Follow-up results of brain metastasis patients undergoing repeat Gamma Knife radiosurgery

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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.

ABBREVIATIONSHR = hazard ratio; IQR = interquartile range; KPS = Karnofsky Performance Scale; M-RPA = modified recursive partitioning analysis; MST = median survival time; RTOG = Radiation Therapy Oncology Group; SRS = stereotactic radiosurgery; WBRT = whole-brain radiotherapy.

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.

ABBREVIATIONSHR = hazard ratio; IQR = interquartile range; KPS = Karnofsky Performance Scale; M-RPA = modified recursive partitioning analysis; MST = median survival time; RTOG = Radiation Therapy Oncology Group; SRS = stereotactic radiosurgery; WBRT = whole-brain radiotherapy.

Due to prognostic improvements in cancer patients, mainly due to recent advances in systemic cancer treatment, recent estimates suggest that the number of patients with brain metastases has been gradually rising.13,18,32 Stereotactic radiosurgery (SRS) has influenced recent treatment recommendations for brain metastasis patients, although whole-brain radiotherapy (WBRT) has long been the standard treatment for brain metastases.4,12,27,28 The primary argument against WBRT stems from the risk of deterioration of neurocognitive function, which cannot be ignored in long-surviving patients.1,5 Second, because WBRT is generally considered to be unrepeatable, the availability of an alternative treatment for brain metastases allows WBRT to be reserved for subsequent treatment attempts, i.e., in cases with meningeal dissemination or miliary metastases for which only WBRT is effective. SRS has overcome several of these limitations, and therefore an increasing number of patients with brain metastases have recently been treated with SRS alone.9,23,35

In brain metastasis patients who undergo SRS alone, new brain metastases inevitably appear with relatively high incidences during post-SRS follow-up. Using high-performance MR imaging, Hanssens et al. reported that new tumors were diagnosed in 40% of 835 brain metastasis patients who had undergone SRS alone.11 Recently published retrospective and prospective studies based on more than 1000 brain metastasis patients treated with SRS alone disclosed that re-SRS for new tumors was required in 22% to 34% of all cases.16,30,31,43,46 Several retrospective studies, which were based on relatively small patient numbers, have documented re-SRS to be safe and effective.7,20,32,47 However, no follow-up results based on large numbers of brain metastasis patients undergoing second SRS have yet been published. Herein, we retrospectively reviewed the medical records of patients who underwent second SRS mainly for newly developed or, uncommonly, for recurrent brain metastases in order to reappraise efficacy, with a special focus on neurological status maintenance and the safety of this treatment strategy.

Methods

Patient Population

All data collection was performed under an institutional review board–approved retrospective review. The data set consisted of 3102 consecutive brain metastasis patients who were treated with Gamma Knife SRS during the 17-year period between July 1998 and June 2015. After excluding 156 patients who had undergone WBRT before the first SRS, 895 patients who received a second SRS were identified. For a new brain metastasis that developed after the second SRS, our approach was similar to that used for patients with an initially diagnosed brain metastasis. Basically, instead of immediately performing the second SRS, we conducted meticulous follow-up MRI for any new lesions with a diameter of less than 1 cm. However, if the new lesions were located in a critical or eloquent area, like the brainstem, optic apparatus, or motor area, we performed the second SRS without further observation even if the maximum lesion diameter was smaller than 1 cm. After 36 patients who had undergone WBRT after the first SRS procedure were excluded from the study, 859 patients remained for analysis (680 [79.2%] patients with new tumors, 83 [9.7%] patients with local recurrence of irradiated tumors, and 96 [11.2%] patients with both). The median interval between the first and second procedures was 6.4 months (range 0.5–74.4 months; interquartile range [IQR] 4.3–10.4 months). Because all patients were referred to our institution by their primary physicians, the decision as to whether SRS could be performed was made by the second author (M.Y.). We fundamentally did not perform SRS on patients with low Karnofsky Performance Scale (KPS) scores because of systemic diseases, a noncooperative state due to poor neurocognitive function, meningeal dissemination, and/or an expected survival period of 3 months or less. The characteristics of the pre–second SRS cases are shown in Table 1, along with characteristics noted before the first SRS. Because all patients had been referred to our institution, as previously mentioned, the primary physicians had already made the decision as to whether to perform surgery for brain metastases. For this reason, 196 (22.8%) of the 859 patients had undergone surgery before the first SRS.

TABLE 1.

Summary of pre–first and pre–second SRS demographic characteristics*

CharacteristicPre–1st SRSPre–2nd SRS
No. of patients3102859
Age, yrs
  Mean6664
  Range19–9621–88
  IQR57–7356–71
Sex
  Male1842 (59.4)483 (56.2)
  Female1260 (40.6)376 (43.8)
Neurological symptom
  Yes1601 (51.6)404 (47.0)
  No1501 (48.4)455 (53.0)
Primary cancer status
  Controlled1028 (33.1)390 (45.4)
  Uncontrolled2074 (66.9)469 (54.6)
KPS score
  ≥80%2379 (76.7)727 (84.6)
  ≤70%723 (23.3)132 (15.4)
M-RPA class
  1+2a712 (23.0)225 (27.4)
  2b951 (30.7)310 (37.7)
  2c+31439 (46.4)287 (34.9)
Primary cancer
  Non–small cell lung cancer1711 (55.2)487 (56.7)
  Small cell lung cancer292 (9.4)77 (9.0)
  Breast358 (11.5)117 (13.6)
  Gastrointestinal tract359 (11.6)89 (10.4)
  Kidney123 (4.0)34 (4.0)
  Other259 (8.3)55 (6.4)
Prior surgery
  Yes570 (18.4)196 (22.8)
  No2532 (81.6)663 (77.2)
Presentation
  Synchronous531 (17.1)147 (17.1)
  Metachronous2571 (82.9)712 (82.9)
No. of tumors
  Median34
  Range1–891–48
  IQR1–82–10
Tumor vol, cm3
  Cumulative
    Median5.52.13
    Range0.01–126.20.02–64.1
    IQR1.86–12.950.70–5.81
  Largest tumor
    Median3.701.14
    Range0.01–94.20.01–45.26
    IQR1.10–8.820.35–3.50
Peripheral dose (Gy)
  Median21.024.0
  Range5.8–32.010.0–25.0
  IQR20.0–24.020.0–24.0
Maximum dose (Gy)
  Median3532.0
  Range15.0–60.03.8–50.0
  IQR30.0–40.030.0–40.0
Mos btwn 1st & 2nd SRS
  Median6.4
  Range0.5–74.4
  IQR4.2–10.5

Values are presented as the number of patients (%) unless otherwise indicated.

Refer to the studies by Yamamoto et al.44,45

The treatment strategies were explained in detail to each patient, as well as at least 1 adult relative, and written informed consent was obtained from all patients by the second author (M.Y.) before both the first and second SRS procedures were performed. Because our previous report described our radiosurgical techniques in detail, they are not repeated herein.40,43 Briefly, SRS was performed using a Leksell Gamma Knife Model B unit (1998e2003; Elekta Instruments AB) before June 2003, a Leksell Gamma Knife Model C unit (Elekta Instruments AB) after June 2003 but before December 2013, or a Leksell Perfexion unit (Elekta Instruments AB) thereafter.

Clinical Outcomes

The post–second SRS primary end point was overall survival, and the post–second SRS secondary end points were neurological death, neurological deterioration, local recurrence of the treated tumor at the time of the second SRS, irradiation-induced major complications, and further salvage SRS for new or recurrent lesions. For each end point, failures were regarded as events and any other end points were censored. The overall survival time was defined as the interval between the second SRS and death due to any cause (e.g., progression of systemic metastases and/or brain metastases, other disease unrelated to cancer, accident, suicide) or the day of the last follow-up. Neurological death was defined as death caused by any intracranial disease, including tumor recurrence, carcinomatous meningitis, cerebral dissemination, and progression of other untreated intracranial tumors. The local recurrence-free survival time was defined as the interval between the second SRS and the day when the follow-up MRI demonstrated local recurrence (at the irradiated lesion at the time of the second SRS). Basically, local recurrence was detected by MRI (regression of the enhanced area on T1-weighted imaging after contrast agent administration and an enlarged tumor core on T2-weighted MR imaging).15 However, because it is difficult to distinguish recurrence from necrosis, we needed to perform 11C-methionine PET on 71 cases in order to make an accurate determination.22,37,41 Thus, all findings of recurrence on MRI and/or PET were regarded as events and any other findings were censored.

Also, the third SRS–free survival time was analyzed based on the interval between the second SRS and the day that the third SRS was performed; all repeat SRS procedures for such lesions were regarded as events and any other procedures were censored.

The neurological deterioration–free survival time was defined as the interval between the second SRS and the day when any brain disease causing neurological worsening manifested (i.e., local recurrence, progression of new lesions, and SRS-induced complications). Decreases in the KPS scores in patients with scores of 20% or less due to neurological worsening were regarded as events and any others as censored. Patients with major complications included those with Radiation Therapy Oncology Group (RTOG) neurotoxicity of Grade 2 or worse and, even if the grade was either 0 or 1, those in whom surgical intervention was required based on sequential MRI follow-up that demonstrated progressive enlargement of a cyst and/or a mass lesion that made further observation excessively high risk. All of these conditions were regarded as events and any other events were censored.29

Statistical Analysis

All data were analyzed according to the intention-to-treat principle. For the baseline variables, summary statistics were constructed using frequencies and proportions for categorical data and the medians, IQRs, and ranges for continuous variables. The standard Kaplan-Meier method was used to analyze the overall and neurological death–free survival periods. Also, univariate and multivariate analyses using Cox proportional hazard modeling were performed to determine the pre–second SRS clinical factors that favor longer survival.

For time-to-event outcome analyses of the 4 aforementioned end points, a competing risk analysis was applied because death is a competing risk for these end points. The standard Kaplan-Meier method was applied, i.e., follow-up of a patient who developed a competing event (e.g., death) was simply censored. We considered the competing risk analysis to have been necessary, as in our prior studies, for evaluation of these data. Also, to identify the baseline and clinical variables associated with the 4 aforementioned outcomes, competing risk analyses were performed with the Fine-Gray generalization of the proportional hazards model to account for death as a competing risk. Fine-Gray generalization makes use of the subdistribution hazard to model cumulative incidence, thereby quantifying the overall benefit or harm of an exposure.

All comparisons were planned, and the tests were 2-sided. A p value < 0.05 was considered to be statistically significant. All statistical analyses were performed by a statistician (Y.S.) using SAS software (version 9.4; SAS Institute) and the R statistical program (version 3.10). Before performing the statistical analyses, the database was cleaned by one of the coauthors (Y.H.). These 2 authors were not involved in either SRS treatment or patient follow-up.

Results

The median follow-up time among the 70 censored observations was 10.3 months (IQR 2.2–35.9 months; maximum 147.2 months) after the second SRS; 789 patients (91.9%) had died as of the end of March 2016. 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 (Table 2). As shown in Fig. 1A, the overall median survival time (MST) after the second SRS was 7.4 months (95% CI 7.0–8.2 months). The actuarial survival rates were 58.2%, 34.7%, 23.0%, 15.6%, 9.1%, and 4.3% at 6, 12, 18, 24, 36, and 60 months, respectively, after the second SRS. As shown in Table 3, the multivariable analysis revealed female sex (hazard ratio [HR] 1.423; 95% CI 1.233–1.644; p < 0.0001), KPS score 80% or better (HR 1.753; 95% CI 1.410–2.167; p < 0.0001), better modified recursive partitioning analysis (M-RPA) class (2b vs 1+2a: HR 1.483; 95% CI 1.220–1.807; p < 0.0001) (2c+3 vs 2b; HR 1.353; 95% CI 1.133–1.613; p = 0.0008), a smaller number of tumors (5 or more vs 4 or fewer: HR 1.404; 95% CI 1.190–1.657; p < 0.0001), and a peripheral dose of 24 Gy or more (HR 1.376; 95% CI 1.172–1.612; p = 0.0001) to be significant predictive factors of longer post–second SRS survival. Figure 1B shows neurological death–free survival. The actuarial neurological death–free survival rates were 94.4%, 86.6%, 80.8%, 74.1%, 66.6%, and 57.1% at 6, 12, 18, 24, 36, and 60 months, respectively, after the second SRS. As shown in Tables 2 and 4, the crude incidence of neurological deterioration was 7.1% and the cumulative incidences were 4.5%, 5.8%, 6.7%, 7.2%, and 7.5% at 12, 24, 36, 48, and 60 months, respectively, after the 2nd SRS.

TABLE 2.

Crude incidences of various treatment results after the first and second SRS procedures*

VariablePost–1st SRS (n = 3098)Post–2nd SRS (n = 859)
Neurological death313 (11.0)111 (14.5)
Neurological deterioration382 (12.3)61 (7.1)
Local recurrence180 (8.0)90 (15.8)
Salvage SRS935 (30.2)281 (32.7)
Salvage WBRT108 (3.5)28 (3.3)
Salvage surgery43 (1.4)16 (1.9)
SRS-related complications88 (2.8)25 (2.9)

Values are presented as the number of patients (%).

Based on 2721 (first SRS) and 765 (second SRS) deceased patients whose causes of death were determined (112 patients in first SRS group and 24 patients in second SRS group were excluded because the causes of death were unavailable).

Based on 2243 (first SRS) and 571 (second SRS) patients (859 patients in the first SRS group and 288 patients in second SRS group were excluded because the neuroimaging results were unavailable).

FIG. 1.
FIG. 1.

Survival probability (A) and neurological death–free survival (B) after the first (dotted line) and second (solid line) SRSs, as estimated using the standard Kaplan-Meier method.

TABLE 3.

Univariable and multivariable analyses of survival after the second SRS

VariableUnivariableMultivariable
HR (95% CI)p ValueHR (95% CI)p Value
Age, yrs
  ≥65 vs <651.038 (0.902–1.194)0.6045
Sex
  Male vs female1.291 (1.121–1.487)0.00041.423 (1.233–1.644)<0.0001
KPS score
  <80% vs ≥80%2.237 (1.838–2.703)<0.00011.753 (1.410–2.167)<0.0001
M-RPA
  2b vs 1+2a1.700 (1.421–2.039)<0.00011.483 (1.220–1.807)<0.0001
  2c+3 vs 2b1.622 (1.375–1.913)<0.00011.353 (1.133–1.613)0.0008
Original tumor site
  Lung vs non-lung1.065 (0.919–1.238)0.4031
No. of lesions
  ≥2 vs 11.793 (1.510–2.143)<0.00011.239 (0.989–1.558)0.0626
  ≥5 vs ≤41.689 (1.463–1.949)<0.00011.404 (1.190–1.657)<0.0001
Tumor volume, cm3
  Cumulative: ≥10 vs <101.561 (1.281–1.887)<0.00011.076 (0.787–1.441)0.6356
  Largest tumor: ≥10 vs <101.609 (1.256–2.029)0.00031.370 (0.940–2.012)0.1014
Type of recurrence
  Remote vs local1.291 (1.020–1.659)0.03321.294 (0.976–1.734)0.0737
  Both vs local1.644 (1.204–2.251)0.00181.379 (0.974–1.959)0.0702
Minimum dose, Gy
  <24 vs ≥241.398 (1.213–1.609)<0.00011.376 (1.172–1.612)0.0001
TABLE 4.

Cumulative incidences of various treatment results after the second SRS*

VariableCumulative Incidences
12 Mos24 Mos36 Mos48 Mos60 Mos
Neurological deterioration0.0450.0580.0670.0720.075
Local recurrence0.1120.1490.1560.1650.170
Repeat SRS0.2770.3280.3360.3400.340
SRS-related complications0.0140.0200.0240.0300.030

Calculated using competing risk analysis.

Based on 571 patients: 288 patients were excluded because the post–second SRS neuroimaging results were unavailable.

Post–second SRS neuroimaging examinations were available in 571 patients. In the remaining 288 patients, post–second SRS neuroimaging examinations could not be performed due to early death or deterioration of the patient's general condition soon after the second SRS. The post–second SRS MST of this subset was 3.1 months (IQR 1.5–5.7 months). As shown in Tables 2 and 4, the crude incidence of local recurrence was 15.8%, and the cumulative incidences were 11.2%, 14.9%, 15.6%, 16.5%, and 17.0% at 12, 24, 36, 48, and 60 months, respectively, after the second SRS. As shown in Table 5, the multivariable analysis revealed that a maximum tumor volume of 10 cm3 or larger (HR 2.760; 95% CI 1.073–8.036; p = 0.0346) and locally recurrent lesions that had been irradiated at the first SRS (HR 2.433; 95% CI 1.318–4.445; p = 0.0048) were significantly unfavorable predictors for local control after the second SRS. The mean peripheral dose that was administered to the locally recurrent lesions was slightly lower than the dose administered to the newly appearing lesions, but this difference did reach statistical significance (20.2 Gy vs 22.4 Gy; p < 0.0001).

TABLE 5.

Univariable and multivariable analyses of local recurrence after the second SRS

VariableUnivariableMultivariable
HR (95% CI)p ValueHR (95% CI)p Value
Age, yrs
  ≥65 vs <651.366 (0.898–2.104)0.1462
Sex
  Male vs female1.205 (0.796–1.829)0.3773
KPS
  <80% vs ≥80%2.261 (1.047–4.321)0.03901.999 (0.912–3.897)0.0804
M-RPA
  1+2a vs 2b1.323 (0.814–2.188)0.2608
  2c+3 vs 2b1.600 (0.881–2.862)0.1209
Original tumor sites
  Non-lung vs lung1.545 (1.013–2.340)0.04371.294 (0.830–1.997)0.2526
No. of lesions
  1 vs ≥21.284 (0.830–1.961)0.2568
  ≤4 vs ≥51.326 (0.842–2.162)0.2287
Tumor volume, cm3
  Cumulative: ≥10 vs <104.550 (2.762–7.233)<0.00011.220 (0.452–2.771)0.6685
  Largest tumor: ≥10 vs <106.671 (3.763–11.197)<0.00012.760 (1.073–8.036)0.0346
Type of recurrence
  Local vs remote4.951 (3.031–7.902)<0.00012.433 (1.318–4.445)0.0048
  Both vs remote3.643 (1.967–6.364)0.00012.986 (1.570–5.368)0.0013
Minimum dose, Gy
  <24 vs ≥242.821 (1.863–4.289)<0.00011.511 (0.907–2.496)0.1121

Regarding post–second SRS salvage treatment, WBRT was performed in 28 (3.3%) patients, surgical intervention was performed on 16 (1.9%) patients, and a third SRS was performed in 281 (32.7%) patients. The cumulative incidences of performing the third SRS procedures were 27.7%, 32.8%, 33.6%, 34.0%, and 34.0% at 12, 24, 36, 48, and 60 months, respectively, after the second SRS.

SRS-induced complications occurred in 25 patients (2.9%), with a median post–second SRS period of 16.8 months (range 0.6–95.0 months; IQR 5.6–29.3 months) and 4, 1, 13, 7, and 0 months for patients with RTOG Grades 0, 1, 2, 3, and 4, respectively. 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, respectively, after the second SRS. The most common symptom was motor dysfunction (12 patients; 48.0%), followed by visual field defect and decreased neurocognitive function in 2 patients each (8.0% each) and balance disturbance, oculomotor nerve disturbance, and facial nerve paresis in 1 patient each (4.0% each). Univariable analysis revealed no significant predictive factors. According to the univariable analyses, none of the pre–second SRS clinical factors and radiosurgical parameters were related to a higher incidences of complications.

Discussion

This study was retrospective. However, based on the relatively large sample size and the application of adequate statistical methods—i.e., competing risk analyses for secondary end points—this is the first analysis to demonstrate the importance of second SRS for patients with new post–first SRS or recurrent brain metastases. As mentioned previously, several retrospective studies, which were based on relatively small patient numbers, have documented re-SRS to be safe and effective.7,20,32,47 Those studies considered overall survival, neurological death, tumor control, and/or SRS-induced complications with no maintenance of the neurological condition being described. Maintenance of good neurological function and, eventually, a decreased incidence of neurological death, have recently been recognized as being crucial for managing patients with brain metastases. We consider our herein-reported data set, with a relatively large sample size, to show that second SRS has the potential to achieve prolonged maintenance of neurological function and minimize neurological death based on the results that are essentially the same as those obtained with first SRS (Fig. 1B; Table 2). To summarize, the crude incidence of neurological death after the second SRS (14.5%) was slightly higher than that after the first SRS (11.2%), while the crude incidence of neurological deterioration after the second SRS (7.1%) was slightly lower than that after the first SRS (12.1%) (Table 2). However, these differences were negligible. Kwon et al. and Shuto et al. reported neurological death rates after the second SRS as 42.4% and 33.3%, respectively—i.e., much higher than our present value of 14.5%.20,32 There were large differences in some of the baseline clinical characteristics between Kwon et al.'s and our series: 67% of all patients had undergone WBRT and 36% underwent re-SRS for recurrent tumors in Kwon et al.'s series, while 9.7% of our patients received re-SRS and WBRT was an exclusion criterion in the present study.

Overall Survival

The reported post–second SRS MSTs—7 to 8 months—are consistent with our result of 7.4 months.7,20 Kwon et al. reported actuarial survival rates to be 57.6% and 28.0% at 6 and 12 months after the second SRS, respectively,20 which again is essentially the same as our results: 58.4% and 34.8%, respectively. Furthermore, as shown in Fig. 1A, the post–second SRS MST and actuarial survival rates were almost the same as those after the first SRS. In our previously published study, good prognostic factors after the first SRS were KPS score 90% or greater, single brain metastasis, controlled primary tumor, and no extracranial metastasis.44 Also, we recently reported these results to be consistent even with those obtained after the second SRS.42 Shuto et al. reported that good prognostic factors after repeat SRS include a tumor number of 15 or less.32 In our study, female sex, KPS score 80% or better, better M-RPA class, a smaller number of tumors, and a peripheral dose of 24 Gy or higher were found to be good prognostic factors after the second SRS (Table 3).

Local Control

In this study, the local control rate after the second SRS—15.8%—is not unsatisfactory and was actually higher than that after the first SRS (8.0%) (Table 2). Kwon et al. reported an actuarial local recurrence–free rate of 90.7% at 6 months after the second SRS.20 Nevertheless, they used the original Kaplan-Meier method, which is not considered to be optimal for modern medical statistics. In this study, the cumulative incidence was determined by competing risk analysis to be 11.2% at 12 months after the second SRS (Table 4). Woo et al. reported the absence of a rapid fall-off radiation dose around a lesion to be an unfavorable factor for local recurrence.39 Furthermore, the type of primary cancer was also reported to be related to local control.9,34 Our present results indicate remote recurrence (vs local recurrence) and maximum tumor volume less than 10 cm3 to be factors that favor good local control. Regarding this difference—i.e., remote versus local recurrence—a relatively high incidence of local recurrence probably stems from relatively low doses at the time of the second SRS.

Complications

Debate continues as to whether multiple SRS procedures correlate with a higher incidence of complications. Shuto et al. reported the rate of radiation-induced injury to be 9.2% in patients undergoing SRS more than 4 times.32 However, in our previous study based on 167 patients who survived over 3 years after the first SRS, univariable analyses failed to show that numbers of SRS procedures, as either a continuous or a categorical variable, correlated with a higher incidence of SRS-induced complications.41 As shown in Table 2, the crude incidence of post–second SRS complications (2.9%) was almost the same as that after the first SRS (2.8%). Also, as shown in Table 4, the cumulative incidences of post–second SRS complications, which were determined using a competing risk analysis, were low compared with those of the JLGK0901 Study: 6% to 8%, 10% to 11%, 11% to 12%, 12% to 13%, and 12% to 14% at 1, 2, 3, 4, and 5 years after the first SRS.46

Patient Selection for the Second SRS

The second SRS protocol is mostly performed in patients with new lesions. As mentioned previously, no special considerations are necessary for new brain metastases that develop after the first SRS; i.e., the approach should be similar to that used for patients with an initially diagnosed brain metastasis. Nevertheless, performing the second SRS is not urgent if the diameter of the largest lesion is less than 1 cm. In fact, meticulous follow-up MRI is recommended until the diameter of a new lesion exceeds 1 cm. If small lesions are detected by follow-up post–SRS MRI, some tumors will grow slowly while others will be controlled, or possibly even disappear, in response to systemic chemotherapy or targeted therapy. In such cases, re-SRS can be postponed. Also, among such patients, there will be a subset whose general conditions deteriorate remarkably due to systemic cancer progression before the brain lesions increase in size to exceed 1 cm in diameter. In such cases, re-SRS offers no benefits. However, if new lesions are located near critical or eloquent areas, like the brainstem, optic apparatus, or motor area, the second SRS should be performed without further observation even if the maximum lesion diameter is 2 to 3 mm.

In contrast, the second SRS should not be delayed for patients with recurrent lesions. However, differentiation of tumor recurrence from necrotic changes is difficult in some cases based on MR imaging alone.17,19 In such cases, perfusion-weighted MRI,2,14,24,36 MR spectroscopy,8,19,36 201Tl SPECT,31 and PET using 2-deoxy-[18F]fluoro-D-glucose3,6,8 have been used, though none of these examinations has sufficient diagnostic certainty. Therefore, we recommend using 11C-methionine PET because its sensitivity and specificity are far greater than with the aforementioned methods.25,26,37

For patients with new and/or recurrent lesions, a prognostic grading index needs to be developed for re-SRS. Five indices—recursive partitioning analysis,10 Score Index for Radiosurgery,38 Basic Score for Brain Metastases,21 Graded Prognostic Assessment,33 and M-RPA40,44,45—were proposed for patients with initially diagnosed brain metastases. As we reported elsewhere, our M-RPA system was shown to be the most applicable to patients receiving re-SRS in terms of the proportions of patients in the 3 M-RPA subclasses and MST separation among the 3 groups and to better reflect patient status changes as well as post–re-SRS MSTs.

Limitations of This Study

This was a retrospective study, and as such the major limitation would be the obvious heterogeneity of the clinical factors. Second, there were considerable biases in patient selection, as well as in post–first and post–second SRS observations. Also, meticulous follow-up imaging was lacking in approximately 25% of our cohort because most of these patients deteriorated or died rather early due to systemic disease progression before post–second SRS imaging examinations could be performed. Third, data on systemic chemotherapy or targeted therapy, which are considered to be very important for discussing overall survival, tumor control, new lesion appearance, etc., are lacking in the present study because our prospectively accumulated database does not include such information. Immunomodulatory agent therapy is not as yet covered by the Japanese National Insurance System and, therefore, has been administered only to very limited numbers of patients (e.g., patients participating in clinical trials).

Conclusions

We conclude that carefully selected patients with recurrent tumors, either new or locally recurrent, are favorable candidates for second SRS. In other words, post–second SRS results—not only overall survival but also other secondary end points—were not inferior to those after the first SRS. In particular, maintenance of a good neurological condition can be expected even at 5 years after the second SRS in over 90% of patients.

Acknowledgments

We are very grateful to Bierta E. Barfod, MD—who has more than 25 years of experience in proofreading English medical articles and presently works at Katsuta Hospital Mito GammaHouse—for her help with English-language editing.

References

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    Barajas RFChang JSSneed PKSegal MRMcDermott MWCha S: Distinguishing recurrent intra-axial metastatic tumor from radiation necrosis following Gamma Knife radiosurgery using dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging. AJNR Am J Neuroradiol 30:3673722009

    • Search Google Scholar
    • Export Citation
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    Belohlávek OSimonová GKantorová INovotný J JrLiscák R: Brain metastases after stereotactic radiosurgery using the Leksell Gamma Knife: can FDG PET help to differentiate radionecrosis from tumour progression?. Eur J Nucl Med Mol Imaging 30:961002003

    • Search Google Scholar
    • Export Citation
  • 4

    Bindal RKSawaya RLeavens MELee JJ: Surgical treatment of multiple brain metastases. J Neurosurg 79:2102161993

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    Chang ELWefel JSHess KRAllen PKLang FFKornguth DG: Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 10:103710442009

    • Search Google Scholar
    • Export Citation
  • 6

    Chao STAhluwalia MSBarnett GHStevens GHMurphy ESStockham AL: Challenges with the diagnosis and treatment of cerebral radiation necrosis. Int J Radiat Oncol Biol Phys 87:4494572013

    • Search Google Scholar
    • Export Citation
  • 7

    Chen JCPetrovich ZGiannotta SLYu CApuzzo ML: Radiosurgical salvage therapy for patients presenting with recurrence of metastatic disease to the brain. Neurosurgery 46:8608672000

    • Search Google Scholar
    • Export Citation
  • 8

    Chernov MHayashi MIzawa MOchiai TUsukura MAbe K: Differentiation of the radiation-induced necrosis and tumor recurrence after gamma knife radiosurgery for brain metastases: importance of multi-voxel proton MRS. Minim Invasive Neurosurg 48:2282342005

    • Search Google Scholar
    • Export Citation
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    Flickinger JCKondziolka DLunsford LDCoffey RJGoodman MLShaw EG: A multi-institutional experience with stereotactic radiosurgery for solitary brain metastasis. Int J Radiat Oncol Biol Phys 28:7978021994

    • Search Google Scholar
    • Export Citation
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    Gaspar LScott CRotman MAsbell SPhillips TWasserman T: Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 37:7457511997

    • Search Google Scholar
    • Export Citation
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    Hanssens PKarlsson BYeo TTChou NBeute G: Detection of brain micrometastases by high-resolution stereotactic magnetic resonance imaging and its impact on the timing of and risk for distant recurrences. J Neurosurg 115:4995042011

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    • Export Citation
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    Hazuka MBKinzie JJ: Brain metastases: results and effects of re-irradiation. Int J Radiat Oncol Biol Phys 15:4334371988

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    Hochstenbag MMTwijnstra AHofman PWouters EFten Velde GP: MR-imaging of the brain of neurologic asymptomatic patients with large cell or adenocarcinoma of the lung Does it influence prognosis and treatment?. Lung Cancer 42:1891932003

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    • Export Citation
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    Hoefnagels FWLagerwaard FJSanchez EHaasbeek CJKnol DLSlotman BJ: Radiological progression of cerebral metastases after radiosurgery: assessment of perfusion MRI for differentiating between necrosis and recurrence. J Neurol 256:8788872009

    • Search Google Scholar
    • Export Citation
  • 15

    Kano HKondziolka DLobato-Polo JZorro OFlickinger JCLunsford LD: T1/T2 matching to differentiate tumor growth from radiation effects after stereotactic radiosurgery. Neurosurgery 66:4864922010

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    • Export Citation
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    Karlsson BHanssens PWolff RSöderman MLindquist CBeute G: Thirty years' experience with Gamma Knife surgery for metastases to the brain. J Neurosurg 111:4494572009

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    Kickingereder PDorn FBlau TSchmidt MKocher MGalldiks N: Differentiation of local tumor recurrence from radiation-induced changes after stereotactic radiosurgery for treatment of brain metastasis: case report and review of the literature. Radiat Oncol 8:52592013

    • Search Google Scholar
    • Export Citation
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    Kim SYKim JSPark HSCho MJKim JOKim JW: Screening of brain metastasis with limited magnetic resonance imaging (MRI): clinical implications of using limited brain MRI during initial staging for non-small cell lung cancer patients. J Korean Med Sci 20:1211262005

    • Search Google Scholar
    • Export Citation
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    Kimura TSako KTanaka KGotoh TYoshida HAburano T: Evaluation of the response of metastatic brain tumors to stereotactic radiosurgery by proton magnetic resonance spectroscopy, 201TlCl single-photon emission computerized tomography, and gadolinium-enhanced magnetic resonance imaging. J Neurosurg 100:8358412004

    • Search Google Scholar
    • Export Citation
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    Kwon KYKong DSLee JINam DHPark KKim JH: Outcome of repeated radiosurgery for recurrent metastatic brain tumors. Clin Neurol Neurosurg 109:1321372007

    • Search Google Scholar
    • Export Citation
  • 21

    Lorenzoni JDevriendt DMassager NDavid PRuíz SVanderlinden B: Radiosurgery for treatment of brain metastases: estimation of patient eligibility using three stratification systems. Int J Radiat Oncol Biol Phys 60:2182242004

    • Search Google Scholar
    • Export Citation
  • 22

    Matsuo MMiwa KShinoda JKako NNishibori HSakurai K: Target definition by C11-methionine-PET for the radiotherapy of brain metastases. Int J Radiat Oncol Biol Phys 74:7147222009

    • Search Google Scholar
    • Export Citation
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    Mehta MPRozental JMLevin ABMackie TRKubsad SSGehring MA: Defining the role of radiosurgery in the management of brain metastases. Int J Radiat Oncol Biol Phys 24:6196251992

    • Search Google Scholar
    • Export Citation
  • 24

    Mitsuya KNakasu YHoriguchi SHarada HNishimura TBando E: Perfusion weighted magnetic resonance imaging to distinguish the recurrence of metastatic brain tumors from radiation necrosis after stereotactic radiosurgery. J Neurooncol 99:81882010

    • Search Google Scholar
    • Export Citation
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    Momose TNariai TKawabe TInaji MTanaka YWatanabe S: Clinical benefit of 11C methionine PET imaging as a planning modality for radiosurgery of previously irradiated recurrent brain metastases. Clin Nucl Med 39:9399432014

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    • Export Citation
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    Nariai TTanaka YWakimoto HAoyagi MTamaki MIshiwata K: Usefulness of l-[methyl-11C] methionine–positron emission tomography as a biological monitoring tool in the treatment of glioma. J Neurosurg 103:4985072005

    • Search Google Scholar
    • Export Citation
  • 27

    Noordijk EMVecht CJHaaxma-Reiche HPadberg GWVoormolen JHHoekstra FH: The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age. Int J Radiat Oncol Biol Phys 29:7117171994

    • Search Google Scholar
    • Export Citation
  • 28

    Patchell RATibbs PAWalsh JWDempsey RJMaruyama YKryscio RJ: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 322:4945001990

    • Search Google Scholar
    • Export Citation
  • 29

    Radiation Therapy Oncology Group: Cooperative Group Common Toxicity Criteria.. (https://www.rtog.org/ResearchAssociates/AdverseEventReporting/CooperativeGroup-CommonToxicityCriteria.aspx) [Accessed July 8 2016]

    • Export Citation
  • 30

    Serizawa THirai TNagano OHiguchi YMatsuda SOno J: Gamma Knife surgery for 1–10 brain metastases without prophylactic whole-brain radiation therapy: analysis of cases meeting the Japanese prospective multi-institute study (JLGK0901) inclusion criteria. J Neurooncol 98:1631672010

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    • Export Citation
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    Yamamoto MKawabe THiguchi YSato YNariai TBarfod BE: Delayed complications in patients surviving at least 3 years after stereotactic radiosurgery for brain metastases. Int J Radiat Oncol Biol Phys 85:53602013

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    Yamamoto MKawabe THiguchi YSato YNariai TWatanabe S: Validity of prognostic grading indices for brain metastasis patients undergoing repeat radiosurgery. World Neurosurg 82:124212492014

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Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: M Yamamoto. Acquisition of data: M Yamamoto, Kawabe, Watanabe. Analysis and interpretation of data: M Yamamoto, Koiso, Kawabe. Drafting the article: Koiso. Critically revising the article: M Yamamoto, T Yamamoto, Matsumura, Kasuya. Reviewed submitted version of manuscript: M Yamamoto, Koiso, Kawabe, Watanabe, T Yamamoto, Matsumura, Kasuya. Approved the final version of the manuscript on behalf of all authors: M Yamamoto. Statistical analysis: Sato, Higuchi. Study supervision: M Yamamoto, T Yamamoto, Matsumura, Kasuya.

Supplemental Information

Previous Presentations

Portions of this work were presented in an oral form on October 14, 2015, at the 74th Annual Meeting of the Japan Neurosurgical Society, Sapporo, Japan.

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Article Information

Contributor Notes

INCLUDE WHEN CITING DOI: 10.3171/2016.6.GKS161404.Correspondence Masaaki Yamamoto, Katsuta Hospital, Mito GammaHouse, Nakane 5125-2, Hitachinaka, Ibaraki 312-0011, Japan. email: bcd06275@nifty.com.

© AANS, except where prohibited by US copyright law.

Headings
Figures
  • View in gallery

    Survival probability (A) and neurological death–free survival (B) after the first (dotted line) and second (solid line) SRSs, as estimated using the standard Kaplan-Meier method.

References
  • 1

    Aoyama HTago MKato NToyoda TKenjyo MHirota S: Neurocognitive function of patients with brain metastasis who received either whole brain radiotherapy plus stereotactic radiosurgery or radiosurgery alone. Int J Radiat Oncol Biol Phys 68:138813952007

    • Search Google Scholar
    • Export Citation
  • 2

    Barajas RFChang JSSneed PKSegal MRMcDermott MWCha S: Distinguishing recurrent intra-axial metastatic tumor from radiation necrosis following Gamma Knife radiosurgery using dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging. AJNR Am J Neuroradiol 30:3673722009

    • Search Google Scholar
    • Export Citation
  • 3

    Belohlávek OSimonová GKantorová INovotný J JrLiscák R: Brain metastases after stereotactic radiosurgery using the Leksell Gamma Knife: can FDG PET help to differentiate radionecrosis from tumour progression?. Eur J Nucl Med Mol Imaging 30:961002003

    • Search Google Scholar
    • Export Citation
  • 4

    Bindal RKSawaya RLeavens MELee JJ: Surgical treatment of multiple brain metastases. J Neurosurg 79:2102161993

  • 5

    Chang ELWefel JSHess KRAllen PKLang FFKornguth DG: Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 10:103710442009

    • Search Google Scholar
    • Export Citation
  • 6

    Chao STAhluwalia MSBarnett GHStevens GHMurphy ESStockham AL: Challenges with the diagnosis and treatment of cerebral radiation necrosis. Int J Radiat Oncol Biol Phys 87:4494572013

    • Search Google Scholar
    • Export Citation
  • 7

    Chen JCPetrovich ZGiannotta SLYu CApuzzo ML: Radiosurgical salvage therapy for patients presenting with recurrence of metastatic disease to the brain. Neurosurgery 46:8608672000

    • Search Google Scholar
    • Export Citation
  • 8

    Chernov MHayashi MIzawa MOchiai TUsukura MAbe K: Differentiation of the radiation-induced necrosis and tumor recurrence after gamma knife radiosurgery for brain metastases: importance of multi-voxel proton MRS. Minim Invasive Neurosurg 48:2282342005

    • Search Google Scholar
    • Export Citation
  • 9

    Flickinger JCKondziolka DLunsford LDCoffey RJGoodman MLShaw EG: A multi-institutional experience with stereotactic radiosurgery for solitary brain metastasis. Int J Radiat Oncol Biol Phys 28:7978021994

    • Search Google Scholar
    • Export Citation
  • 10

    Gaspar LScott CRotman MAsbell SPhillips TWasserman T: Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 37:7457511997

    • Search Google Scholar
    • Export Citation
  • 11

    Hanssens PKarlsson BYeo TTChou NBeute G: Detection of brain micrometastases by high-resolution stereotactic magnetic resonance imaging and its impact on the timing of and risk for distant recurrences. J Neurosurg 115:4995042011

    • Search Google Scholar
    • Export Citation
  • 12

    Hazuka MBKinzie JJ: Brain metastases: results and effects of re-irradiation. Int J Radiat Oncol Biol Phys 15:4334371988

  • 13

    Hochstenbag MMTwijnstra AHofman PWouters EFten Velde GP: MR-imaging of the brain of neurologic asymptomatic patients with large cell or adenocarcinoma of the lung Does it influence prognosis and treatment?. Lung Cancer 42:1891932003

    • Search Google Scholar
    • Export Citation
  • 14

    Hoefnagels FWLagerwaard FJSanchez EHaasbeek CJKnol DLSlotman BJ: Radiological progression of cerebral metastases after radiosurgery: assessment of perfusion MRI for differentiating between necrosis and recurrence. J Neurol 256:8788872009

    • Search Google Scholar
    • Export Citation
  • 15

    Kano HKondziolka DLobato-Polo JZorro OFlickinger JCLunsford LD: T1/T2 matching to differentiate tumor growth from radiation effects after stereotactic radiosurgery. Neurosurgery 66:4864922010

    • Search Google Scholar
    • Export Citation
  • 16

    Karlsson BHanssens PWolff RSöderman MLindquist CBeute G: Thirty years' experience with Gamma Knife surgery for metastases to the brain. J Neurosurg 111:4494572009

    • Search Google Scholar
    • Export Citation
  • 17

    Kickingereder PDorn FBlau TSchmidt MKocher MGalldiks N: Differentiation of local tumor recurrence from radiation-induced changes after stereotactic radiosurgery for treatment of brain metastasis: case report and review of the literature. Radiat Oncol 8:52592013

    • Search Google Scholar
    • Export Citation
  • 18

    Kim SYKim JSPark HSCho MJKim JOKim JW: Screening of brain metastasis with limited magnetic resonance imaging (MRI): clinical implications of using limited brain MRI during initial staging for non-small cell lung cancer patients. J Korean Med Sci 20:1211262005

    • Search Google Scholar
    • Export Citation
  • 19

    Kimura TSako KTanaka KGotoh TYoshida HAburano T: Evaluation of the response of metastatic brain tumors to stereotactic radiosurgery by proton magnetic resonance spectroscopy, 201TlCl single-photon emission computerized tomography, and gadolinium-enhanced magnetic resonance imaging. J Neurosurg 100:8358412004

    • Search Google Scholar
    • Export Citation
  • 20

    Kwon KYKong DSLee JINam DHPark KKim JH: Outcome of repeated radiosurgery for recurrent metastatic brain tumors. Clin Neurol Neurosurg 109:1321372007

    • Search Google Scholar
    • Export Citation
  • 21

    Lorenzoni JDevriendt DMassager NDavid PRuíz SVanderlinden B: Radiosurgery for treatment of brain metastases: estimation of patient eligibility using three stratification systems. Int J Radiat Oncol Biol Phys 60:2182242004

    • Search Google Scholar
    • Export Citation
  • 22

    Matsuo MMiwa KShinoda JKako NNishibori HSakurai K: Target definition by C11-methionine-PET for the radiotherapy of brain metastases. Int J Radiat Oncol Biol Phys 74:7147222009

    • Search Google Scholar
    • Export Citation
  • 23

    Mehta MPRozental JMLevin ABMackie TRKubsad SSGehring MA: Defining the role of radiosurgery in the management of brain metastases. Int J Radiat Oncol Biol Phys 24:6196251992

    • Search Google Scholar
    • Export Citation
  • 24

    Mitsuya KNakasu YHoriguchi SHarada HNishimura TBando E: Perfusion weighted magnetic resonance imaging to distinguish the recurrence of metastatic brain tumors from radiation necrosis after stereotactic radiosurgery. J Neurooncol 99:81882010

    • Search Google Scholar
    • Export Citation
  • 25

    Momose TNariai TKawabe TInaji MTanaka YWatanabe S: Clinical benefit of 11C methionine PET imaging as a planning modality for radiosurgery of previously irradiated recurrent brain metastases. Clin Nucl Med 39:9399432014

    • Search Google Scholar
    • Export Citation
  • 26

    Nariai TTanaka YWakimoto HAoyagi MTamaki MIshiwata K: Usefulness of l-[methyl-11C] methionine–positron emission tomography as a biological monitoring tool in the treatment of glioma. J Neurosurg 103:4985072005

    • Search Google Scholar
    • Export Citation
  • 27

    Noordijk EMVecht CJHaaxma-Reiche HPadberg GWVoormolen JHHoekstra FH: The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age. Int J Radiat Oncol Biol Phys 29:7117171994

    • Search Google Scholar
    • Export Citation
  • 28

    Patchell RATibbs PAWalsh JWDempsey RJMaruyama YKryscio RJ: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 322:4945001990

    • Search Google Scholar
    • Export Citation
  • 29

    Radiation Therapy Oncology Group: Cooperative Group Common Toxicity Criteria.. (https://www.rtog.org/ResearchAssociates/AdverseEventReporting/CooperativeGroup-CommonToxicityCriteria.aspx) [Accessed July 8 2016]

    • Export Citation
  • 30

    Serizawa THirai TNagano OHiguchi YMatsuda SOno J: Gamma Knife surgery for 1–10 brain metastases without prophylactic whole-brain radiation therapy: analysis of cases meeting the Japanese prospective multi-institute study (JLGK0901) inclusion criteria. J Neurooncol 98:1631672010

    • Search Google Scholar
    • Export Citation
  • 31

    Serizawa TSaeki NHiguchi YOno JMatsuda SSato M: Diagnostic value of thallium-201 chloride single-photon emission computerized tomography in differentiating tumor recurrence from radiation injury after Gamma Knife surgery for metastatic brain tumors. J Neurosurg 102:Suppl2662712005

    • Search Google Scholar
    • Export Citation
  • 32

    Shuto TFujino HInomori SNagano H: Repeated Gamma Knife radiosurgery for multiple metastatic brain tumours. Acta Neurochir (Wien) 146:9899932004

    • Search Google Scholar
    • Export Citation
  • 33

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