5.5–10.6 months) in the C-series (p = 0.41). Actuarial survival rates at the 6th and 12th post–3-st-GK-Tx months were, respectively, 55.1% and 35.2% in the M-series and 62.5% and 26.4% in the C-series (HR 1.175, 95% CI 0.790–1.728, p = 0.42). Cumulative incidences at the 12th post–3-st-GK-Tx, determined by competing risk analyses, of neurological deterioration (14.2% in C-series vs 12.8% in M-series), neurological death (7.2% vs 7.7%), local recurrence (4.8% vs 6.2%), repeat SRS (25.9% vs 18.0%), and SRS-related complications (2.3% vs 5.1%) did not differ significantly between the 2 series.

CONCLUSIONS

There were no significant differences in post–3-st-GK-Tx results between the 2 series in terms of overall survival times, neurological death, maintained neurological status, local control, repeat SRS, and SRS-related complications. The previously published results (C-series) are considered to be validated by the M-series results.

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Takashi Shuto, Atsuya Akabane, Masaaki Yamamoto, Toru Serizawa, Yoshinori Higuchi, Yasunori Sato, Jun Kawagishi, Kazuhiro Yamanaka, Hidefumi Jokura, Shoji Yomo, Osamu Nagano and Hidefumi Aoyama

OBJECTIVE

Previous Japanese Leksell Gamma Knife Society studies (JLGK0901) demonstrated the noninferiority of stereotactic radiosurgery (SRS) alone as the initial treatment for patients with 5–10 brain metastases (BMs) compared with those with 2–4 BMs in terms of overall survival and most secondary endpoints. The authors studied the aforementioned treatment outcomes in a subset of patients with BMs from non–small cell lung cancer (NSCLC).

METHODS

Patients with initially diagnosed BMs treated with SRS alone were enrolled in this prospective observational study. Major inclusion criteria were the existence of up to 10 tumors with a maximum diameter of less than 3 cm each, a cumulative tumor volume of less than 15 cm3, and no leptomeningeal dissemination in patients with a Karnofsky Performance Scale score of 70% or better.

RESULTS

Among 1194 eligible patients, 784 with NSCLC were categorized into 3 groups: group A (1 tumor, n = 299), group B (2–4 tumors, n = 342), and group C (5–10 tumors, n = 143). The median survival times were 13.9 months in group A, 12.3 months in group B, and 12.8 months in group C. The survival curves of groups B and C were very similar (hazard ratio [HR] 1.037; 95% CI 0.842–1.277; p < 0.0001, noninferiority test). The crude and cumulative incidence rates of neurological death, deterioration of neurological function, newly appearing lesions, and leptomeningeal dissemination did not differ significantly between groups B and C. SRS-induced complications occurred in 145 (12.1%) patients during the median post-SRS period of 9.3 months (IQR 4.1–17.4 months), including 46, 54, 29, 11, and 5 patients with a Common Terminology Criteria for Adverse Events v3.0 grade 1, 2, 3, 4, or 5 complication, respectively. The cumulative incidence rates of adverse effects in groups A, B, and C 60 months after SRS were 13.5%, 10.0%, and 12.6%, respectively (group B vs C: HR 1.344; 95% CI 0.768–2.352; p = 0.299). The 60-month post-SRS rates of neurocognitive function preservation were 85.7% or higher, and no significant differences among the 3 groups were found.

CONCLUSIONS

In this subset analysis of patients with NSCLC, the noninferiority of SRS alone for the treatment of 5–10 versus 2–4 BMs was confirmed again in terms of overall survival and secondary endpoints. In particular, the incidence of neither post-SRS complications nor neurocognitive function preservation differed significantly between groups B and C. These findings further strengthen the already-reported noninferiority hypothesis of SRS alone for the treatment of patients with 5–10 BMs.

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Masaaki Yamamoto, Toru Serizawa, Yoshinori Higuchi, Osamu Nagano, Hitoshi Aiyama, Takao Koiso, Shinya Watanabe, Takuya Kawabe, Yasunori Sato and Hidetoshi Kasuya

OBJECTIVE

With the aging of the population, increasing numbers of elderly patients with brain metastasis (BM) are undergoing stereotactic radiosurgery (SRS). Among recently reported prognostic grading indexes, only the basic score for brain metastases (BSBM) is applicable to patients 65 years or older. However, the major weakness of this system is that no BM-related factors are graded. This prompted the authors to develop a new grading system, the elderly-specific (ES)–BSBM.

METHODS

For this IRB-approved, retrospective cohort study, the authors used their prospectively accumulated database comprising 3267 consecutive patients undergoing Gamma Knife SRS for BMs during the 1998–2016 period at the Mito GammaHouse. Among these 3267 patients, 1789 patients ≥ 65 years of age were studied (Yamamoto series [Y-series]). Another series of 1785 patients ≥ 65 years of age in whom Serizawa and colleagues performed Gamma Knife SRS during the same period (Serizawa series [S-series]) was used for validity testing of the ES-BSBM.

RESULTS

Two factors were identified as strongly impacting longer survival after SRS by means of multivariable analysis using the Cox proportional hazard model with a stepwise selection procedure. These factors are the number of tumors (solitary vs multiple: HR 1.450, 95% CI 1.299–1.621; p < 0.0001) and cumulative tumor volume (≤ 15 cm3 vs > 15 cm3: HR 1.311, 95% CI 1.078–1.593; p = 0.0067). The new index is the addition of scores 0 and 1 for these 2 factors to the BSBM. The ES-BSBM system is based on categorization into 3 classes by adding these 2 scores to those of the original BSBM. Each ES-BSBM category has 2 possible scores. For the category ES-BSBM 4–5, the score is either 4 or 5; for ES-BSBM 2–3, the score is either 2 or 3; and for ES-BSBM 0–1, the score is either 0 or 1. In the Y-series, the median survival times (MSTs, months) after SRS were 17.5 (95% CI 15.4–19.3) in ES-BSBM 4–5, 6.9 (95% CI 6.4–7.4) in ES-BSBM 2–3, and 2.8 (95% CI 2.5–3.6) in ES-BSBM 0–1 (p < 0.0001). Also, in the S-series, MSTs were, respectively, 20.4 (95% CI 17.2–23.4), 7.9 (95% CI 7.4–8.5), and 3.2 (95% CI 2.8–3.6) (p < 0.0001). The ES-BSBM system was shown to be applicable to patients with all primary tumor types as well as to those 80 years or older.

CONCLUSIONS

The authors found that the addition of the number of tumors and cumulative tumor volume as scoring factors to the BSBM system significantly improved the prognostic value of this index. The present study is strengthened by testing the ES-BSBM in a different patient group.

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Toru Serizawa, Yoshinori Higuchi, Osamu Nagano, Shinji Matsuda, Junichi Ono, Naokatsu Saeki, Tatsuo Hirai, Akifumi Miyakawa and Yuta Shibamoto

Object

The Basic Score for Brain Metastases (BSBM) proposed by Lorenzoni and colleagues is one of the best grading systems for predicting survival periods after stereotactic radiosurgery (SRS) for brain metastases. However, it includes no brain factors and cannot predict neurological outcomes, such as preservation of neurological function and prevention of neurological death. Herein, the authors propose a modified BSBM, adding 4 brain factors to the original BSBM, enabling prediction of neurological outcomes, as well as of overall survival, in patients undergoing SRS.

Methods

To serve as neurological prognostic scores (NPSs), the authors scored 4 significant brain factors for both preservation of neurological function (qualitative survival) and prevention of neurological death (neurological survival) as 0 or 1 as described in the following: > 10 brain tumors = 0 or ≤ 10 = 1, total tumor volume > 15 cm3 = 0 or ≤ 15 cm3 = 1, MRI findings of localized meningeal dissemination (yes = 0 or no = 1), and neurological symptoms (yes = 0 or no = 1). According to the sum of NPSs, patients were classified into 2 subgroups: Subgroup A with a total NPS of 3 or 4 and Subgroup B with an NPS of 0, 1, or 2. The authors defined the modified BSBM according to the NPS subgroup classification applied to the original BSBM groups. The validity of this modified BSBM in 2838 consecutive patients with brain metastases treated with SRS was verified.

Results

Patients included 1868 with cancer of the lung (including 1604 with non–small cell lung cancer), 355 of the gastrointestinal tract, 305 of the breast, 176 of the urogenital tract, and 134 with other cancers. Subgroup A had 2089 patients and Subgroup B 749. Median overall survival times were 2.6 months in BSBM 0 (382 patients), 5.7 in BSBM 1 (1143), 11.4 in BSBM 2 (1011) and 21.7 in BSBM 3 (302), and pairwise differences between the BSBM groups were statistically significant (all p < 0.0001). One-year qualitative survival rates were 64.6% (modified BSBM 0A, 204 patients), 45.0% (0B, 178), 82.5% (1A, 825), 63.3% (1B, 318), 86.4% (2A, 792), 73.7% (2B, 219), 91.4% (3A, 268), and 73.5% (3B, 34). One-year neurological survival rates were 82.6% (0A), 52.4% (0B), 90.5% (1A), 78.1% (1B), 91.1% (2A), 83.2% (2B), 93.9% (3A), and 76.3% (3B), where A and B identify the subgroup. Statistically significant differences in both qualitative and neurological survivals between Subgroups A and B were detected in all BSBM groups.

Conclusions

The authors' new index, the modified BSBM, was found to be excellent for predicting neurological outcomes, independently of life expectancy, in SRS-treated patients with brain metastases.

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Toshinori Hasegawa, Takenori Kato, Yoshihisa Kida, Motohiro Hayashi, Takahiko Tsugawa, Yoshiyasu Iwai, Mitsuya Sato, Hisayo Okamoto, Tadashige Kano, Seiki Osano, Osamu Nagano and Kiyoshi Nakazaki

OBJECT

The aim of this study was to explore the efficacy and safety of stereotactic radiosurgery for patients with facial nerve schwannomas (FNSs).

METHODS

This study was a multiinstitutional retrospective analysis of 42 patients with FNSs treated with Gamma Knife surgery (GKS) at 1 of 10 medical centers of the Japan Leksell Gamma Knife Society (JLGK1301). The median age of the patients was 50 years. Twenty-nine patients underwent GKS as the initial treatment, and 13 patients had previously undergone surgery. At the time of the GKS, 33 (79%) patients had some degree of facial palsy, and 21 (50%) did not retain serviceable hearing. Thirty-five (83%) tumors were solid, and 7 (17%) had cystic components. The median tumor volume was 2.5 cm3, and the median prescription dose to the tumor margin was 12 Gy.

RESULTS

The median follow-up period was 48 months. The last follow-up images showed partial remission in 23 patients and stable tumors in 19 patients. Only 1 patient experienced tumor progression at 60 months, but repeat GKS led to tumor shrinkage. The actuarial 3- and 5-year progression-free survival rates were 100% and 92%, respectively. During the follow-up period, 8 patients presented with newly developed or worsened preexisting facial palsy. The condition was transient in 3 of these patients. At the last clinical follow-up, facial nerve function improved in 8 (19%) patients, remained stable in 29 (69%), and worsened in 5 (12%; House-Brackmann Grade III in 4 patients, Grade IV in 1 patient). With respect to hearing function, 18 (90%) of 20 evaluated patients with a pure tone average of ≤ 50 dB before treatment retained serviceable hearing.

CONCLUSIONS

GKS is a safe and effective treatment option for patients with either primary or residual FNSs. All patients, including 1 patient who required repeat GKS, achieved good tumor control at the last follow-up. The incidence of newly developed or worsened preexisting facial palsy was 12% at the last clinical follow-up. In addition, the risk of hearing deterioration as an adverse effect of radiation was low. These results suggest that GKS is a safe alternative to resection.