Comparison of prognostic indices in patients who undergo melanoma brain metastasis radiosurgery

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  • 1 Departments of Neurological Surgery and
  • | 2 Radiation Oncology,
  • | 3 Center for Image-Guided Neurosurgery, and
  • | 4 Division of Hematology/Oncology,
  • | 5 Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and
  • | 6 Department of Neurological Surgery, Stanford University, Stanford, California
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OBJECTIVE

The goal of this study was to use 4 prognostic indices to compare survival times of patients who underwent Gamma Knife stereotactic radiosurgery (SRS) to treat melanoma brain metastases.

METHODS

The authors analyzed 422 consecutive patients (1440 brain metastases) who underwent Gamma Knife SRS. The median total brain tumor volume was 4.7 cm3 (range 0.3–69.3 cm3), and the median number of metastases was 2 (range 1–32). One hundred thirty-two patients underwent whole-brain radiation therapy. Survival times were compared using recursive partitioning analysis (RPA), the Score Index for Radiosurgery (SIR), the Basic Score for Brain Metastases (BSBM), and the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA).

RESULTS

The overall survival times after SRS were compared. With the RPA index, survival times were 2.6 months (Class III, n = 27), 5.5 months (Class II, n = 348), and 13.0 months (Class I, n = 47). With the DS-GPA index, survival times were 2.8 months (Scores 0–1, n = 67), 4.2 months (Scores 1.5–2.0, n = 143), 6.6 months (Scores 2.5–3.0, n = 111), and 9.4 months (Scores 3.5–4.0, n = 101). With the SIR, survival times were 3.2 months (Scores 0–3, n = 56), 5.8 months (Scores 4–7, n = 319), and 12.7 months (Scores 8–10, n = 47). With the BSBM index, survival times were 2.6 months (BSBM0, n = 47), 5.4 months (BSBM1, n = 282), 11.0 months (BSBM2, n = 86), and 8.8 months (BSBM3, n = 7). The DS-GPA index was the most balanced by case numbers in each class and provided the overall best prognostic index for overall survival.

CONCLUSIONS

The DS-GPA index proved most balanced and predictive of survival for patients with melanoma who underwent SRS as part of management for brain metastases. Patients whose DS-GPA score was ≥ 2.5 had predictably improved survival times after SRS.

ABBREVIATIONS

BSBM = Basic Score for Brain Metastases; DS-GPA = Diagnosis-Specific Graded Prognostic Assessment; HR = hazard ratio; KPS = Karnofsky Performance Scale; MST = median survival time; OS = overall survival; RPA = recursive partitioning analysis; SIR = Score Index for Radiosurgery; SRS = stereotactic radiosurgery; WBRT = whole-brain radiation therapy.

OBJECTIVE

The goal of this study was to use 4 prognostic indices to compare survival times of patients who underwent Gamma Knife stereotactic radiosurgery (SRS) to treat melanoma brain metastases.

METHODS

The authors analyzed 422 consecutive patients (1440 brain metastases) who underwent Gamma Knife SRS. The median total brain tumor volume was 4.7 cm3 (range 0.3–69.3 cm3), and the median number of metastases was 2 (range 1–32). One hundred thirty-two patients underwent whole-brain radiation therapy. Survival times were compared using recursive partitioning analysis (RPA), the Score Index for Radiosurgery (SIR), the Basic Score for Brain Metastases (BSBM), and the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA).

RESULTS

The overall survival times after SRS were compared. With the RPA index, survival times were 2.6 months (Class III, n = 27), 5.5 months (Class II, n = 348), and 13.0 months (Class I, n = 47). With the DS-GPA index, survival times were 2.8 months (Scores 0–1, n = 67), 4.2 months (Scores 1.5–2.0, n = 143), 6.6 months (Scores 2.5–3.0, n = 111), and 9.4 months (Scores 3.5–4.0, n = 101). With the SIR, survival times were 3.2 months (Scores 0–3, n = 56), 5.8 months (Scores 4–7, n = 319), and 12.7 months (Scores 8–10, n = 47). With the BSBM index, survival times were 2.6 months (BSBM0, n = 47), 5.4 months (BSBM1, n = 282), 11.0 months (BSBM2, n = 86), and 8.8 months (BSBM3, n = 7). The DS-GPA index was the most balanced by case numbers in each class and provided the overall best prognostic index for overall survival.

CONCLUSIONS

The DS-GPA index proved most balanced and predictive of survival for patients with melanoma who underwent SRS as part of management for brain metastases. Patients whose DS-GPA score was ≥ 2.5 had predictably improved survival times after SRS.

ABBREVIATIONS

BSBM = Basic Score for Brain Metastases; DS-GPA = Diagnosis-Specific Graded Prognostic Assessment; HR = hazard ratio; KPS = Karnofsky Performance Scale; MST = median survival time; OS = overall survival; RPA = recursive partitioning analysis; SIR = Score Index for Radiosurgery; SRS = stereotactic radiosurgery; WBRT = whole-brain radiation therapy.

Stereotactic radiosurgery (SRS) is a minimally invasive treatment option for patients with brain metastases, which occur in 10%–40% of patients with melanoma.1,16,17,19,20 The management options for melanoma brain metastases include resection in cases of symptomatic surgically accessible tumors, whole-brain radiotherapy (WBRT), chemotherapy, use of molecularly targeted antitumor agents,11,21 and other novel treatment modalities.3,7,13 In recent years, WBRT has been relegated to patients with miliary or meningeal melanoma brain metastases, because melanoma is thought to be relatively radioresistant.4,6

Several prognostic grading systems for the survival of patients with brain metastases have been proposed. These prognostic indices are commonly used as a guide for treatment decision making and for trial eligibility. The recursive partitioning analysis (RPA) classification5 is one of the major grading systems for assessing the prognosis of patients with brain metastases. Other prognostic indices, such as the Score Index for Radiosurgery (SIR)21 and the Basic Score for Brain Metastases (BSBM),12 were subsequently developed. The Graded Prognostic Assessment (GPA) was updated recently to the Diagnosis-Specific GPA (DS-GPA) index.18 In this study, we compared the predictive accuracy of these 4 major brain metastasis prognostic indices in patients with metastatic brain melanoma.

Methods

Data Collection

The data were collected retrospectively in a review of patient medical records. When not available from our medical records, patient survival data were obtained from the Internet-based Social Security Index. This study was approved by University of Pittsburgh Institutional Review Board.

Patient Population

Between August 1987 and December 2012, 444 consecutive patients underwent Gamma Knife SRS for melanoma brain metastases at the University of Pittsburgh Medical Center. Twenty-two patients were excluded from the analysis because we could not obtain their complete data, which left a final series of 422 patients (1440 brain metastases). Additional therapies included systemic chemotherapy in 203 (48%) patients, immunotherapy (e.g., interferon-α and interleukin 2) in 207 (49%) patients, local extracranial radiation therapy in 56 (13%) patients, and vaccine therapy in 39 (9%) patients. Only 1 patient with BRAF mutation underwent vemurafenib molecularly targeted antitumor agent therapy, and this patient died 3.7 months after SRS as a result of the progression of numerous new brain metastases. Demographics and clinical data of the patient population are shown in Table 1.

TABLE 1.

Demographics and clinical data

Characteristic/DemographicAll PatientsPatients Who Underwent Only SRS
No.%No.%
Sex
  Male2846716565
  Female138338735
Age
  ≥65 yrs1453416766
  <65 yrs277668534
No. of metastases
  1142349036
  2–3131317329
  4–681195120
  ≥768163815
Initial cerebral presentation
  Staging MRI2235316967
  Seizures4210239
  Tumor hemorrhage409125
  Mass effect (w/o bleed)117284819
Location of metastases
  Lobar supratentorial12018376084
  Deep supratentorial735344
  Cerebellum1218789
  Brainstem292172
  Cranium161152
Previous CNS therapy
  WBRT1323100
  Craniotomy651500
  Cyst aspiration4100
  Stereotactic biopsy14300
Previous systemic therapy
  Chemotherapy2034812449
  Immunotherapy2074913152
  Extracranial radiation56133715
Extent of systemic disease
  CNS only246114
  Primary site only389239
  Primary + 1 lymph node chain45112912
  Primary + >1 lymph node chain or visceral85204719
  Disseminated (>2 visceral sites)2305514256
Systemic disease status
  Active3137418774
  Controlled109266526
Main neurological symptom
  None2275416666
  Headache only389198
  Seizures18494
  Focal deficits119285020
  Cognitive deficits20583
KPS score
  90–1002676317971
  70–80128306124
  <70276125

For the management of brain metastases, Gamma Knife SRS was used as the primary option in 252 (60%) patients. One hundred thirty-two (31%) patients underwent initial WBRT before SRS, typically 30 Gy (range 21–60 Gy) in 10–14 fractions. Sixty-five (15%) patients underwent craniotomy before SRS, 4 (1%) patients underwent needle cyst aspiration, and 14 (3%) patients underwent stereotactic biopsy.

Grading Systems

RPA5 consists of the following 3 classes: I (patients < 65 years old, Karnofsky Performance Scale [KPS] score ≥ 70, controlled primary tumor, and no extracranial metastases), II (all patients not at Class I or III), and III (KPS score < 70). The SIR21 was obtained by summing the points from the following 5 variables: age (0, ≥ 60 years; 1, 51–59 years; 2, ≤ 50 years); KPS score at the time of SRS (0, ≤ 50; 1, 60–70; 2, 80–100); systemic disease status (0, progressive; 1, stable or partial remission; 2, complete remission or no evidence of disease); volume of the largest lesion (0, > 13 cm3; 1, 5–13 cm3; 2, < 5 cm3); and number of lesions (0, ≥ 3; 1, 2; 2, 1). Each SIR score was subgrouped as 0–3, 4–7, or 8–10. The BSBM12 was obtained by summing the points of the following 3 variables: KPS score (0, 50–70; 1, 80–100); control of primary tumor (0, no; 1, yes); and extracranial metastases (0, yes; 1, no). The DS-GPA18 was obtained by summing the points of the following 2 variables: KPS score (0, < 70; 1, 70–80; 2, 90–100) and number of brain metastases (0, > 3; 1, 2–3; 2, 1). We evaluated the prognostic grading scales based on the distribution of patient populations in each class of the grading scale and differences that appeared when pairs of adjacent classes in the same scale were compared. The best prognostic grading scales demonstrated a well-balanced patient population in each class and large differences in outcomes between adjacent pairs of classes.

Stereotactic Radiosurgery Procedures

A dose plan that conformed closely to tumor volume was designed using dose-planning software (Kula or Gamma Plan) supplied by the Gamma Knife manufacturer (Elekta AB). The median dose to margin was 18 Gy (range 10–22 Gy), and the median maximal dose was 33.3 Gy (range 20–50 Gy). The doses used were based on tumor location, tumor volume, and history of WBRT. The median target volume for the individual tumors was 1.4 cm3 (range 0.03–37.2 cm3), and the median target volume for the largest tumor was 3.3 cm3. The median total tumor volume treated per procedure was 4.7 cm3 (range 0.03–69.3 cm3). SRS was performed using a Leksell Gamma Knife model U, B, or C or the Perfexion model.

Statistical Analysis

The SPSS 22 software (IBM Corp.) was used for statistical analyses. Kaplan-Meier analyses were performed to assess overall survival (OS). The log-rank test for categorical data and the Cox proportional hazards model for continuous data were performed as univariate analyses. Multivariate analyses were performed to assess the prognostic value of different variables using the Cox proportional hazard.

Results

Patient Survival

At the time of assessment, 383 patients were deceased and 39 were alive. Among the deceased patients, 114 (30%) died as a result of brain disease progression, 10 (3%) patients died as a result of intracranial hemorrhage from brain metastases, 93 (24%) died as a result of systemic disease, and 156 (41%) died from an unknown cause. The median survival time (MST) from diagnosis of the primary tumor was 47.7 months (95% CI 41.25–52.89 months). The MST from the diagnosis of brain metastases was 8.3 months (95% CI 7.34–9.26 months). The MST after SRS was 5.7 months (95% CI 4.97–6.37 months). The OS rates after SRS were 71.3% at 3 months, 47.7% at 6 months, 25.8% at 12 months, 11.8% at 24 months, 5.0% at 36 months, and 1.8% at 5 years. Results of the univariate and multivariate analyses are shown in Table 2. Patient survival was not significantly associated with the year in which patients underwent their SRS (p = 0.119 [1988–2007 vs 2008–2012]; p = 0.853 [1988–2009 vs 2010–2012]).

TABLE 2.

Prognostic values for patient survival

VariableHigh-Risk GroupUnivariate AnalysisMultivariate Analysis
p ValueHR (95% CI)p ValueHR (95% CI)
Entire group
  AgeOlder0.1481.01 (0.99–1.01)0.191NA
  SexMale0.4500.92 (0.75–1.14)NANA
  KPS scoreLower<0.00010.99 (0.98–0.99)0.0010.986 (0.978–0.994)
  No. of brain tumorsLarger no.<0.00011.07 (1.05–1.10)<0.00011.067 (1.044–1.091)
  Largest tumorLarger0.0121.02 (1.01–1.03)0.241NA
  Total tumor volLarger<0.00011.02 (1.01–1.03)0.0061.016 (1.005–1.028)
  Previous chemotherapyNo0.0011.42 (1.16–1.74)0.125NA
  Previous immunotherapyNo0.5080.93 (0.76–1.14)NANA
  Previous WBRTYes<0.00011.57 (1.263–1.944)0.0021.411 (1.129–1.764)
  Interval from primary cancer diagnosis to brain metastasisShorter0.1581.001 (1.000–1.002)0.468NA
  Neurological symptomsYes0.0641.22 (0.99–1.51)NANA
  Extracranial statusActive<0.00011.96 (1.55–2.48)<0.00012.200 (1.725–2.806)
SRS-alone group
  AgeOlder0.0471.01 (1.00–1.02)0.191NA
  SexMale0.7810.96 (0.73–1.26)NANA
  KPS scoreLower0.0280.99 (0.98–0.99)0.0230.987 (0.975–0.998)
  No. of brain tumorsLarger no.<0.00011.07 (1.04–1.10)<0.00011.067 (1.039–1.095)
  Largest tumor volLarger0.0241.03 (1.00–1.05)0.057NA
  Total tumor volLarger<0.00011.04 (1.02–1.06)0.0051.027 (1.008–1.046)
  Previous chemotherapyNo<0.00051.62 (1.24–2.12)0.0321.355 (1.026–1.798)
  Previous immunotherapyNo0.4810.91 (0.70–1.18)NANA
  Interval from primary cancer diagnosis to brain metastasisShorter0.3441.001 (0.99–1.002)NANA
  Neurological symptomsYes0.4370.437 (0.68–1.18)NANA
  Extracranial statusActive<0.00011.95 (1.44–2.66)<0.00012.158 (1.559–2.987)

NA = not applicable.

In the entire group, 132 (31%) patients underwent WBRT before SRS, 65 (15%) had undergone craniotomy, 4 (1%) had undergone cyst aspiration, and 14 (3%) had undergone diagnostic stereotactic biopsy. In the group of patients who underwent SRS as a primary CNS treatment (252), 225 patients died and 27 survived. The MST from diagnosis of the primary tumor was 47.1 months (95% CI 38.07–56.07 months), and the MST from the diagnosis of brain metastases was 7.9 months (95% CI 6.78–9.09 months). The MST after SRS was 6.4 months (95% CI 5.52–7.34 months). The OS rates after SRS were 74.7% at 3 months, 52.2% at 6 months, 27.9% at 12 months, 13.0% at 24 months, 6.1% at 36 months, and 2.3% at 5 years. Results of the univariate and multivariate analyses are shown in Table 2.

Prognostic Grading Systems

In the entire series, the OS curves after SRS according to the 4 major grading systems are shown in Fig. 1. As shown in Table 3, the RPA, SIR, and BSBM grading systems had large discrepancies in their patient numbers. A total of 82% of the patients were classified at RPA Class II, 76% at SIR Scores 4–7, and 67% at BSBM1. However, with DS-GPA grading, the patient population was better distributed into each score group (Scores 0–1, 16%; Scores 1.5–2, 34%; Scores 2.5–3, 26%; Scores 3.5–4, 24%).

FIG. 1.
FIG. 1.

Kaplan-Meier curves for OS of the patients for each index according to individual class in patients with melanoma brain metastases in the entire series (n = 422). MST values are in months.

TABLE 3.

Statistical results of quantitative survival

Grading SystemClass/ScoreNo.%MST (mos)95% CIComparisonHR95% CIp Value
Entire series
  RPAI471113.09.90–16.1
II348825.54.81–6.19vs Class I1.81.26–2.430.001
III2762.61.89–3.25vs Class II1.81.20–2.650.004
  SIR8–10471112.76.96–18.4
4–7319765.85.14–6.46vs Scores 8–101.61.16–2.230.004
0–356133.21.65–4.82vs Scores 4–71.61.20–2.140.002
  BSBM3728.80.0–6.43
2862011.07.22–14.8vs Score 31.00.40–2.470.994
1282675.44.70–6.16vs Score 21.71.32–2.210.0001
047112.61.76–3.38vs Score 12.21.63–3.070.0001
  DS-GPA3.5–4101249.47.14–11.6
2.5–3111266.65.13–8.13vs Scores 3.5–41.31.01–1.800.048
1.5–2143344.23.20–5.26vs Scores 2.5–31.41.09–1.840.010
0–167162.91.86–3.89vs Scores 1.5–21.41.01–1.840.041
SRS-alone series
  RPAI301212.47.94–16.86
II210835.74.74–6.72vs Class I1.81.20–2.820.005
III1252.10.33–.3.93vs Class II1.40.75–2.550.296
  SIR8–10321315.41.17–29.69
4–7197786.45.46–7.34vs Scores 8–101.81.12–2.670.005
0–32393.11.14–5.21vs Scores 4–71.71.07–2.610.024
  BSBM3313.70–8.9
2552212.47.40–17.40vs Score 30.20.07–0.760.016
1175696.15.01–7.13vs Score 21.81.29–2.520.001
01982.01.46–2.48vs Score 13.21.96–5.200.0001
  DS-GPA3.5–468279.75.61–13.85
2.5–369276.62.85–9.41vs Scores 3.5–41.51.01–2.090.043
1.5–286345.02.96–7.10vs Scores 2.5–31.30.90–1.750.184
0–129122.82.40–3.20vs Scores 1.5–21.51.00–2.380.053

The MSTs after SRS according to the RPA grading scales were 13.0 months (Class I), 5.5 months (Class II), and 2.6 months (Class III) (Table 3). The RPA grading revealed statistically significant differences when pairs of adjacent classes were compared (p = 0.001, hazard ratio [HR] 1.8 [RPA Class I vs II]; p = 0.004, HR 1.8 [Class II vs III]). The OS rates 6 months after SRS were 81% in RPA Class I, 45% in RPA Class II, and 22% in RPA Class III (Table 4).

TABLE 4.

OS times according to each grading index

Grading SystemClass/ScoreNo.%OS (%)
6

Mos
12

Mos
24

Mos
36

Mos
Entire series
  RPAI471180.556.616.610.0
II3488245.322.711.64.8
III27622.211.17.40
  SIR8–10471167.650.021.69.6
4–73197648.225.011.55.0
0–3561328.69.55.70
  BSBM37257.142.900
2862071.949.419.710.9
12826744.921.210.83.5
0471119.16.42.10
  DS-GPA3.5–41012465.842.323.010.5
2.5–31112653.527.814.19.5
1.5–21433440.321.65.32.7
0–1671626.66.34.70
SRS-alone series
  RPAI301279.451.824.212.1
II2108349.425.111.75.4
III12533.316.78.30
  SIR8–10321371.255.027.513.8
4–71977852.225.211.55.2
0–323926.113.04.30
  BSBM33133.3000
2552274.250.125.114.7
11756950.223.710.74.3
019810.55.300
  DS-GPA3.5–4682765.443.924.613.8
2.5–3692754.226.613.14.5
1.5–2863447.323.67.12.8
0–1291231.06.93.40

The MSTs after SRS according to the SIR system were 3.2 months (Scores 1–3), 5.8 months (Scores 4–7), and 12.7 months (Scores 8–10). The SIR revealed statistically significant differences when pairs of adjacent SIR groups were compared (p = 0.004, HR 1.6 [Scores 8–10 vs 4–7; p = 0.002, HR 1.6 [Scores 4–7 vs 0–3]). The OS rates 6 months after SRS were 68% (Scores 8–10), 48% (Scores 4–7), and 29% (Scores 0–3) (Table 4).

The MSTs after SRS according to the BSBM classification were 2.6 months (BSBM0), 5.4 months (BSBM1), 11.0 months (BSBM2), and 2.6 months (BSBM3). The BSBM grading revealed statistically significant differences when pairs of adjacent BSBM grading groups were compared, except for BSBM3 vs BSBM2 (p = 0.994 [BSBM3 vs BSBM2]; p = 0.0001, HR 1.7 [BSBM2 vs BSBM1]; p = 0.0001, HR 2.2 [BSBM1 vs BSBM0]). The OS rates 6 months after SRS were 57% (BSBM3), 72% (BSBM2), 45% (BSBM1), and 27% (BSBM0) (Table 4).

The MSTs after SRS according to the DS-GPA were 2.9 months (Scores 0–1), 4.2 months (Scores 1.5–2), 6.6 months (Scores 2.5–3), and 9.4 months (Scores 3.5–4). The DS-GPA grading revealed statistically significant differences when pairs of adjacent classes were compared (p = 0.048, HR 1.3 [Scores 3.5–4 vs 2.5–3]; p = 0.010, HR 1.4 [Scores 2.5–3 vs 1.5–2]; p = 0.041, HR 1.4 [Scores 1.5–2 vs 0–1]). The OS rates 6 months after SRS were 66% (Scores 3.5–4), 54% (Scores 2.5–3), 40% (Scores 1.5–2), and 27% (Scores 0–1) (Table 4).

Stereotactic Radiosurgery as the Primary Strategy for Treating Brain Metastasis

In the group of patients who underwent SRS as the primary management for brain metastases (n = 242), the post-SRS OS curves are shown in Fig. 2 according to the 4 major grading systems. As shown in Table 3, the RPA, SIR, and BSBM grading systems had large discrepancies in patient numbers among their groups. A total of 83% of the patients were classified at RPA Class II, 78% at SIR Scores 4–7, and 69% at BSBM1. However, with DS-GPA grading, the patient population was better distributed into each score group (Scores 0–1, 12%; Scores 1.5–2, 34%; Scores 2.5–3, 27%; Scores 3.5–4, 27%).

FIG. 2.
FIG. 2.

Kaplan-Meier curves for OS of the patients for each index according to individual class in patients who underwent SRS as primary treatment for their melanoma brain metastases (n = 252). MST values are in months.

The MSTs after SRS according to RPA were 12.4 months (Class I), 5.7 months (Class II), and 2.1 months (Class III) (Table 3). The RPA grading revealed statistically significant differences when RPA Classes I and II were compared (p = 0.005), whereas RPA Class II was not statistically different from RPA Class III (p = 0.296). RPA Class I was significantly associated with a longer survival time than was RPA Class III (p = 0.013). The OS rates 6 months after SRS were 79% (Class I), 49% (Class II), and 33% (Class III) (Table 4).

The MSTs after SRS according to the SIR were 3.1 months (Scores 1–3), 6.4 months (Scores 4–7), and 15.4 months (Scores 8–10). The SIR scores revealed statistically significant differences when pairs of adjacent SIR score groups were compared (p = 0.005 [Scores 8–10 vs 4–7; p = 0.024 [Scores 4–7 vs 0–3]). The OS rates 6 months after SRS were 71% (Scores 8–10), 55% (Scores 4–7), and 26% (Scores 0–3) (Table 4).

The MSTs after SRS according to the BSBM were 2.0 months (BSBM0), 6.1 months (BSBM1), 12.4 months (BSBM2), and 3.7 months (BSBM3). BSBM grading revealed statistically significant differences when pairs of adjacent BSBM groups were compared (p = 0.016 [BSBM3 vs BSBM2]; p = 0.001 [BSBM2 vs BSBM1]; p = 0.0001 [BSBM1 vs BSBM0]). The OS rates 6 months after SRS were 33% (BSBM3), 74% (BSBM2), 50% (BSBM1), and 11% (BSBM0) (Table 4).

The MSTs after SRS according to the DS-GPA were 2.8 months (Scores 0–1), 5.0 months (Scores 1.5–2), 6.6 months (Scores 2.5–3), and 9.7 months (Scores 3.5–4). DS-GPA grading revealed statistically significant differences when Scores 3.5–4 vs 2.5–3 were compared (p = 0.043), whereas comparisons of Scores 2.5–3 vs 1.5–2 and Scores 1.5–2 vs 0–1 were not statistically different. DS-GPA Scores 3.5–4 were significantly associated with longer survival times than were DS-GPA Scores 1.5–2 (p < 0.0001, HR 2.0 [95% CI 1.48–2.59]) and Scores 0–1 (p < 0.0001, HR 3.0 [95% CI 2.12–4.20]). The OS rates 6 months after SRS were 65% (Scores 3.5–4), 54% (Scores 2.5–3), 47% (Scores 1.5–2), and 31% (Scores 0–1) (Table 4).

Discussion

Role of Prognostic Indices

Brain metastases are a heterogeneous entity, and survival time is related to the type of primary cancer, systemic control, type of treatment, and responses to treatment. Factors that affect prognosis are relevant to therapeutic decision making. Survival predictions can be difficult when they are applied to individual patients, so the quest for the best system is important.9 The prognostic indices for brain metastases can identify patients whose MST after SRS can be estimated with greater accuracy. The RPA classification was the earliest and most commonly validated predictive grading system. The RPA classification was based on patients who underwent WBRT, but it was reported recently to be applicable also to patients who underwent SRS.8,10,15,23,24 In most reports, the largest numbers of patients are found to be at RPA Class II. In our study, 82% of the patients with melanoma were classified at RPA Class II. The RPA classes were highly correlated with patient survival (p = 0.001 [Class I vs II]; p = 0.004 [Class II vs III]) (Table 3). The SIR requires a more complex calculation because it consists of 5 prognostic factors. Moreover, the SIR requires a volume of the largest lesion at the time of SRS. Sperduto et al.18 suggested that the role of prognostic indices is to better predict outcome to guide decision making before and during treatment. Volume measurement is usually performed at the time of SRS, which makes its prognostic scoring difficult before treatment. The SIR also suffers from an unbalanced patient proportion within each prognostic class. In our study, 76% of the patients were classified as having an SIR score of 4–7. In fact, all 3 SIR score groups (Scores 8–10, 4–7, and 0–3) were highly correlated with patient survival (p = 0.004 [Scores 8–10 vs 4–7]; p = 0.002 [Scores 4–7 vs 0–3]) (Table 3).

The BSBM consists of the following 3 systemic prognostic factors: KPS score, control of primary tumor, and presence of extracranial metastases. Most patients are found to have a BSBM score of 1. In our study, 67% of the patients were classified at BSBM1, and only 2% of the patients were classified at BSBM3. When compared with BSBM2, BSBM3 was not associated with patient survival (p = 0.994), because too few patients were in the BSBM3 group (Table 3). Sperduto et al.18 mentioned that prognostic factors for patients with brain metastases varied according to diagnosis, and for each diagnosis, a robust separation into different GPA scores was discerned, which implies considerable heterogeneity in outcome. Therefore, they updated their initial GPA to the DS-GPA. Although the RPA was based on patients who underwent WBRT, the DS-GPA was derived from patient populations treated with WBRT, craniotomy, SRS, or a combination of multiple treatment modalities. The DS-GPA contains the following 4 prognostic score groups: DS-GPA Scores 0–1, 1.5–2, 2.5–3, and 3.5–4. In this study, the distributions of patients in various DS-GPA groups were reasonably balanced within each prognostic score group (Scores 3.5–4, 24%; Scores 2.5–3, 26%; Scores 1.5–2, 34%; Scores 0–1, 16%) (Table 3). The DS-GPA was significantly correlated with patient survival between each DS-GPA score group. Overall, we found that the DS-GPA was the best grading system for the prediction of OS of patients with melanoma, all of whom received SRS as primary or adjuvant management.

Stereotactic Radiosurgery as a Primary Brain Metastasis Treatment

In many previous reports of brain metastasis grading systems, many patients underwent WBRT before SRS.10,14,24 Previous WBRT was a poor prognostic predictor for patients with brain metastases.10 Adding WBRT to SRS did not seem to improve patient survival, but it might have improved both local tumor control and distant tumor control at 6 months.2 However, in a previous study,10 managing patients with WBRT followed by salvage or boost SRS was associated with decreased OS. This observation provided additional evidence that SRS without WBRT is a reasonable initial treatment option for most patients with melanoma and brain metastases. In our current study, 31% of the patients underwent previous WBRT, 15% had undergone previous craniotomy, and 1% had undergone cyst aspiration as their brain metastasis treatment, which left the study with 252 patients who underwent SRS as their primary brain metastasis treatment. We evaluated 4 prognostic grading indices in patients with SRS as their primary brain metastasis treatment (Table 3). In multivariate analysis, for both the entire group and the SRS-alone group, factors associated with shorter OS after SRS included lower KPS score, larger number of brain metastases, larger total tumor volume, and active extracranial metastases (Table 2). Of those who underwent SRS alone, the largest proportion (83%) of patients was at RPA Class II. RPA Class I was significantly associated with longer OS than RPA Class II (p = 0.005), whereas RPA Class II was not associated with OS when compared with RPA Class III (p = 0.296), which might be a result of the smaller number (n = 12) of patients at RPA Class III (Table 3). The SIR also suffered from unbalanced patient proportions within the prognostic classes (Scores 4–7, 78%). However, all 3 SIR score groups (Scores 8–10, 4–7, and 0–3) were highly correlated with patient survival (p = 0.005 [Scores 8–10 vs 4–7]; p = 0.024 [Scores 4–7 vs 0–3]) (Table 3). Although the BSBM also suffered from unbalanced patient proportions within the prognostic classes (BSBM1, 69%), all BSBM classes were significantly correlated with OS (p = 0.016 [BSBM3 vs BSBM2]; p = 0.001 [BSBM2 vs BSBM1]; p = 0.0001 [BSBM1 vs BSBM0]). In the SRS-alone group, the DS-GPA had a well-balanced proportion of patients within the prognostic score groups (Scores 3.5–4, 27%; Scores 2.5–3, 27%; Scores 1.5–2, 34%; Scores 0–1, 12%). DS-GPA Scores 3.5–4 were significantly associated with longer OS than were DS-GPA Scores 2.5–3 (p = 0.043). Other DS-GPA score groups were not correlated with OS, which might be because of the small numbers of patients in each DS-GPA score group. GPA Scores 3.5–4 were significantly associated with longer OS than were GPA Scores 1.5–2 (p < 0.0001) and 0–1 (p < 0.0001). We believe that the DS-GPA was the best grading system for the prediction of OS because of the better balance in patient numbers in each score group. Patients whose DS-GPA score was ≥ 2.5 had significantly improved survival after SRS. However, results of recent studies that used molecularly targeted antitumor agents, such as vemurafenib, dabrafenib, and trametinib, suggested that these agents can result in remarkable improvement in selected patients with melanoma.11,22 The impact of these agents on existing intracranial disease is unknown at present, but a reduction in the risk of new intracranial melanoma spread might have a major effect on survival. Therefore, our finding that the DS-GPA score currently best predicts the response of brain SRS in patients with melanoma might evolve in the future.

Study Limitations

We acknowledge that this retrospective study had inherent limitations and that the results might relate in part to selection bias. In an attempt to offset the variations in referral patterns and significant treatment paradigms, such as the use of SRS for increasing numbers of metastases, these results were analyzed and a 20-year time period was used. We found that patient survival was not significantly associated with the year in which the patients underwent their SRS. In the future, molecularly targeted antitumor agents might further improve survival in patients with melanoma and intracranial spread. Over the next 10 years, we anticipate performing a follow-up analysis of the outcomes of melanoma after it spreads to the brain in patients who underwent molecular therapy as a part of the standard of care.

Conclusions

The 4 major grading systems studied here yielded statistically significant differences in patients with melanoma brain metastases. However, in this series of patients with melanoma selected for SRS, the RPA, SIR, and BSBM had significant variations in the numbers of patients distributed into graded subgroups. Among these 4 major grading systems, the DS-GPA index proved most balanced and predictive of survival. Patients who had a DS-GPA score of ≥ 2.5 had significantly improved survival after SRS.

Acknowledgments

We thank Professor Douglas Kondziolka, MD (NYU Langone Medical Center), for his significant contribution to patient management at the University of Pittsburgh.

Disclosures

Dr. Lunsford is a consultant for and stockholder in Elekta AB and a consultant for the Focused Ultrasound Foundation; and Dr. Kirkwood is a consultant for BMS, Roche, Amgen, Green Peptide, and Genentech. This study is supported by an Elekta research grant.

Author Contributions

Conception and design: Kano. Acquisition of data: Kano, Morales-Restrepo, Iyer, Weiner, Mousavi. Drafting the article: Kano. Critically revising the article: Kano, Kirkwood, Tarhini, Flickinger, Lunsford. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Kano. Statistical analysis: Kano. Study supervision: Kano.

References

  • 1

    Bafaloukos D, Gogas H: The treatment of brain metastases in melanoma patients. Cancer Treat Rev 30:515520, 2004

  • 2

    Brown PD, Brown CA, Pollock BE, Gorman DA, Foote RL: Stereotactic radiosurgery for patients with “radioresistant” brain metastases. Neurosurgery 62:Suppl 2 790801, 2008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Christopoulou A, Retsas S, Kingsley D, Paddick I, Lindquist C: Integration of Gamma Knife surgery in the management of cerebral metastases from melanoma. Melanoma Res 16:5157, 2006

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Doss LL, Memula N: The radioresponsiveness of melanoma. Int J Radiat Oncol Biol Phys 8:11311134, 1982

  • 5

    Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, et al. : Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 37:745751, 1997

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Geara FB, Ang KK: Radiation therapy for malignant melanoma. Surg Clin North Am 76:13831398, 1996

  • 7

    Hara W, Tran P, Li G, Su Z, Puataweepong P, Adler JR Jr, et al. : Cyberknife for brain metastases of malignant melanoma and renal cell carcinoma. Neurosurgery 64:2 Suppl A26A32, 2009

    • Search Google Scholar
    • Export Citation
  • 8

    Kondziolka D, Kano H, Harrison GL, Yang HC, Liew DN, Niranjan A, et al. : Stereotactic radiosurgery as primary and salvage treatment for brain metastases from breast cancer. Clinical article. J Neurosurg 114:792800, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Kondziolka D, Parry PV, Lunsford LD, Kano H, Flickinger JC, Rakfal S, et al. : The accuracy of predicting survival in individual patients with cancer. J Neurosurg 120:2430, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Liew DN, Kano H, Kondziolka D, Mathieu D, Niranjan A, Flickinger JC, et al. : Outcome predictors of Gamma Knife surgery for melanoma brain metastases. Clinical article. J Neurosurg 114:769779, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB, et al. : Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol 13:10871095, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Lorenzoni J, Devriendt D, Massager N, David P, Ruíz S, Vanderlinden B, et al. : Radiosurgery for treatment of brain metastases: estimation of patient eligibility using three stratification systems. Int J Radiat Oncol Biol Phys 60:218224, 2004

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Mathieu D, Kondziolka D, Cooper PB, Flickinger JC, Niranjan A, Agarwala S, et al. : Gamma Knife radiosurgery in the management of malignant melanoma brain metastases. Neurosurgery 60:471482, 2007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Serizawa T, Higuchi Y, Nagano O, Hirai T, Ono J, Saeki N, et al. : Testing different brain metastasis grading systems in stereotactic radiosurgery: Radiation Therapy Oncology Group's RPA, SIR, BSBM, GPA, and modified RPA. J Neurosurg 117:Suppl 3137, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Serizawa T, Higuchi Y, Nagano O, Matsuda S, Ono J, Saeki N, et al. : A new grading system focusing on neurological outcomes for brain metastases treated with stereotactic radiosurgery: the modified Basic Score for Brain Metastases. J Neurosurg 121:Suppl 3543, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Sloan AE, Nock CJ, Einstein DB: Diagnosis and treatment of melanoma brain metastasis: a literature review. Cancer Contr 16:248255, 2009

  • 17

    Sperduto PW, Berkey B, Gaspar LE, Mehta M, Curran W: A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database. Int J Radiat Oncol Biol Phys 70:510514, 2008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Sperduto PW, Kased N, Roberge D, Xu Z, Shanley R, Luo X, et al. : Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases. J Clin Oncol 30:419425, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Tarhini AA, Agarwala SS: Management of brain metastases in patients with melanoma. Curr Opin Oncol 16:161166, 2004

  • 20

    Tsao H, Atkins MB, Sober AJ: Management of cutaneous melanoma. N Engl J Med 351:9981012, 2004

  • 21

    Weltman E, Salvajoli JV, Brandt RA, de Morais Hanriot R, Prisco FE, Cruz JC, et al. : Radiosurgery for brain metastases: a score index for predicting prognosis. Int J Radiat Oncol Biol Phys 46:11551161, 2000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Wolf A, Zia S, Verma R, Pavlick A, Wilson M, Golfinos JG, et al. : Impact on overall survival of the combination of BRAF inhibitors and stereotactic radiosurgery in patients with melanoma brain metastases. J Neurooncol 127:607615, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Yamamoto M, Kawabe T, Higuchi Y, Sato Y, Barfod BE, Kasuya H, et al. : Validity of three recently proposed prognostic grading indexes for breast cancer patients with radiosurgically treated brain metastases. Int J Radiat Oncol Biol Phys 84:11101115, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Yamamoto M, Sato Y, Serizawa T, Kawabe T, Higuchi Y, Nagano O, et al. : Subclassification of recursive partitioning analysis Class II patients with brain metastases treated radiosurgically. Int J Radiat Oncol Biol Phys 83:13991405, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

Contributor Notes

Correspondence Hideyuki Kano, Department of Neurological Surgery, University of Pittsburgh, Ste. B-400, UPMC Presbyterian, 200 Lothrop St., Pittsburgh, PA 15213. email: kanoh@upmc.edu.

INCLUDE WHEN CITING Published online January 20, 2017; DOI: 10.3171/2016.9.JNS161011.

Disclosures Dr. Lunsford is a consultant for and stockholder in Elekta AB and a consultant for the Focused Ultrasound Foundation; and Dr. Kirkwood is a consultant for BMS, Roche, Amgen, Green Peptide, and Genentech. This study is supported by an Elekta research grant.

  • View in gallery

    Kaplan-Meier curves for OS of the patients for each index according to individual class in patients with melanoma brain metastases in the entire series (n = 422). MST values are in months.

  • View in gallery

    Kaplan-Meier curves for OS of the patients for each index according to individual class in patients who underwent SRS as primary treatment for their melanoma brain metastases (n = 252). MST values are in months.

  • 1

    Bafaloukos D, Gogas H: The treatment of brain metastases in melanoma patients. Cancer Treat Rev 30:515520, 2004

  • 2

    Brown PD, Brown CA, Pollock BE, Gorman DA, Foote RL: Stereotactic radiosurgery for patients with “radioresistant” brain metastases. Neurosurgery 62:Suppl 2 790801, 2008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Christopoulou A, Retsas S, Kingsley D, Paddick I, Lindquist C: Integration of Gamma Knife surgery in the management of cerebral metastases from melanoma. Melanoma Res 16:5157, 2006

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Doss LL, Memula N: The radioresponsiveness of melanoma. Int J Radiat Oncol Biol Phys 8:11311134, 1982

  • 5

    Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, et al. : Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 37:745751, 1997

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Geara FB, Ang KK: Radiation therapy for malignant melanoma. Surg Clin North Am 76:13831398, 1996

  • 7

    Hara W, Tran P, Li G, Su Z, Puataweepong P, Adler JR Jr, et al. : Cyberknife for brain metastases of malignant melanoma and renal cell carcinoma. Neurosurgery 64:2 Suppl A26A32, 2009

    • Search Google Scholar
    • Export Citation
  • 8

    Kondziolka D, Kano H, Harrison GL, Yang HC, Liew DN, Niranjan A, et al. : Stereotactic radiosurgery as primary and salvage treatment for brain metastases from breast cancer. Clinical article. J Neurosurg 114:792800, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Kondziolka D, Parry PV, Lunsford LD, Kano H, Flickinger JC, Rakfal S, et al. : The accuracy of predicting survival in individual patients with cancer. J Neurosurg 120:2430, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Liew DN, Kano H, Kondziolka D, Mathieu D, Niranjan A, Flickinger JC, et al. : Outcome predictors of Gamma Knife surgery for melanoma brain metastases. Clinical article. J Neurosurg 114:769779, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB, et al. : Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol 13:10871095, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Lorenzoni J, Devriendt D, Massager N, David P, Ruíz S, Vanderlinden B, et al. : Radiosurgery for treatment of brain metastases: estimation of patient eligibility using three stratification systems. Int J Radiat Oncol Biol Phys 60:218224, 2004

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Mathieu D, Kondziolka D, Cooper PB, Flickinger JC, Niranjan A, Agarwala S, et al. : Gamma Knife radiosurgery in the management of malignant melanoma brain metastases. Neurosurgery 60:471482, 2007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Serizawa T, Higuchi Y, Nagano O, Hirai T, Ono J, Saeki N, et al. : Testing different brain metastasis grading systems in stereotactic radiosurgery: Radiation Therapy Oncology Group's RPA, SIR, BSBM, GPA, and modified RPA. J Neurosurg 117:Suppl 3137, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Serizawa T, Higuchi Y, Nagano O, Matsuda S, Ono J, Saeki N, et al. : A new grading system focusing on neurological outcomes for brain metastases treated with stereotactic radiosurgery: the modified Basic Score for Brain Metastases. J Neurosurg 121:Suppl 3543, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Sloan AE, Nock CJ, Einstein DB: Diagnosis and treatment of melanoma brain metastasis: a literature review. Cancer Contr 16:248255, 2009

  • 17

    Sperduto PW, Berkey B, Gaspar LE, Mehta M, Curran W: A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database. Int J Radiat Oncol Biol Phys 70:510514, 2008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Sperduto PW, Kased N, Roberge D, Xu Z, Shanley R, Luo X, et al. : Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases. J Clin Oncol 30:419425, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Tarhini AA, Agarwala SS: Management of brain metastases in patients with melanoma. Curr Opin Oncol 16:161166, 2004

  • 20

    Tsao H, Atkins MB, Sober AJ: Management of cutaneous melanoma. N Engl J Med 351:9981012, 2004

  • 21

    Weltman E, Salvajoli JV, Brandt RA, de Morais Hanriot R, Prisco FE, Cruz JC, et al. : Radiosurgery for brain metastases: a score index for predicting prognosis. Int J Radiat Oncol Biol Phys 46:11551161, 2000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Wolf A, Zia S, Verma R, Pavlick A, Wilson M, Golfinos JG, et al. : Impact on overall survival of the combination of BRAF inhibitors and stereotactic radiosurgery in patients with melanoma brain metastases. J Neurooncol 127:607615, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Yamamoto M, Kawabe T, Higuchi Y, Sato Y, Barfod BE, Kasuya H, et al. : Validity of three recently proposed prognostic grading indexes for breast cancer patients with radiosurgically treated brain metastases. Int J Radiat Oncol Biol Phys 84:11101115, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Yamamoto M, Sato Y, Serizawa T, Kawabe T, Higuchi Y, Nagano O, et al. : Subclassification of recursive partitioning analysis Class II patients with brain metastases treated radiosurgically. Int J Radiat Oncol Biol Phys 83:13991405, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

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