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Yukihiro Goto, Yuichi Furuno, Takuya Kawabe, Kei Ohwada, Kazunori Tatsuzawa, Hiroyasu Sasajima and Naoya Hashimoto

A 34-year-old man with a 1-week history of diplopia was referred to the authors' hospital. Neurological examination revealed left abducens nerve palsy. Computed tomography showed a lesion in the left sphenoid sinus involving the medial wall of the left internal carotid artery (ICA) and osteolytic change at the clivus bordering the lesion. Magnetic resonance imaging demonstrated an extensive soft-tissue mass occupying the left sphenoid sinus. Surgical intervention by the endoscopic transnasal method allowed most of the lesion to be removed. Only the portion attached to the medial wall of the ICA was not removed. Postoperatively, the lesion was diagnosed as a giant cell tumor (GCT) and the patient received 120 mg of subcutaneous denosumab every 4 weeks, with additional doses on Days 8 and 15 during the first month of therapy. MRI a week after starting denosumab revealed shrinkage of the initially fast-growing residual tumor. The patient was discharged upon completion of the third denosumab administration. GCT is an aggressive stromal tumor developing mainly in young adults. Complete resection is recommended for GCT in the literature. However, size and location of the CGT often limit this approach. Various adjuvant treatments for skull base GCTs have been reported, including radiation and chemotherapy. However, the roles of adjuvant therapies have yet to be clearly defined. Denosumab, a monoclonal antibody, was recently approved for GCT in several countries. Denosumab may permit less invasive treatments for patients with GCTs while avoiding deleterious outcomes, and may also limit disease progression and recurrence.

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Masaaki Yamamoto, Takuya Kawabe, Yasunori Sato, Yoshinori Higuchi, Tadashi Nariai, Bierta E. Barfod, Hidetoshi Kasuya and Yoichi Urakawa

Object

Although stereotactic radiosurgery (SRS) alone for patients with 4–5 or more tumors is not a standard treatment, a trend for patients with 5 or more tumors to undergo SRS alone is already apparent. The authors' aim in the present study was to reappraise whether SRS results for ≥ 5 tumors differ from those for 1–4 tumors.

Methods

This institutional review board–approved retrospective cohort study used the authors' database of prospectively accumulated data that included 2553 consecutive patients who underwent SRS, not in combination with concurrent whole-brain radiotherapy, for brain metastases (METs) between 1998 and 2011. These 2553 patients were divided into 2 groups: 1553 with tumor numbers of 1–4 (Group A) and 1000 with ≥ 5 tumors (Group B). Because there was considerable bias in pre-SRS clinical factors between Groups A and B, a case-matched study was conducted. Ultimately, 1096 patients (548 each in Groups A and B) were selected. The standard Kaplan-Meier method was used to determine post-SRS survival and the post-SRS neurological death–free survival times. Competing risk analysis was applied to estimate cumulative incidences of local recurrence, repeat SRS for new lesions, neurological deterioration, and SRS-induced complications.

Results

The post-SRS median survival time was significantly longer in the 548 Group A patients (7.9 months, 95% CI 7.0–8.9 months) than in the 548 Group B patients (7.0 months 95% [CI 6.2–7.8 months], HR 1.176 [95% CI 1.039–1.331], p = 0.01). However, incidences of neurological death were very similar: 10.6% in Group A and 8.2% in Group B (p = 0.21). There was no significant difference between the groups in neurological death–free survival intervals (HR 0.945, 95% CI 0.636–1.394, p = 0.77). Furthermore, competing risk analyses showed that there were no significant differences between the groups in cumulative incidences of local recurrence (HR 0.577, 95% CI 0.312–1.069, p = 0.08), repeat SRS (HR 1.133, 95% CI 0.910–1.409, p = 0.26), neurological deterioration (HR 1.868, 95% CI 0.608–1.240, p = 0.44), and major SRS-related complications (HR 1.105, 95% CI 0.490–2.496, p = 0.81).

In the authors' cohort, age ≤ 65 years, female sex, a Karnofsky Performance Scale score ≥ 80%, cumulative tumor volume ≤ 10 cm3, controlled primary cancer, no extracerebral METs, and neurologically asymptomatic status were significant factors favoring longer survival equally in both groups.

Conclusions

This retrospective study suggests that increased tumor number is an unfavorable factor for longer survival. However, the post-SRS median survival time difference, 0.9 months, between the two groups is not clinically meaningful. Furthermore, patients with 5 or more METs have noninferior results compared to patients with 1–4 tumors, in terms of neurological death, local recurrence, repeat SRS, maintenance of good neurological state, and SRS-related complications. A randomized controlled trial should be conducted to test this hypothesis.

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Takuya Kawabe, Masaaki Yamamoto, Yasunori Sato, Bierta E. Barfod, Yoichi Urakawa, Hidetoshi Kasuya and Katsuyoshi Mineura

Object

Because brainstem metastases are not deemed resectable, stereotactic radiosurgery (SRS) is the only treatment modality expected to achieve a radical cure. The authors describe their treatment results, focusing particularly on how long patients can survive without neurological deterioration following SRS for brainstem metastases.

Methods

This was an institutional review board–approved, retrospective cohort study in which the authors pulled from their database information on 2553 consecutive patients with brain metastases who underwent Gamma Knife surgery (GKS) at the Mito GammaHouse between July 1998 and July 2011. Among the 2553 patients, excluding cases in which there was meningeal dissemination, 200 cases of brainstem metastases (78 women and 122 men with a mean age of 64 years [range 36–86 years]) were identified and analyzed. The most common primary site was the lung (137 patients) followed by the gastrointestinal tract (24 patients), breast (17 patients), kidney (12 patients), and others (10 patients). Among the 200 patients, 15 patients (7.5%) harbored at least 2 tumors in the brainstem: 11 patients had 2 tumors, 2 patients had 3 tumors, and 1 patient each had 4 or 5 tumors. Therefore, a total of 222 tumors were irradiated. These 222 tumors were located in the pons (121 lesions), the midbrain (65 lesions), and the medulla oblongata (36 lesions). The mean and median tumor volumes were 1.3 and 0.2 cm3 (range 0.005–10.7 cm3), and the median peripheral radiation dose was 18.0 Gy (range 12.0–25.0 Gy).

Results

The overall median survival time (MST) was 6.0 months. Distribution of MSTs across Recursive Partitioning Analysis (RPA) classes showed that the MSTs were 9.4 months in Class I (20 patients), 6.0 months in Class II (171 patients), and 1.9 months in Class III (9 patients). Better Karnofsky Performance Scale score, single metastasis, and well-controlled primary tumor were significant predictive factors for longer survival. The neurological and qualitative survival rates were 90.8% and 89.2%, respectively, at 24 months post-GKS. Better KPS score and smaller tumor volume tended to be associated with prolonged qualitative survival. Follow-up imaging studies were available for 129 patients (64.5%). The tumor control rate was 81.8% at 24 months post-GKS. Smaller tumor volume tended to contribute to tumor control.

Conclusions

The present results indicate that GKS is effective in the treatment of brainstem metastases, particularly from the viewpoint of maintaining a good neurological condition in the patient.

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Shinya Watanabe, Masaaki Yamamoto, Takuya Kawabe, Takao Koiso, Tetsuya Yamamoto, Akira Matsumura and Hidetoshi Kasuya

OBJECTIVE

The aim of this study was to reappraise long-term treatment outcomes of stereotactic radiosurgery (SRS) for vestibular schwannomas (VSs). The authors used a database that included patients who underwent SRS with a unique dose-planning technique, i.e., partial tumor coverage designed to avoid excess irradiation of the facial and cochlear nerves, focusing on tumor control and hearing preservation. Clinical factors associated with post-SRS tumor control and long-term hearing preservation were also analyzed.

METHODS

This institutional review board–approved, retrospective cohort study used the authors' prospectively accumulated database. Among 207 patients who underwent Gamma Knife SRS for VSs between 1990 and 2005, 183 (who were followed up for at least 36 post-SRS months) were studied. The median tumor volume was 2.0 cm3 (range 0.05–26.2 cm3). The median prescribed dose at the tumor periphery was 12.0 Gy (range 8.8–15.0 Gy; 12.0 Gy was used in 171 patients [93%]), whereas tumor portions facing the facial and cochlear nerves were irradiated with 10.0 Gy. As a result, 72%–99% of each tumor was irradiated with the prescribed dose. The mean cochlear doses ranged from 2.3 to 5.7 Gy (median 4.1 Gy).

RESULTS

The median durations of imaging and audiometric follow-up were 114 months (interquartile range 73–144 months) and 59 months (interquartile range 33–109 months), respectively. Tumor shrinkage was documented in 110 (61%), no change in 48 (27%), and enlargement in the other 22 (12%) patients. A further procedure (FP) was required in 15 (8%) patients. Thus, the tumor growth control rate was 88% and the clinical control rate (i.e., no need for an FP) was 92%. The cumulative FP-free rates were 96%, 93%, and 87% at the 60th, 120th, and 180th post-SRS month, respectively. Six (3%) patients experienced facial pain, and 2 developed transient facial palsy. Serviceable hearing was defined as a pure tone audiogram result better than 50 dB. Among the 66 patients with serviceable hearing before SRS who were followed up, hearing acuity was preserved in 23 (35%). Actuarial serviceable hearing preservation rates were 49%, 24%, and 12% at the 60th, 120th, and 180th post-SRS month, respectively. On univariable analysis, only cystic-type tumor (HR 3.36, 95% CI 1.18–9.36; p = 0.02) was shown to have a significantly unfavorable association with FP. Multivariable analysis followed by univariable analysis revealed that higher age (≥ 65 years: HR 2.66, 95% CI 1.16–5.92; p = 0.02), larger tumor volume (≥ 8 cm3: HR 5.36, 95% CI 1.20–17.4; p = 0.03), and higher cochlear dose (mean cochlear dose > 4.2 Gy: HR 2.22, 95% CI 1.07–4.77; p = 0.03) were unfavorable factors for hearing preservation.

CONCLUSIONS

Stereotactic radiosurgery achieved good long-term results in this series. Tumor control was acceptable, and there were few serious complications in patients with small- to medium-sized VSs. Unfortunately, hearing preservation was not satisfactory. However, the longer the observation period, the more important it becomes to compare post-SRS hearing decreases with the natural decline in untreated cases.

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Masaaki Yamamoto, Takuya Kawabe, Yasunori Sato, Yoshinori Higuchi, Tadashi Nariai, Shinya Watanabe and Hidetoshi Kasuya

Object

Although stereotactic radiosurgery (SRS) alone is not a standard treatment for patients with 4–5 tumors or more, a recent trend has been for patients with 5 or more, or even 10 or more, tumors to undergo SRS alone. The aim of this study was to reappraise whether the treatment results for SRS alone for patients with 10 or more tumors differ from those for patients with 2–9 tumors.

Methods

This was an institutional review board–approved, retrospective cohort study that gathered data from the Katsuta Hospital Mito GammaHouse prospectively accumulated database. Data were collected for 2553 patients who consecutively had undergone Gamma Knife SRS alone, without whole-brain radiotherapy (WBRT), for newly diagnosed (mostly) or recurrent (uncommonly) brain metastases during 1998–2011. Of these 2553 patients, 739 (28.9%) with a single tumor were excluded, leaving 1814 with multiple metastases in the study. These 1814 patients were divided into 2 groups: those with 2–9 tumors (Group A, 1254 patients) and those with 10 or more tumors (Group B, 560 patients). Because of considerable bias in pre-SRS clinical factors between groups A and B, a case-matched study, which used the propensity score matching method, was conducted for clinical factors (i.e., age, sex, primary tumor state, extracerebral metastases, Karnofsky Performance Status, neurological symptoms, prior procedures [surgery and WBRT], volume of the largest tumor, and peripheral doses). Ultimately, 720 patients (360 in each group) were selected. The standard Kaplan-Meier method was used to determine post-SRS survival times and post-SRS neurological death–free survival times. Competing risk analysis was applied to estimate cumulative incidence for local recurrence, repeat SRS for new lesions, neurological deterioration, and SRS-induced complications.

Results

Post-SRS median survival times did not differ significantly between the 2 groups (6.8 months for Group A vs 6.0 months for Group B; hazard ratio [HR] 1.133, 95% CI 0.974–1.319, p = 0.10). Furthermore, rates of neurological death were very similar: 10.0% for group A and 9.4% for group B (p = 0.89); neurological death–free survival times did not differ significantly between the 2 groups (HR 1.073, 95% CI 0.649–1.771, p = 0.78). The cumulative incidence of local recurrence (HR 0.425, 95% CI 0.0.181–0.990, p = 0.04) and repeat SRS for new lesions (HR 0.732, 95% CI 0.554–0.870, p = 0.03) were significantly lower for Group B than for Group A patients. No significant differences between the groups were found for cumulative incidence for neurological deterioration (HR 0.994, 95% CI 0.607–1.469, p = 0.80) or SRS-related complications (HR 0.541, 95% CI 0.138–2.112, p = 0.38).

Conclusions

Post-SRS treatment results (i.e., median survival time; neurological death–free survival times; and cumulative incidence for local recurrence, repeat SRS for new lesions, neurological deterioration, and SRS-related complications) were not inferior (neither less effective nor less safe) for patients in Group B than for those in Group A. We conclude that carefully selected patients with 10 or more tumors are not unfavorable candidates for SRS alone. A randomized controlled trial should be conducted to test this hypothesis.

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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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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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Takao Koiso, Masaaki Yamamoto, Takuya Kawabe, Shinya Watanabe, Yasunori Sato, Yoshinori Higuchi, Tetsuya Yamamoto, Akira Matsumura and Hidetoshi Kasuya

OBJECTIVE

Stereotactic radiosurgery (SRS) without upfront whole-brain radiotherapy (WBRT) has influenced recent treatment recommendations for brain metastasis patients. However, in brain metastasis patients who undergo SRS alone, new brain metastases inevitably appear with relatively high incidences during post-SRS follow-up. However, little is known about the second SRS results. The treatment results of second SRS were retrospectively reviewed, mainly for newly developed or, uncommonly, for recurrent brain metastases in order to reappraise the efficacy of this treatment strategy with a special focus on the maintenance of neurological status and safety.

METHODS

This was an institutional review board–approved, retrospective cohort study that used a prospectively accumulated database, including 3102 consecutive patients with brain metastases who underwent SRS between July 1998 and June 2015. Among these 3102 patients, 859 (376 female patients; median age 64 years; range 21–88 years) who underwent a second SRS without WBRT were studied with a focus on overall survival, neurological death, neurological deterioration, local recurrence, salvage SRS, and SRS-induced complications after the second SRS. Before the second SRS, the authors also investigated the clinical factors and radiosurgical parameters likely to influence these clinical outcomes. For the statistical analysis, the standard Kaplan-Meier method was used to determine post–second SRS survival and neurological death. A competing risk analysis was applied to estimate post–second SRS cumulative incidences of local recurrence, neurological deterioration, salvage SRS, and SRS-induced complications.

RESULTS

The post–second SRS median survival time was 7.4 months (95% CI 7.0–8.2 months). The actuarial survival rates were 58.2% and 34.7% at 6 and 12 months after the second SRS, respectively. Among 789 deceased patients, the causes of death could not be determined in 24 patients, but were confirmed in the remaining 765 patients to be nonbrain diseases in 654 (85.5%) patients and brain diseases in 111 (14.5%) patients. The actuarial neurological death–free survival rates were 94.4% and 86.6% at 6 and 12 months following the second SRS. Multivariable analysis revealed female sex, Karnofsky Performance Scale score of 80% or greater, better modified recursive partitioning analysis class, smaller tumor numbers, and higher peripheral dose to be significant predictive factors for longer survival. The cumulative incidences of local recurrence were 11.2% and 14.9% at 12 and 24 months after the second SRS. The crude incidence of neurological deterioration was 7.1%, and the respective cumulative incidences were 4.5%, 5.8%, 6.7%, 7.2%, and 7.5% at 12, 24, 36, 48, and 60 months after the second SRS. SRS-induced complications occurred in 25 patients (2.9%) after a median post–second SRS period of 16.8 months (range 0.6–95.0 months; interquartile range 5.6–29.3 months). The cumulative incidences of complications were 1.4%, 2.0%, 2.4%, 3.0%, and 3.0% at 12, 24, 36, 48, and 60 months after the second SRS, respectively.

CONCLUSIONS

Carefully selected patients with recurrent tumors—either new or locally recurrent—are favorable candidates for a second SRS, particularly in terms of neurological status maintenance and the safety of this treatment strategy.

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Shinya Watanabe, Masaaki Yamamoto, Yasunori Sato, Takuya Kawabe, Yoshinori Higuchi, Hidetoshi Kasuya, Tetsuya Yamamoto, Akira Matsumura and Bierta E. Barfod

Object

Recently, an increasing number of patients with brain metastases, even patients over 80 years of age, have been treated with stereotactic radiosurgery (SRS). However, there is little information on SRS treatment results for patients with brain metastases 80 years of age and older. The authors undertook this study to reappraise whether SRS treatment results for patients 80 years of age or older differ from those of patients who are 65–79 years old.

Methods

This was an institutional review board–approved, retrospective cohort study. Among 2552 consecutive brain metastasis patients who underwent SRS during the 1998–2011 period, we studied 165 who were 80 years of age or older (Group A) and 1181 who were age 65–79 years old (Group B). Because of the remarkable disproportion in patient numbers between the 2 groups and considerable differences in pre-SRS clinical factors, the authors conducted a case-matched study using the propensity score matching method. Ultimately, 330 patients (165 from each group, A and B) were selected. For time-to-event outcomes, the Kaplan-Meier method was used to estimate overall survival and competing risk analysis was used to estimate other study end points, as appropriate.

Results

Although the case-matched study showed that post-SRS median survival time (MST, months) was shorter in Group A patients (5.3 months, 95% CI 3.9–7.0 months) than in Group B patients (6.9 months, 95% CI 5.0–8.1 months), this difference was not statistically significant (HR 1.147, 95% CI 0.921–1.429, p = 0.22). Incidences of neurological death and deterioration were slightly lower in Group A than in Group B patients (6.3% vs 11.8% and 8.5% vs 13.9%), but these differences did not reach statistical significance (p = 0.11 and p = 0.16). Furthermore, competing risk analyses showed that the 2 groups did not differ significantly in cumulative incidence of local recurrence (HR 0.830, 95% CI 0.268–2.573, p = 0.75), rates of repeat SRS (HR 0.738, 95% CI 0.438–1.242, p = 0.25), or incidence of SRS-related complications (HR 0.616, 95% CI 0.152–2.495, p = 0.49). Among the Group A patients, post-SRS MSTs were 11.6 months (95% CI 7.8–19.6 months), 7.9 months (95% CI 5.2–10.9 months), and 2.8 months (95% CI; 2.4–4.6 months) in patients whose disease status was modified–recursive partitioning analysis (RPA) Class(es) I+IIa, IIb, and IIc+III, respectively (p < 0.001).

Conclusions

Our results suggest that patients 80 years of age or older are not unfavorable candidates for SRS as compared with those 65–79 years old. Particularly, even among patients 80 years and older, those with modified-RPA Class I+IIa or IIb disease are considered to be favorable candidates for more aggressive treatment of brain metastases.

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Hitoshi Aiyama, Masaaki Yamamoto, Takuya Kawabe, Shinya Watanabe, Takao Koiso, Yasunori Sato, Yoshinori Higuchi, Eiichi Ishikawa, Tetsuya Yamamoto, Akira Matsumura and Hidetoshi Kasuya

OBJECTIVE

Although the conformity index (CI) and the gradient index (GI), which were proposed by Paddick and colleagues, are both logically considered to correlate with good posttreatment results after stereotactic radiosurgery (SRS), this hypothesis has not been confirmed clinically. The authors’ aim was to reappraise whether high CI values correlate with reduced tumor progression rates, and whether low GI values correlate with reduced complication incidences.

METHODS

This was an institutional review board–approved, retrospective cohort study conducted using a prospectively accumulated database including 3271 patients who underwent Gamma Knife SRS for brain metastases (BMs) during the 1998–2016 period. Among the 3271 patients, 925 with a single BM at the time of SRS (335 women and 590 men, mean age 66 [range 24–93] years) were studied. The mean/median CIs were 0.62/0.66 (interquartile range [IQR] 0.53–0.74, range 0.08–0.88) and the mean/median GIs were 3.20/3.09 (IQR 2.83–3.39, range 2.27–11.4).

RESULTS

SRS-related complications occurred in 38 patients (4.1%), with a median post-SRS interval of 11.5 (IQR 6.0–25.8, maximum 118.0) months. Cumulative incidences of post-SRS complications determined by a competing risk analysis were 2.2%, 3.2%, 3.6%, 3.8%, and 3.9% at the 12th, 24th, 36th, 48th, and 60th post-SRS month, respectively. Multivariable analyses showed that only two clinical factors (i.e., peripheral doses and brain volume receiving ≥ 12 Gy) correlated with complication rates. However, neither CIs nor GIs impacted the incidences of complications. Among the 925 patients, post-SRS MRI was performed at least once in 716 of them, who were thus eligible for local progression evaluation. Among these 716 patients, local progression was confirmed in 96 (13.4%), with a median post-SRS interval of 10.8 (IQR 6.7–19.5, maximum 59.8) months. Cumulative incidences of local progression determined by a competing risk analysis were 7.7%, 12.6%, 14.2%, 14.8%, and 15.3% at the 12th, 24th, 36th, 48th, and 60th post-SRS month, respectively. Multivariable analyses showed neurological symptoms, extracerebral metastases, repeat SRS, and CIs to correlate with incidences of local progression, whereas GIs had no impact on local tumor progression. Particularly, cumulative incidences of local progression were significantly lower in patients with CIs < 0.65 than in those with CIs ≥ 0.65 (adjusted hazard ratio 1.870, 95% confidence interval 1.299–2.843; p = 0.0034).

CONCLUSIONS

To the authors’ knowledge, this is the first analysis to focus on the clinical significance of CI and GI based on a large series of patients with BM. Contrary to the majority opinion that dose planning with higher CI and lower GI results in good post-SRS outcomes (i.e., low local progression rates and minimal complications), this study clearly showed that the lower the CIs were, the lower the local progression rates were, and that the GI did not impact complication rates.