Gamma Knife Surgery versus Reoperation for Recurrent Glioblastoma Multiforme

PEER-REVIEW REPORTS

Gamma Knife Surgery versus Reoperation for Recurrent Glioblastoma Multiforme Bente Sandvei Skeie1,2, Per Øyvind Enger 2,6, Jan Brøgger 3, Jeremy Christopher Ganz 2, Frits Thorsen 5, Jan Ingeman Heggdal 4, Paal-Henning Pedersen1,2

Key words 䡲 Gamma knife surgery 䡲 Glioblastoma multiforme 䡲 Operation 䡲 Stereotactic radiosurgery 䡲 Tumor recurrence Abbreviations and Acronyms CI: Confidence interval EBRT: External beam radiation therapy GBM: Glioblastoma multiforme GKS: Gamma knife surgery HR: Hazard ratio KPS: Karnofsky performance score MRI: Magnetic resonance image PCV: Procarbazine, lomustibe, and vincristine RPA: Recursive partitioning analysis RTOG: Radiation Therapy Oncology Group From the Departments of 1Surgical Sciences, 2 Neurosurgery, 3Neurology, 4Oncology and Medical Physics, and 5Biomedicine, Haukeland University Hospital, Bergen; and 6Oncomatrix Research Lab, Department of Biomedicine, University of Bergen, Bergen, Norway To whom correspondence should be addressed: Bente Sandvei Skeie, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2012) 78, 6:658-669. http://dx.doi.org/10.1016/j.wneu.2012.03.024 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter © 2012 Elsevier Inc. All rights reserved.

INTRODUCTION Glioblastoma multiforme (GBM) constitutes 50% of all glial tumors (5). The prognosis has not improved much over recent decades, with a short median survival of 14.6 months (8, 9, 40, 43). Because of their infiltrative growth, radical surgery is not possible. For the same reason, conventional fractionated radiotherapy has a limited effect; it is not possible to deliver an effective dose to all of the infiltrating tumor cells because of the concomitant toxicity to adjacent normal brain (19). Although chemotherapeutic drugs in combination with radiation may prolong survival, they still have a limited efficacy and do not offer the prospect of a definite cure (41). Thus, GBMs inevitably recur despite multimodal treatment, often within months after surgery.

658

www.SCIENCEDIRECT.com

䡲 BACKGROUND: The optimal management of patients with recurrent glioblastoma multiforme (GBM) is a subject of controversy. These patients may be candidates for both reoperation and/or gamma knife surgery (GKS). Few studies have addressed the role of GKS for relapsing gliomas, and the results have not been compared with reoperation. To validate the efficacy and safety of GKS, we compared the survival and complication rates of GKS and reoperation for recurrent GBMs. 䡲 METHODS: This study retrospectively reviewed 77 consecutive patients with histopathologically confirmed GBMs retreated for recurrent GBM between 1996 and 2007. Thirty-two patients underwent GKS, 26 reoperation and 19 both procedures. 䡲 RESULTS: The median time from the second intervention to tumor progression was longer after GKS than after resection, P ⴝ 0.009. Median survival after retreatment was 12 months for the 51 patients receiving GKS compared with 6 months for reoperation only (P ⴝ 0.001, hazard ratio [HR] 2.4), and 19 months versus 16 months from the time of primary diagnosis (P ⴝ 0.021, HR 1.8). A multivariate analysis adjusted for possible confounding factors (tumor volume, recursive partitioning analysis class, neurological deficits, time to recurrence, adjuvant therapy, and tumor location) showed significantly longer survival for patients treated with GKS, both from retreatment (P ⴝ 0.013, HR 4.1) and from primary diagnosis (P ⴝ 0.002, HR 5.8). The adjusted results were still significant after separate analysis according to tumor volume <5 mL, 5 to 20 mL, and >20 mL. The complications rate was 9.8% after GKS and 25.2% after reoperation. 䡲 CONCLUSIONS: GKS may be an alternative to open surgery for small GBMs at the time of recurrences, with a significantly lower complication rate and a possible survival benefit compared with reoperation.

Many centers routinely combine surgery with fractionated radiation therapy and chemotherapy for newly diagnosed GBMs. However, the optimal treatment of recurrent GBMs has not yet been established (16). Consequently, clinical practice varies between institutions. Most GBMs recur locally in the resection cavity, and are therefore potential candidates both for surgery as well as focused radiation therapy (28). Several reports have investigated the role of surgery for recurrent GBMs in adults previously given multimodal treatment, and suggest that a subset of patients may benefit from a reoperation (3, 13, 38). However, these studies clearly suffer from a selection bias, and do not support reoperation for tumor recurrences on a routine basis (38).

Radiosurgery with gamma knife surgery (GKS) combines the delivery of high radiation doses to the target volume with a sharp dose decrease toward the surrounding brain (22). Thisapproachpermitsthedeliveryofdoseshigh enough to achieve cell death in the tumor, while at the same time avoiding radiation damage to the adjacent normal brain tissue. GKS can be administered as a boost in conjunction with external beam radiation therapy (EBRT), or at the time of recurrence. Nwokedi et al. reported prolonged survival in a retrospective series of GBM patients treated with GKS within 4 weeks of EBRT (29). Others reported a trend toward increasedsurvivalwhenGKSwasgivenatthetime of tumor progression compared with GKS as an initial boost (17). One prospective randomized trial showed no effect of GKS on survival

WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2012.03.024

PEER-REVIEW REPORTS BENTE SANDVEI SKEIE ET AL.

GKS VS. REOPERATION FOR RGM

Figure 1. Examples of glioblastoma multiforme cases treated with radiosurgery.

when GKS was administered before fractionated radiation therapy. Thus, the role and timing of gamma knife treatment with respect to GBM recurrences is, like surgical treatment, controversial (37). To our knowledge, there are no previous reports comparing surgery and GKS for GBM recurrences. The present work includes 77 patients with GBM tumor recurrences treated with GKS, reoperation or both. The aim of this study was to analyze survival outcome according to treatment group.

PATIENTS AND METHODS Study Population We reviewed 77 consecutive patients, including 49 men and 28 women who were treated for recurrent tumor, either with GKS, reoperation, or both between 1996 and 2007 at the Department of Neurosurgery at Haukeland University HospitalofBergen.Thisstudyincludedonlypa-

tients with pathologically confirmed GBM, corresponding to the Radiation Therapy Oncology Group-recursive partitioning analysis (RTOGRPA) class III-VI described by Curran et al. (7). We had no information about the O6-methylguanine-DNA methyltransferase promoter methylation status (15) of the patients. Thirtytwo patients were treated with GKS, 26 patients were reoperated, and 19 patients were treated with both procedures. Of the 19 patients receiving both retreatment modalities, 13 had surgery for the first recurrence and radiosurgery for a second recurrence. Six of the 19 patients in the combined treatment group received both retreatments during the same hospital stay because of residual tumor seen on the postoperative magnetic resonance image (MRI) after resection. The other 13 had surgery for the first recurrence and radiosurgery for a second recurrence. A total of 113 interventions were performed. Fifty-two (67.5%) patients underwent one single retreatment, 16 (20.8%) patients had two retreatments, 8 (10.4%) patients had three

WORLD NEUROSURGERY 78 [6]: 658-669, DECEMBER 2012

interventions, and 1 patient (1.3%) had five interventions for tumor recurrence. The retreatment modality was selected on a case-by-case basis as a function of tumor size, location, and the functional status of the patient. Patients with lower Karnofsky performance scores (KPS) and smaller and surgically inaccessible tumors tended more often to receive GKS rather than repeat resection. The patients’ age, RPA class, neurological deficits, adjuvant therapy, and tumor’s relation to eloquent brain, right versus left side of the brain, and time to recurrence were, however, comparable for the two treatment groups. Recurrent disease was confirmed by the onset of contrast enhancement or increasing volumes showing enhancement on repeat MRI. Differentiating second-time recurrent tumor after retreatment reliably from radiation injury based on MRI without a biopsy is difficult (4). Progressive contrast enhancements over time usually represent a mixture of viable tumor and radiation-induced necrosis and may even in

www.WORLDNEUROSURGERY.org

659

PEER-REVIEW REPORTS BENTE SANDVEI SKEIE ET AL.

GKS VS. REOPERATION FOR RGM

Table 1. Overall Patient and Treatment Characteristics Parameters Number of patients

Number of Patients (%) 77

GKS Reoperation

GKS ⴙ Reoperation

P Values

32

26

Male

49 (64%)

12

9

19 7

Female

28 (36%)

20

17

12

0.974

51

54

50

0.493

Age (years) Median

55.3

Range

27–73

⬎50

52 (67.5%)

15

4

6

⬍50

25 (32.5%)

17

22

16

0.039 0.078

KPS 76

73

78

81

’70

Mean

61 (79.2%)

21

23

17

⬍70

16 (20.8%)

11

3

2

0.046

4.3

4.1

0.283

RPA

4.0

4.3

Neurological deficits No

14 (18.2%)

6

3

5

Yes

46 (59.7)

16

19

11

Epilepsy

17 (22.1%)

10

4

3

0.319

11.0

9.3

10.4

0.854

Time to recurrence Mean (months)

10.3

⬍5 months

33 (42.9%)

14

7

12

5–10 months

20 (26.0%)

9

10

1

⬎10 months

24 (31.2%)

9

9

6

0.080

Adjuvant therapy Stupp protocol

29 (37.%)

3

3

1

PCV and EBRT

13 (16.9%)

15

8

6

EBRT without chemotherapy

30 (39%)

1

7

5

5 (6.5%)

13

10

7

72 (93.5%)

29

26

17

5 (6.5%)

3

0

2

Right side

38 (49.4%)

16

8

9

Left side

35 (45.5)

13

18

10

No

46 (59.7)

14

8

9

Yes

31 (40.3)

18

18

10

12.4

35.2

13.9

None

0.992

Location Unifocal Multifocal/deep seated

0.260

Tumor location 0.321

Eloquent brain 0.475

Tumor volume Mean (mL)

17.9

⬍5 mL

21 (27.3%)

14

0

7

5–20 mL

21 (27.3%)

10

4

7

⬎20 mL

21 (27.3%)

6

10

5

⬍0.001

0.006 Continues

660

www.SCIENCEDIRECT.com

some cases be caused by radiation injury only (27, 34). Metabolic imaging, MR spectroscopy, MR perfusion, and positron emission tomography were not used on a routine basis, but as a supplementinindividualcases.Theretreatment modality was chosen based on the “clinician’s best educated judgments” after discussion between neurosurgeons and oncologists and in consultation with experienced neuroradiologists. Examples of GBM cases treated with radiosurgery are shown in Figure 1. The mean follow-up time was 20.1 months (range 1 to 114 months) from the primary operation and 8.9 months from retreatment. Follow-up MRI was availablefor98(86.7%)oftheretreatments.The patients lost to follow-up were equally distributed among the three treatment groups. Patient and treatment characteristics are given for the three groups separately in Table 1. Prior Treatment All patients had gross total resection of the tumor as the initial treatment. Standard therapy also included EBRT within 8 weeks after surgery, with doses varying from 39 to 60 Gy (1.6 to 3Gyin13to30fractions).Theoncologicaltreatment has changed over the years. From 1996 up to and including 2004, patients received radiation doses of 39 to 54 Gy alone or in combination with procarbazine, lomustine, and vincristine (PCV). From 2005, patients received the Stupp protocol (42) with temozolomide and a high EBRT dose of 60 Gy (2 Gy in 30 fractions). Thus 29 patients (37.7%) were treated with the Stupp protocol, 13 patients (16.9%) were treated with EBRT in combination with PCV, 30 patients (38.9%) were treated with EBRT alone, and 5 patients (6.5%) had no radiation or chemotherapy. Some patients had a second treatment with chemotherapy or radiation after the second surgery/GKS. A margin dose of 12 Gy was prescribed to the contrast-enhancing regions on T1-weighted MRIs, and was delivered with the Leksell gamma knife (Elekta Instrument AB, Stockholm, Sweden) using the Gamma Plan software. The median margin dose was 12.2 Gy (range 8 to 20 Gy), and the median central dose was 31 Gy (range 16 to 57 Gy). A wide range of margin doses was used to balance the risks and expected benefit of treatment. This is in line with previous studies that report margin doses from 3 to 24 Gy (17, 29, 32, 37).Doseselectionwasbasedontumorvolume, prior radiation dose to the area, time since EBRT, and location of the lesion. Proximity to eloquent brain or radiosensitive structures such as brainstem, anterior visual pathways, and co-

WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2012.03.024

PEER-REVIEW REPORTS BENTE SANDVEI SKEIE ET AL.

GKS VS. REOPERATION FOR RGM

Table 1. Continued Parameters

Number of Patients (%)

GKS Reoperation

GKS ⴙ Reoperation

P Values

Neuronavigation at primary surgery Yes

22 (28.6%)

11

11

8

No

55 (71.4%)

21

21

11

0.052

Complications Yes

19 (24.7%)

3

12

4

No

58 (75.3%)

29

14

15

0.005

GKS, gamma knife surgery; KPS, Karnofsky performance score; RPA, recursive partitioning analysis; PCV, procarbazine, lomustibe, and vincristine; EBRT, external beam radiation therapy.

chlea as well as proximity to cerebrospinal fluid (resection cavity, ventricles, and subarachnoid space), blood vessels, and bone affect the chosen dose. Generally lower doses were used for larger volumes to restrict the volume of normal brain contained within the 12-Gy volumes (12). We tried to restrict the volume of the brainstem receiving ⬎12 Gy to 1 mL (11) and the maximum dose to the anterior visual pathways to ⬍8 Gy and cochlea to ⬍4 Gy (Figure 1). The average treatment time in the gamma knife was 34 minutes (range 5 to 78 minutes).

Statistics Patient and treatment-related parameters were compared between the treatment groups. To analyze the effect of reoperation versus GKS, the patients were analyzed in two treatment groups: GKS: yes/no and reoperation: yes/no, and as three separate retreatment groups: GKS, resection, or both. The ␹2 test, Student t test, and the one-way analysis of variance test were performed to compare groups. Survival from GKS, reoperation, and primary surgery was estimated by the KaplanMeier method. A multivariate analysis of outcome according to treatment group was conducted unadjusted and adjusted for possible confounding factors including RPA class, neurological deficits, time to recurrence, adjuvant therapy, tumor location (unifocal versus multifocal, eloquent versus noneloquent brain, and left- versus right-sided tumor), and tumor volume. Univariate and multivariate analyses were performed using the Cox proportional hazards model. All 113 interventions were analyzed for local tumor control, time to tumor progression (Kaplan-Meier method), and clinical outcome (␹2 test and Student t test). Probability values ⬍.05 were

considered statistically significant. All statistical analyses were performed using SPSS 18.0 (SPSS, Inc., Chicago, Illinois, USA).

RESULTS Survival Analysis and Local Tumor Control Local tumor control could be assessed for 98 of 113 interventions, and was achieved in 9 of 48 (18.8%) GKS procedures and in 1 of 50 (2.0%) reoperations, P ⫽ 0.032, ␹2 ⫽ 4.59. The actuarial local tumor control rates at 1, 3, 6, and 12 months were 85.4%, 66.7%, 49.4%, and 25.0% after GKS treatment and 76.0%, 36.0%, 16.0%, and 14.0% after resection. The median time from second intervention to tumor progression was 6 months (95% confidence interval [CI]: 2.86 to 9.14) after GKS and 2 months (95% CI 0.61to3.39)afterresection,P⫽0.009, ␹2 ⫽9.4. The median survival time for the whole series was 17 months from the initial diagnosis. The overall survival rate was 72.7% at 12 months, 29.9% at 24 months, and 7.3% after 60 months. For the GKS treatment group (51 patients), the median survival time was 19 months, versus 16 months for patients treated with surgery only (26 patients) (P ⫽ 0.021). The potential impact of various factors on survival was estimated using a univariate Cox regression model (Table 2). Prognostic factors for longer survival after the initial diagnosis include GKS treatment, increased time to recurrence, adjuvant treatment, unifocal tumor, and tumor volume ⬍20 mL. From the time of recurrence, median survival times were 12 months for the GKS group versus 6 months for the patients who received reoperation only (P ⫽ 0.001), as shown in Figure 2A. The survival rates in the

WORLD NEUROSURGERY 78 [6]: 658-669, DECEMBER 2012

GKS group were 80.4% at 6 months, 43.1% at 12 months, and 17.6% at 24 months, versus 46.2% at 6 months, 15.4% at 12 months, and 0% at 24 months for the group not receiving GKS. The time from primary treatment was not significantly different for the treatment groups. Patients treated with GKS more often had KPS ⬍70 (P ⫽ 0.046), age ⬎50 years (P ⫽ 0.039), smaller tumor volumes (P ⬍ 0.001), and received further treatment (surgery, GKS, and chemotherapy) more often (Table 1). Longer survival times after retreatment were seen for the GKS treatment group (P ⬍ 0.001), among patients with smaller tumor volumes (P ⬍ 0.001) or tumor involvement of noneloquent brain regions (P ⫽ 0.030), and for patients receiving further interventions with surgery or GKS after the first retreatment (P ⫽ 0.003, Table 2). Finally, we analyzed the outcomes according to treatment group, unadjusted and adjusted for possible confounding factors in a multivariate analysis. Potential impact by various factors on survival both from retreatment (Table 3, Figures 2B and 2C) and from primary diagnosis (Table 4) was estimated as hazard ratios (HR), using a multivariate Cox proportional hazards model. In the unadjusted analysis, longer survivals from both retreatment and primary diagnosis were seen among patients treated in the gamma knife (P ⬍ 0.01). The relative risk of death for patients not undergoing GKS was 2.4 from retreatment and 1.8 from diagnosis compared with patients treated in the gamma knife. After adjusting for possible confounders (RPA class, neurological deficits before surgery, time to retreatment, adjuvant therapy, and tumor location) in Model A (77 patients), the HR for patients not treated with GKS increased to 8.2 from retreatment (P ⬍ 0.01) and 7.4 (P ⬍ 0.01) from primary diagnosis. In the adjusted Model B, also including tumor volume that was available for only 63 of the 77 patients, the HR in favor of GKS were 4.1 (P ⫽ 0.013) from retreatment and 5.8 (P ⫽ 0.002) from primary diagnosis. Other factors for improved survival after retreatment in Model A were RPA class (P ⫽ 0.028) and adjuvant therapy with EBRT and PCV (P ⫽ 0.001), and in Model B: tumor volume (P ⫽ 0.008) and reoperation (P ⫽ 0.029). Late recurrence and adjuvant therapy (EBRT and PCV) were associated with

www.WORLDNEUROSURGERY.org

661

PEER-REVIEW REPORTS BENTE SANDVEI SKEIE ET AL.

GKS VS. REOPERATION FOR RGM

Table 2. Results of Univariate Analysis of Survival Outcome According to Various Prognostic Factors in 77 Patients with Recurrent Glioblastoma Multiforme Number of Patients

Survival (Median) After Retreatment, Months (95% CI)

GKS

51

12 (9.4–14.6)

No GKS

26

6 (4.3–7.7)

Reoperation

45

8 (5.5–10.5)

No reoperation

32

9 (6.8–11.2)

GKS ⫹ reoperation

19

15 (12.8–40.4)

GKS

32

9 (8.7–14.9)

Reoperation

26

6 (5.1–9.2)

7

17 (11.8–32.5)

Parameter

P Values

Survival (Median) After Primary Diagnosis, Months (95% CI)

P Values

Treatment group 19 (16.4–21.6) ⬍0.001

16 (13.3–18.7)

0.015

16 (13.2–18.8) 0.735

18 (14.7–21.3)

0.823

21 (21.2–55.9) 18 (16.7–30.8) ⬍0.001

16 (13.4–20.2)

0.014

RPA Class III

21 (15.5–40.0)

Class IV

45

10 (8.6–21.5)

17 (19.5–36.6)

Class V

23

9 (7.5–10.5)

16 (13.6–20.0)

Class VI

2

3 (0.0–35.6)

ⱖ70

61

10 (10.0–21.3)

⬍70

16

9 (6.4–12.3)

⬍50

25

13 (10.3–21.6)

ⱖ50

52

9 (9.8–18.9)

0.071

23 (22.0–26.0)

0.179

14 (13.3–28.8)

0.141

KPS 17 (19.4–33.3) 0.464

Age group (years) 20 (20.5–43.7) 0.137

16 (15.5–27.9)

0.684

16 (17.0–30.1)

0.090

Gender Female

28

8 (6.2–21.4)

Male

49

10 (9.8–17.2)

14

12 (6.7–36.2)

18 (17.0–37.5) 0.584

Neurological deficits No Yes

46

8 (7.6–14.1)

Epilepsy

17

12 (8.7–20.1)

24

12 (9.3–28.0)

19 (15.8–49.5) 14 (15.9–29.4) 0.129

21 (16.9–29.7)

0.266

Time to recurrence ⬎10 months 5–10 months

20

6 (5.2–18.4)

⬍5 months

33

10 (8.7–13.0)

29

9 (7.9–19.1)

31 (29.5–53.9) 16 (13.7–26.0) 0.257

13 (11.7–16.3)

⬍0.001

Adjuvant primary treatment Stupp protocol

19 (17.5–39.1)

PCV and EBRT

13

15 (7.9–38.6)

29 (23.9–58.2)

EBRT

30

8 (7.8–13.4)

13 (13.3–25.1)

None

5

6 (2.7–11.3)

Yes

61

10 (10.0–19.7)

No

5

8 (5.2–9.6)

0.095

6 (4.4–11.2)

0.094

13 (8.3–16.1)

⬍0.001

Unifocal tumor 18 (20.0–32.0) 0.023 Continues

662

www.SCIENCEDIRECT.com

WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2012.03.024

PEER-REVIEW REPORTS BENTE SANDVEI SKEIE ET AL.

GKS VS. REOPERATION FOR RGM

Table 2. Continued Survival (Median) After Retreatment, months (95% CI)

Number of Patients

Parameter

Survival (Median) After Primary Diagnosis, months (95% CI)

P Values

P Values

Right- versus left-sided tumor Left

35

9 (9.5–29.5)

Right

38

11 (8.6–15.1)

Yes

46

8 (7.8–12.7)

No

31

13 (10.2–28.3)

18 (18.5–39.4) 0.239

17 (16.8–28.5)

0.115

Eloquent brain 16 (15.5–26.3) 0.030

20 (20.3–42.8)

0.068

Tumor volume ⬍5 mL

21

13 (13.5–25.8)

21 (21.4–46.7)

5–20 mL

21

12 (8.3–34–8)

22 (19.3–48.0)

⬎20 mL

21

6 (4.5–9.4)

None

52

8 (5.9–10.1)

Two retreatments

16

11 (9.7–12.3)

9

21 (9.9–32.1)

⬍0.001

⬍0.001

12 (10.2–16.6)

Further intervention after GKS/reoperation

Three or more retreatments

16 (13.0–19.0) 16 (10.1–21.9) 0.003

30 (12.0–48.0)

0.001

CI, confidence interval; GKS, gamma knife surgery; RPA, recursive partitioning analysis; KPS, Karnofsky performance score; PCV, procarbazine, lomustibe, and vincristine; EBRT, external beam radiation therapy.

Cumulative Survival

0.8

0.6 p=0.001

0.4

HR 2.4

C 1.0

1.0 GKS yes no

0.8

0.6 p<0.001 0.4

0.2

0.2

0.0

0.0

HR 8.2

GKS 0.8 Cumulative Survival

B GKS yes no

Cumulative Survival

A1.0

There was no difference in survival between patients with tumors receiving margin doses of more than 12 Gy versus 12 Gy, different maximum doses, or the degree of tumor dose cover. The use of neuronavigation during primary surgery had no impact on survival. The median overall survivals for RPA class III-VI were 21 months, 17 months, 16 months, and 23 months, respectively. Both gamma knife–treated and reoper-

Because only patients with tumor volumes within the range of GKS (⬍20 mL) could be randomized to reoperation or GKS in a prospective study, the 3 volume groups ⬍5 mL, 5 to 20 mL, and ⬎20 mL were analyzed separately. The adjusted results from multivariate analysis were still highly significant for the medium (P ⫽ 0.041, HR 442.0) and large group (P ⫽ 0.043, HR 38.1). All patients with tumors ⬍5 mL underwent GKS.

longer survival from primary diagnosis in both models. A multivariate Cox proportional hazards model excluding the patients receiving both treatments showed a relative risk of death for patients undergoing reoperation of 1.8 (P ⫽ 0.035) compared with patients treated with GKS in the unadjusted model, 4.9 (P ⬍ 0.001) in the adjusted model A and 1.3 (P ⫽ 0.667) in model B including tumor volume.

yes no

0.6 p=0.013 0.4

HR 4.1

0.2

0.0 0.00 0.00

20.00 40.00 60.00 80.00 100.00 120.00 Time from first retreatment (months)

0.00

20.00 40.00 60.00 80.00 100.00 120.00 Time from frist retreatment

Figure 2. (A) Unadjusted Cox regression plot for survival from retreatment with GKS versus no GKS. (B) Cox regression plot for survival from retreatment with GKS versus no GKS adjusted for multivariate analysis

WORLD NEUROSURGERY 78 [6]: 658-669, DECEMBER 2012

20.00

40.00

60.00

80.00 100.00 120.00

Time from first retreatment (months)

model A. (C) Cox regression plot for survival from retreatment with GKS versus no GKS adjusted for multivariate analysis model B including tumor volume. GKS, gamma knife surgery.

www.WORLDNEUROSURGERY.org

663

PEER-REVIEW REPORTS BENTE SANDVEI SKEIE ET AL.

GKS VS. REOPERATION FOR RGM

Table 3. Results of Multivariate Analysis of Survival Outcome After Primary Diagnosis According to Treatment Group, Unadjusted and Adjusted for Possible Confounding Factors in 77 Patients with Recurrent Glioblastoma Multiforme Adjusted Analysis Model B Survival (Median) After Retreatment Number of Patients

Months (95% CI)

GKS

51

12 (9.4–14.6)

No GKS

26

6 (4.3–7.7)

Reoperation

45

8 (5.5–10.5)

No Reoperation

32

9 (6.8–11.2)

Parameter

Unadjusted Analysis

Adjusted Analysis Model A

Including Tumor Volume

HR (95% CI)

P Values

HR (95% CI)

P Values

HR (95% CI)

P Values

2.4 (1.5–4.09)

0.001

8.2 (3.5–19.33)

⬍0.001

4.1 (1.3–12.5)

0.013

1.1 (0.7–1.7)

0.75

1.9 (0.9–4)

2.4 (1.1–5.4)

0.029

Treatment group GKS

Treatment group reoperation

0.096

RPA classification 3

7

17 (11.8–32.5)

4

45

10 (8.6–21.5)

5

23

6

2

3 (0–36.6)

14

12 (6.7–36.2)

9 (7.5–10.5)

0.028

0.311

3.4 (1.3–9.3)

0.016

2.8 (0.9–8.5)

0.063

2.7 (0.9–8.2)

0.075

2.5 (0.7–8.9)

0.015

16.2 (2.3–114.6)

0.005

4.3 (0.4–42.6)

0.208

Neurological deficits No Yes

46

8 (7.6–14.1)

Epilepsy

17

12 (8.7–21.5)

⬎10

24

12 (9.3–28)

5–10

20

⬍5

33

0.826

0.984

1.1 (0.5–2.5)

0.773

1.1 (0.4–2.8)

0.860

0.9 (0.4–2)

0.825

1.0 (0.4–2.6)

0.922

Time to recurrence (months)

6 (5.2–18.4) 10 (8.7–13)

0.562 1 (0.5–0.8) 1.4 (0.7–3)

0.846

0.96

1.2 (0.5–2.7)

0.772

0.326

0.9 (0.4–2.4)

0.664

Adjuvant therapy Stupp

29

9 (7.9–19.1)

PCV ⫹EBRT

13

15 (7.9–38.6)

0.2 (0.1–0.6)

0.001 0.002

0.2 (0.07–0.7)

0.056 0.007

EBRT

30

8 (7.8–13.4)

1.3 (0.7–2.4)

None

5

6 (2.7–11.3)

Yes

61

10 (10–19.7)

No

5

8 (5.2–9.6)

Right side

38

11 (8.6–15.1)

Left side

35

9 (9.5–29.5)

No

31

13 (10.2–28.3)

Yes

46

8 (7.8–12.7)

21

13 (13.5–25.8)

0.378

0.9 (0.4–1.8)

0.703

3 (0.9–10.9)

0.086

1.7 (0.4–6.3)

0.457

7.2 (0.7–70.8)

0.089

1.8 (0.1–22.5)

0.638

1.1 (0.7–2)

0.632

1.4 (0.7–2.6)

0.314

1.3 (0.6–2.5)

0.495

1.3 (0.6–2.8)

0.565

Unifocal

Tumor location

Eloquent area

Volume categories (mL) ⬍5

0.008 Continues

664

www.SCIENCEDIRECT.com

WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2012.03.024

PEER-REVIEW REPORTS BENTE SANDVEI SKEIE ET AL.

GKS VS. REOPERATION FOR RGM

Table 3. Continued Adjusted Analysis Model B Survival (Median) After Retreatment

Unadjusted Analysis

Parameter

Number of Patients

Months (95% CI)

5–20

21

⬎20

21

GKS ⫹ Reoperation

19

15 (12.8–40.4)

GKS

32

9 (8.7–14.9)

2.1 (1.1–4.0)

Reoperation

26

6 (5.1–9.2)

3.9 (2.0–7.5)

HR (95% CI)

P Values

Adjusted Analysis Model A HR (95% CI)

P Values

Including Tumor Volume HR (95% CI)

P Values

12 (8.3–34.8)

1.6 (0.7–3.5)

0.232

6 (4.5–9.4)

4.6 (1.7–12.2)

0.002

Treatment group ⬍0.01 0.021 ⬍0.01

⬍0.001 1.9 (0.9–4.0) 8.2 (3.5–19.2)

0.096 ⬍0.001

0.023 2.4 (1.1–5.4)

0.029

4.1 (1.3–12.5)

0.013

CI, confidence interval; HR, hazard ratio; GKS, gamma knife surgery; RPA, recursive partitioning analysis; PCV, procarbazine, lomustibe, and vincristine; EBRT, external beam radiation therapy.

ated patients had longer survivals than predicted from RPA, except from class III patients who were reoperated (Table 5). For RPA class IV, which contained the majority of patients, survival after GKS and reoperation was 18 and 13 months, respectively (P ⬍ 0.032). There were too few patients to estimate median survival with statistically significant confidence intervals for reoperated patients in class III and both gamma knife–treated and reoperated patients in class VI.

Clinical Outcome Clinical outcome could be evaluated for 105 of the 113 interventions. Twenty-eight of 52 patients treated with GKS had symptoms of mass effect (10 patients with paresis, 7 with seizures, 5 with headaches, 4 with aphasia, and 2 with disorientation) compared with 40 of 53 resected patients (16 patients with paresis, 9 seizures, 9 headaches, 5 aphasia, and 1 disorientation), P ⫽ 0.013, ␹2 ⫽ 8.70. Fourteen of the 28 patients improved after GKS, 7 patients remained unchanged, and 3 became worse. Similarly, 16 of 40 patients improved after resection, 7 patients remained unchanged, and 16 became worse, P ⫽ 0.209, ␹2 ⫽ 5.869. The change in neurological symptoms for the GKS patients was evaluation at first follow-up 2 to 4 weeks after GKS. The median time for improvement was 25.5 ⫾ 15.6 days after GKS and 4 ⫾ 6.3 days after resection, P ⬍ 0.001. Similarly the median time for worsening was 23.0 ⫾ 7.5 days after GKS and 4 ⫾ 6.9 days after resection, P ⬍ 0.001.

Complications Ten patients (14.3%) had a complication due to the primary surgery. Seven patients had increased neurological deficits, three patients had a postoperative hematoma requiring reoperation, and one patient had a wound infection. Of the 45 patients who underwent reoperation for residual tumor, there were complications in 26.7% (nine patients with increased neurological deficits, one death [2.2%] due to postoperative hemorrhage, one wound infection, and one patient with wound infection, meningitis, and lung embolus). Six patients (24%) showed a decreased postoperative KPS. Among the eight patients undergoing a second reoperation, three patients (37.5%) suffered complications (one death because of an abscess and lung emboli, two with increased neurological deficits). There were no cases of treatment-related adverse events or episodes of acute neurological toxicity during admission among the patients treated with GKS. On follow-up images, 5 of the 51 patients (9.8%) receiving GKS had increasing edema possibly caused by adverse radiation effects. One of the seven patients (14.3%) with a second GKS treatment had a transient worsening of neurological function. This patient had radiation edema after the first GKS. In total, 33.8% of the 77 patients had complications related to open surgery and 9.8% due to radiosurgery, P ⫽ 0.005. The mean hospital stay after reoperation and GKS was 7.2 and 2.2 days, respectively (P ⫽ 0.001).

WORLD NEUROSURGERY 78 [6]: 658-669, DECEMBER 2012

DISCUSSION Nearly all GBM patients suffer a relapse after the initial treatment. These relapses are often left untreated to avoid burdening the patients with time-consuming therapies, potential side effects, and discomfort in the terminal stage of their illness. In this study, we retrospectively reviewed survival outcomes for patients with GBM recurrence treated with GKS, resection, or both procedures. Patients treated with GKS at the time of tumor progression had significantly better local tumor control and significantly longer survival than patients not treated with GKS, both from the time of diagnosis and from the time of retreatment. The present study is retrospective with obvious weaknesses regarding selection bias and nonuniform treatment modalities over time. Larger tumors were more often treated with surgery, and GKS was more often used for surgically inaccessible tumors and patients with a higher risk from open surgery, including those with a lower KPS and higher age. Caution is therefore required when analyzing the data, especially when comparing the different treatment groups. The treatment groups were, however, comparable with respect to all patient-related parameters except tumor volume and the proportion of patients with KPS ⬍70 and age ⬍50. Both were predictors of survival after reoperation and GKS (10, 31) for recurrent GBM. In our study the difference in tumor volume clearly benefited the GKS treatment group, whereas the KPS score and age favored the reoperation group. Patient selection may be the primary

www.WORLDNEUROSURGERY.org

665

PEER-REVIEW REPORTS BENTE SANDVEI SKEIE ET AL.

GKS VS. REOPERATION FOR RGM

Table 4. Results of Multivariate Analysis of Survival Outcome After Gamma Knife Surgery or Reoperation According to Treatment Group, Unadjusted and Adjusted for Possible Confounding Factors in 77 Patients with Recurrent Glioblastoma Multiforme Survival (Median) After Primary Diagnosis

Adjusted Analysis Model B Unadjusted Analysis

Adjusted Analysis Model A

Number of Patients

Months (95% CI)

GKS

51

19 (16.4–21.6)

No GKS

26

16 (13.3–18.7)

Reoperation

45

16 (13.2–18.8)

No reoperation

32

18 (14.7–21.3)

3

7

21 (15.5–33.3)

4

45

17 (19.5–36.6)

2.3 (0.9–6.2)

5

23

16 (13.6–20)

6

2

23 (23–26)

Parameter

HR (95% CI)

P Values

HR (95% CI)

P Values

1.8 (1.1–2.9)

0.021

7.4 (3.2–16.9)

⬍0.001

1.1 (0.6–1.7)

0.828

1.5 (0.7–3)

Including Tumor Volume HR (95% CI)

P Values

Treatment group GKS

5.8 (1.9–17.8)

0.002

2.1 (1–4.5)

0.064

0.094

1.4 (0.5–4)

0.559

2.2 (0.7–6.7)

0.171

1.3 (0.4–4.9)

0.685

5.1 (0.8–31.5)

0.800

1.1 (0.1–8.8)

0.917

Treatment group reoperation

0.291

RPA classification 0.281

0.938

Neurological deficits No

14

19 (15.8–49.5)

0.449

0.544

Yes

46

14 (15.9–29.4)

1.6 (0.7–3.7)

0.299

1.8 (0.6–5.1)

0.274

Epilepsy

17

21 (16.9–29.7)

0.9 (1.1–0.8)

0.907

1.4 (0.6–3.5)

0.481

⬎10

24

31 (29.5–53.9)

5–10

20

16 (13.7–26)

0.5 (0.2–1.0)

0.062

0.2 (0.07–0.6)

0.003

⬍5

33

13 (11.7–16.3)

0.2 (0.1–0.4)

⬍0.001

0.1 (0.04–0.3)

⬍0.001

Stupp

29

19 (17.5–39.1)

PCV ⫹ EBRT

13

29 (23.9–58.2)

EBRT

30

13 (13.3–25.2)

None

5

6 (4.4–11.2)

Time to recurrence (months) ⬍0.001

⬍0.001

Adjuvant therapy ⬍0.001 0.3 (0.1–0.7)

0.007

0.002 0.2 (0.06–0.5)

0.003

1.8 (0.9–3.4)

0.840

1.2 (0.6–2.5)

0.598

13.7 (3.4–56)

⬍0.001

9.4 (2.1–43)

0.004

Unifocal Yes

61

18 (20–32)

No

5

13 (8.3–16.1)

Right side

38

17 (16.8–28.5)

Left side

35

18 (18.5–39.4)

No

31

13 (10.2–28.3)

Yes

46

8 (7.8–12.7)

21

21 (21.4–46.7)

7.5 (0.8–72.8)

0.083

1.8 (0.2–22.3)

0.617

1.2 (0.7–2)

0.598

1.3 (0.7–2.6)

0.374

1.3 (0.6–2.6)

0.495

0.9 (0.4–2.1)

0.854

Tumor location

Eloquent area

Volume (categories) (mL) ⬍5

⬍0.001 Continues

666

www.SCIENCEDIRECT.com

WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2012.03.024

PEER-REVIEW REPORTS BENTE SANDVEI SKEIE ET AL.

GKS VS. REOPERATION FOR RGM

Table 4. Continued Survival (Median) After Primary Diagnosis

Adjusted Analysis Model B Unadjusted Analysis

Adjusted Analysis Model A

Including Tumor Volume

Parameter

Number of Patients

5–20

21

22 (19.3–48)

2.6 (1.1–6.1)

⬎20

21

12 (10.2–16.6)

8.7 (3.1–23.5)

GKS ⫹ Reoperation

19

21 (21.2–55.9)

GKS

32

18 (16.7–30.8)

1.7 (0.9–3.2)

0.091

1.5 (0.7–3.0)

Reoperation

26

16 (13.4–20.2)

2.5 (1.3–4.8)

0.006

7.4 (3.2–16.9)

Months (95% CI)

HR (95% CI)

P Values

HR (95% CI)

P Values

HR (95% CI)

P Values 0.029 ⬍0.001

Treatment group ⬍0.001

0.022

0.291 ⬍0.001

0.008 2.1 (1.0–4.5)

0.064

5.8 (1.9–17.8)

0.002

CI, confidence interval; HR, hazard ratio; GKS, gamma knife surgery; RPA, recursive partitioning analysis; PCV, procarbazine, lomustibe, and vincristine; EBRT, external beam radiation therapy.

reason for the observed survival times rather than the treatment group. However, the multivariate analysis adjusted for possible confounders including tumor volume still showed a survival benefit for patients treated with GKS. The relative risk of death for patients with tumor volumes within the range of GKS (⬍20 mL), who potentially could be randomized both to reoperation and GKS, is significantly higher for reoperated patients (P ⫽ 0.041, HR 442.0). Even for patients with tumors ⬎20 mL, the relative risk of death is 38.1 when the tumors are reoperated compared with lesions treated with GKS. It should be emphasized that the beneficial effects of GKS persisted after stratifying according to prognostic factors implemented in the recursive partitioning analysis described by Curran et al. (7). All cases were classified from RPA class III to VI with an expected survival ranging from 4.6 to 17.9 months. More than 50% of the patients in both treatment groups belonged to class IV, in which GKS had a significantly increased survival compared with surgery.

A survival benefit from GKS for patients with RTOG class III through V has also been suggested by Kondziolka et al. (20). The larger tumors in the reoperation group may represent a biologically different group of tumors and may account for some of the difference in survival between the treatment groups. However, when a decision is made to offer patients active treatment for GBM recurrences, we believe our data support the use of GKS. The longest survival was seen in patients receiving both treatment modalities for their GBM recurrences. This indicates that more treatment increases survival, but also could just reflect that patients with longterm survival will be offered more treatment. Although no patients treated with GKS experienced treatment-related complications during their stay at the hospital, one patient had transient worsening of a neurological deficit and a further two patients had edema on follow-up images possibly related to radiosurgery. In contrast, 12 of the

reoperated patients developed complications related to the operative procedures. Furthermore, one of these patients died after surgery. This postoperative complication rate may seem high compared with the rate after GKS, but it is still in line with the rates reported for reoperation at other centers (1, 14, 25, 36, 44) with a 7.7% to 24% permanent morbidity, a 40% to 67% decrease in postoperative KPS, and a mortality of 4.2% to 5.1%. Given the short life expectancy at this stage, complications presenting in the early postoperative phase will probably impact more strongly on these patients’ lives than radiotoxicity with its later and more gradual onset. Most GBM recurrences are in the vicinity of the resection cavity, and they may be candidates for both surgery and GKS. However, in the advanced stages many of these patients are not deemed eligible for surgery and general anesthesia because of their functional status and the risks inherent in these procedures (2, 14). GKS provides a highly precise delivery of a radiation dose

Table 5. Median Survival (months) in the Different Treatment Groups Based on Recursive Partitioning Analysis Class Stratification Survival Predicted by RPA Class

Overall Survival

No

Survival Both Retreatments

No

Survival Gamma Knife Patients

No

Survival Reoperated Patients

No

Class III

17.9

21

7

21

3

41

3

16

1

RPA Class

Class IV

11.1

17

45

26

13

18

16

13

16

Class V

8.9

16

23

12

2

13

12

16

9

Class VI

4.6

23

2

25

1

18

1

0

RPA, recursive partitioning analysis.

WORLD NEUROSURGERY 78 [6]: 658-669, DECEMBER 2012

www.WORLDNEUROSURGERY.org

667

PEER-REVIEW REPORTS BENTE SANDVEI SKEIE ET AL.

sufficient to induce tumor cell death while sparing the surrounding host tissue. Furthermore, it can be administered using local anesthesia for attachment of the frame, followed by a mild sedation during the rest of the procedure. Because the goal of GBM treatment always involves maintaining an acceptable quality of life for the patient (6), GKS could arguably be the treatment of choice for many of these patients, provided that the results are comparable with those of reoperation. The role of GKS in the management of malignant gliomas has been debated since initial reports suggested a survival benefit from this treatment (24, 35). There are studies that have demonstrated a longer survival among patients considered eligible for radiosurgery even if they did not receive GKS, suggesting that a selection bias may impact on the results (7, 18). On the other hand, Nwokedi et al. reported a longer median survival with GKS administered as a boost after EBRT in GBM patients, compared to EBRT alone (29). Although this was a retrospective study, the prognostic factors in the two groups were well matched. Moreover, others have reported a trend toward longer survival when GBM patients were treated with GKS at the time of tumor progression, compared with GKS as part of the initial management (17). Despite their limited study populations, these studies collectively suggest that some GBM patients may benefit from GKS and that the timing of treatment may influence the overall survival. The RTOG 93-05 trial randomized patients for conventional radiotherapy and carmustine, with or without stereotactic radiosurgery (linear accelerator or GKS) administered up front (37). The investigators reported no significant difference in median survival or 2- and 3-year survival rates between the two groups. Parameters related to quality of life and neurological functions were comparable. However, most centers practice a different schedule, commonly using GKS as an adjuvant boost after EBRT, or at the time of tumor progression (17, 21, 29). In addition, the study only included residual tumors visible on postoperative scans, whereas patients who had a gross total resection were not enrolled. Because the extent of resection has been identified as a prognostic factor in several studies (23, 26, 39), this suggests that the RTOG study

668

www.SCIENCEDIRECT.com

GKS VS. REOPERATION FOR RGM

may also suffer from a selection bias. We therefore suggest that these findings have limited relevance for the management of malignant gliomas at the time of progression, and that they do not provide a definite answer about the role of stereotactic radiosurgery in this setting. There remains a need for randomized prospective studies to evaluate the effect of radiosurgery compared with reoperation in the treatment of GBM. There is also a need to evaluate which target dose is optimal for GBM recurrences and what is the volume limitation for tumors that may be treated with GKS. Because of the high radiation dose already given as a part of the EBRT, we have used a relatively low dose of 12.2 Gy (range 8 to 20 Gy) to the tumor margin. This is in line with previous studies (30, 32), although some investigators would advocate higher prescription doses (15 to 18 Gy) (20, 29). Apart from dose optimization, these patients also will benefit from pharmacological interventions that could potentiate the effects on tumor cells. Thus, future studies should also assess the role of radiosensitizers (33) in GKS for GBM recurrences.

REFERENCES 1. Ammirati M, Galicich JH, Arbit E, Liao Y: Reoperation in the treatment of recurrent intracranial malignant gliomas. Neurosurgery 21:607-614, 1987. 2. Barbagallo GM, Jenkinson MD, Brodbelt AR: “Recurrent” glioblastoma multiforme, when should we reoperate? Br J Neurosurg 22:452-455, 2008. 3. Barker FG 2nd, Chang SM, Gutin PH, Malec MK, McDermott MW, Prados MD, Wilson CB: Survival and functional status after resection of recurrent glioblastoma multiforme. Neurosurgery 42:709720 [discussion 720-703], 1998. 4. Brandsma D, Stalpers L, Taal W, Sminia P, van den Bent MJ: Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol 9:453-461, 2008. 5. Central Brain Tumor Registry of the United States: CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2004-2008. Available at: http:// www.cbtrus.org/2012-NPCR-SEER/CBTRUS_ Report_2004-2008_3-23-2012.pdf. Accessed October 3, 2012. 6. Crowley RW, Pouratian N, Sheehan JP: Gamma knife surgery for glioblastoma multiforme. Neurosurg Focus 20:E17, 2006. 7. Curran WJ Jr, Scott CB, Horton J, Nelson JS, Weinstein AS, Fischbach AJ, Chang CH, Rotman M, Asbell SO, Krisch RE, Nelson DF: Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst 85:704-710, 1993.

CONCLUSIONS GKS may be an alternative to open surgery for small GBMs at the time of recurrence with a significantly lower complication rate and possibly a survival benefit compared with reoperation. Although our results were also valid after multivariate analyses correcting for different prognostic factors, our study is retrospective and can therefore not form a basis for general guidelines regarding the treatment of recurrent GBMs. Controlled prospective trials are needed to answer the question of the relative effectiveness of the two treatments. We suggest the following inclusion criteria based on T1-weighted MRI: 1) new or increased contrast enhancement in the vicinity of the resection cavity on repeat MRI, 2) accessible to GKS with maximum tumor diameter of not more than 4 cm, 3) accessible to surgery. In the absence of prospective randomized studies and other retrospective studies addressing this issue, we suggest that our results may be helpful for clinicians who have such patients in their care.

8. Davis FG, Freels S, Grutsch J, Barlas S, Brem S: Survival rates in patients with primary malignant brain tumors stratified by patient age and tumor histological type: an analysis based on Surveillance, Epidemiology, and End Results (SEER) data, 19731991. J Neurosurg 88:1-10, 1998. 9. Deorah S, Lynch CF, Sibenaller ZA, Ryken TC: Trends in brain cancer incidence and survival in the United States: Surveillance, Epidemiology, and End Results Program, 1973 to 2001. Neurosurg Focus 20:E1, 2006. 10. Elliott RE, Parker EC, Rush SC, Kalhorn SP, Moshel YA, Narayana A, Donahue B, Golfinos JG: Efficacy of gamma knife radiosurgery for small-volume recurrent malignant gliomas after initial radical resection. World Neurosurg 76:128-140, 2011. 11. Ganz JC, Reda WA, Abdelkarim K: Adverse radiation effects after gamma knife surgery in relation to dose and volume. Acta Neurochir (Wien) 151:919, 2009. 12. Ganz JC, Reda WA, Abdelkarim K, Hafez A: A simple method for predicting imaging-based complications following gamma knife surgery for cerebral arteriovenous malformations. J Neurosurg 102(suppl):4-7, 2005. 13. Guyotat J, Signorelli F, Frappaz D, Madarassy G, Ricci AC, Bret P: Is reoperation for recurrence of glioblastoma justified? Oncol Rep 7:899-904, 2000.

WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2012.03.024

PEER-REVIEW REPORTS BENTE SANDVEI SKEIE ET AL.

14. Harsh GRT, Levin VA, Gutin PH, Seager M, Silver P, Wilson CB: Reoperation for recurrent glioblastoma and anaplastic astrocytoma. Neurosurgery 21:615621, 1987. 15. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997-1003, 2005. 16. Hou LC, Veeravagu A, Hsu AR, Tse VC: Recurrent glioblastoma multiforme: a review of natural history and management options. Neurosurg Focus 20:E5, 2006. 17. Hsieh PC, Chandler JP, Bhangoo S, Panagiotopoulos K, Kalapurakal JA, Marymont MH, Cozzens JW, Levy RM, Salehi S: Adjuvant gamma knife stereotactic radiosurgery at the time of tumor progression potentially improves survival for patients with glioblastoma multiforme. Neurosurgery 57:684-692 [discussion 684-692], 2005. 18. Irish WD, Macdonald DR, Cairncross JG: Measuring bias in uncontrolled brain tumor trials--to randomize or not to randomize? Can J Neurol Sci 24:307312, 1997. 19. Jason GW, Pajurkova EM, Taenzer PA, Bultz BD: Acute effects on neuropsychological function and quality of life by high-dose multiple daily fractionated radiotherapy for malignant astrocytomas: assessing the tolerability of a new radiotherapy regimen. Psychooncology 6:151-157, 1997. 20. Kondziolka D, Flickinger JC, Bissonette DJ, Bozik M, Lunsford LD: Survival benefit of stereotactic radiosurgery for patients with malignant glial neoplasms. Neurosurgery 41:776-783 [discussion 783775], 1997. 21. Kondziolka D, Lunsford LD, Flickinger JC: In regard to Dr. Souhami et al. (Int J Radiat Oncol Biol Phys 2004;60:853-860). Int J Radiat Oncol Biol Phys 62: 614-615; author reply 615-616, 2005. 22. Kondziolka D, Lunsford LD, Flickinger JC: The application of stereotactic radiosurgery to disorders of the brain. Neurosurgery 62(suppl 2):707-719 [discussion 719-720], 2008. 23. Kowalczuk A, Macdonald RL, Amidei C, Dohrmann G 3rd, Erickson RK, Hekmatpanah J, Krauss S, Krishnasamy S, Masters G, Mullan SF, Mundt AJ, Sweeney P, Vokes EE, Weir BK, Wollman RL: Quantitative imaging study of extent of surgical resection and prognosis of malignant astrocytomas. Neurosurgery 41:1028-1036 [discussion 1036-1028], 1997. 24. Loeffler JS, Alexander E 3rd, Shea WM, Wen PY, Fine HA, Kooy HM, Black PM: Radiosurgery as part of the initial management of patients with malignant gliomas. J Clin Oncol 10:1379-1385, 1992. 25. Mandl ES, Dirven CM, Buis DR, Postma TJ, Vandertop WP: Repeated surgery for glioblastoma multiforme: only in combination with other salvage therapy. Surg Neurol 69:506-509 [discussion 509], 2008. 26. McGirt MJ, Chaichana KL, Gathinji M, Attenello FJ, Than K, Olivi A, Weingart JD, Brem H, Quinones-Hinojosa AR: Independent association of ex-

GKS VS. REOPERATION FOR RGM

tent of resection with survival in patients with malignant brain astrocytoma. J Neurosurg 110:156-162, 2009. 27. Narang J, Jain R, Arbab AS, Mikkelsen T, Scarpace L, Rosenblum ML, Hearshen D, Babajani-Feremi A: Differentiating treatment-induced necrosis from recurrent/progressive brain tumor using nonmodel-based semiquantitative indices derived from dynamic contrast-enhanced T1-weighted MR perfusion. Neuro Oncol 13:1037-1046, 2011. 28. Norden AD, Young GS, Setayesh K, Muzikansky A, Klufas R, Ross GL, Ciampa AS, Ebbeling LG, Levy B, Drappatz J, Kesari S, Wen PY: Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology 70:779-787, 2008. 29. Nwokedi EC, DiBiase SJ, Jabbour S, Herman J, Amin P, Chin LS: Gamma knife stereotactic radiosurgery for patients with glioblastoma multiforme. Neurosurgery 50:41-46 [discussion 46-47], 2002. 30. Pannullo SC, Fraser JF, Moliterno J, Cobb W, Stieg PE: Stereotactic radiosurgery: a meta-analysis of current therapeutic applications in neuro-oncologic disease. J Neurooncol 103:1-17, 2011. 31. Park JK, Hodges T, Arko L, Shen M, Dello Iacono D, McNabb A, Olsen Bailey N, Kreisl TN, Iwamoto FM, Sul J, Auh S, Park GE, Fine HA, Black PM: Scale to predict survival after surgery for recurrent glioblastoma multiforme. J Clin Oncol 28:38383843, 2010. 32. Pouratian N, Crowley RW, Sherman JH, Jagannathan J, Sheehan JP: Gamma knife radiosurgery after radiation therapy as an adjunctive treatment for glioblastoma. J Neurooncol 94:409-418, 2009. 33. Romanelli P, Conti A, Pontoriero A, Ricciardi GK, Tomasello F, De Renzis C, Innocenzi G, Esposito V, Cantore G: Role of stereotactic radiosurgery and fractionated stereotactic radiotherapy for the treatment of recurrent glioblastoma multiforme. Neurosurg Focus 27:E8, 2009. 34. Rusthoven KE, Olsen C, Franklin W, Kleinschmidt-DeMasters BK, Kavanagh BD, Gaspar LE, Lillehei K, Waziri A, Damek DM, Chen C: Favorable prognosis in patients with high-grade glioma with radiation necrosis: the University of Colorado reoperation series. Int J Radiat Oncol Biol Phys 81:211-217, 2011. 35. Sarkaria JN, Mehta MP, Loeffler JS, Buatti JM, Chappell RJ, Levin AB, Alexander E 3rd, Friedman WA, Kinsella TJ: Radiosurgery in the initial management of malignant gliomas: survival comparison with the RTOG recursive partitioning analysis. Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 32:931-941, 1995. 36. Sipos L, Afra D: Re-operations of supratentorial anaplastic astrocytomas. Acta Neurochir (Wien) 139:99-104, 1997. 37. Souhami L, Seiferheld W, Brachman D, Podgorsak EB, Werner-Wasik M, Lustig R, Schultz CJ, Sause W, Okunieff P, Buckner J, Zamorano L, Mehta MP, Curran WJ Jr: Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for

WORLD NEUROSURGERY 78 [6]: 658-669, DECEMBER 2012

patients with glioblastoma multiforme: report of Radiation Therapy Oncology Group 93-05 protocol. Int J Radiat Oncol Biol Phys 60:853-860, 2004. 38. Soults CB, Canute GS, Ryken TC: Evidence-based review of the role of reoperation in the management of malignant glioma. Neurosurg Focus 4:e11, 1998. 39. Stummer W, Reulen HJ, Meinel T, Pichlmeier U, Schumacher W, Tonn JC, Rohde V, Oppel F, Turowski B, Woiciechowsky C, Franz K, Pietsch T: Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias. Neurosurgery 62:564-576 [discussion 564576], 2008. 40. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO: Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10: 459-466, 2009. 41. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO: Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10:459466, 2009. 42. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352: 987-996, 2005. 43. Tait MJ, Petrik V, Loosemore A, Bell BA, Papadopoulos MC: Survival of patients with glioblastoma multiforme has not improved between 1993 and 2004: analysis of 625 cases. Br J Neurosurg 21:496500, 2007. 44. Young B, Oldfield EH, Markesbery WR, Haack D, Tibbs PA, McCombs P, Chin HW, Maruyama Y, Meacham WF: Reoperation for glioblastoma. J Neurosurg 55:917-921, 1981. Conflict of interest statement: J.C. Ganz and J.I. Heggdal work as consultants to Elekta. Received 18 November 2011; accepted 29 March 2012; published online 04 April 2011 Citation: World Neurosurg. (2012) 78, 6:658-669. http://dx.doi.org/10.1016/j.wneu.2012.03.024 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter © 2012 Elsevier Inc. All rights reserved.

www.WORLDNEUROSURGERY.org

669