gamma_knife_poster.gif (12077 bytes)          Radiosurgery for Malignant Gliomas
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Neurosurg 1999 Jan;90(1):72-7

Treatment of patients with primary glioblastoma multiforme with standard postoperative radiotherapy and radiosurgical boost: prognostic factors and long-term outcome.

Shrieve DC, Alexander E 3rd, Black PM, Wen PY, Fine HA, Kooy HM, Loeffler JS

Department of Radiation Oncology, Harvard Medical School, Boston, Massachusetts, USA.

OBJECT: To assess the value of stereotactic radiosurgery (SRS) as adjunct therapy in patients suffering from glioblastoma multiforme (GBM), the authors analyzed their experience with 78 patients. METHODS: Between June 1988 and January 1995, 78 patients underwent SRS as part of their initial treatment for GBM. All patients had undergone initial surgery or biopsy confirming the diagnosis of GBM and received conventional external beam radiotherapy. Stereotactic radiosurgery was performed using a dedicated 6-MV stereotactic linear accelerator. Thirteen patients were alive at the time of analysis with a median follow-up period of 40.8 months. The median length of actuarial survival for all patients was 19.9 months. Twelve- and 24-month survival rates were 88.5% and 35.9%, respectively. Patient age and Radiation Therapy Oncology Group (RTOG) class were significant prognostic indicators according to univariate analysis (p < 0.05). Twenty-three patients aged younger than 40 years had a median survival time of 48.6 months compared with 55 older patients who had 18.2 months (p < 0.001). Patients in this series fell into RTOG Classes III (27 patients), IV (29 patients), or V (22 patients). Class III patients had a median survival time of 29.5 months following diagnosis; this was significantly longer than median survival times for Classes IV and V, which were 19.2 and 18.2 months, respectively (p = 0.001). Only patient age (< 40 years) was a significant prognostic factor according to multivariate analysis. Acute complications were unusual and limited to exacerbation of existing symptoms. There were no new neuropathies secondary to SRS. Thirty-nine patients (50%) underwent reoperation for symptomatic necrosis or recurrent tumor. The rate of reoperation at 24 months following SRS was 54.8%. CONCLUSIONS: The addition of a radiosurgery boost appears to confer a survival advantage to selected patients.

Int J Radiat Oncol Biol Phys 1995 Jul 15;32(4):931-41
Radiosurgery in the initial management of malignant gliomas: survival comparison with the RTOG recursive partitioning analysis. Radiation Therapy Oncology Group.

Sarkaria J, University of Wisconsin. A total of 115 patients from three institutions (75 from the Joint Center for Radiation Therapy, 30 from the University of Wisconsin, and 10 from the University of Florida) were treated with a combination of surgery, external beam radiation therapy, and linac-based radiosurgery as part of similar institutional protocols from March 1988 through July 1993.The actuarial 2-year and median survival for all patients analyzed was 45% and 96 weeks, respectively. In comparison to the results from a previously published analysis of 1578 patients entered on three Radiation Therapy Oncology Group external beam radiotherapy protocols from 1974 to 1989, those patients treated with radiosurgery had a significantly improved 2-year and median survival (p = 0.01) corresponding with a standardized mortality risk ratio of 0.51. This improvement in survival was seen predominantly for the worse prognostic classes (classes 3-6). The 2-year survival for the radiosurgical patients compared with the previously reported patients was 81% vs. 76% for classes 1/2, 75% vs. 35% for class 3, 34% vs. 15% for class 4, and 21% vs. 6% for classes 5/6, respectively. The addition of radiosurgery to conventional treatment (surgery and external beam radiotherapy) of malignant gliomas appears to improve survival when compared to historical reports. These results should be interpreted with caution because the recursive partitioning model does not completely predict the prognosis of the patients treated in the present study. Although this study suggests that radiosurgery may prolong survival in patients with malignant gliomas, the role of radiosurgery in the management of these patients remains to be defined by a prospective randomized trial.

Int J Radiat Oncol Biol Phys 1995 Apr 30;32(1):205-10
Linac radiosurgery for high-grade gliomas: the University of Florida experience.

Buatti JM. External-beam radiotherapy delivered a median dose of 60 Gy. Stereotactic radiosurgery was delivered to the enhancing tumor volume without margin. Median treatment volume was 14 cm3 (equivalent sphere diameter, 3 cm). The maximum volume of any tumor treated was 22.5 cm3 (equivalent sphere diameter, 3.5 cm). Median stereotactic radiosurgery boost dose was 12.5 Gy, and median prescription sphere was the 80% isodose shell. RESULTS: Despite rigorous selection and aggressive stereotactic boost irradiation, this patient cohort had a median actuarial survival of 17 months. All patients have had progression of intracranial disease within 1 year of radiosurgery, and only 3 of 11 remain alive with a median follow-up of 13 months.

Int J Radiat Oncol Biol Phys 1995 Sep 30;33(2):461-8
Stereotactic radiosurgery as an adjunct to surgery and external beam radiotherapy in the treatment of patients with malignant gliomas.

Gannett University of Arizona. a stereotactic radiosurgery boost was given to 30 patients after completion of fractionated external beam radiotherapy. Fractionated radiation dose ranged from 44 to 62 Gy, with a median of 59.4 Gy. Prescribed stereotactic radiosurgery dose ranged from 0.5 to 18 Gy (median: 10 Gy), and the volume receiving the prescription dose ranged from 2.1 to 158.7 cc (median: 46 cc). The 1- and 2-year disease-specific survival from the date of diagnosis is 57 and 25%  respectively (median survival: 13.9 months). No significant acute or late toxicity has been observed. CONCLUSION: Stereotactic radiosurgery provides a safe and feasible technique for dose escalation in the primary management of unselected malignant gliomas. Longer follow-up and a randomized prospective trial is required to more thoroughly evaluate the role of radiosurgery in the primary management of malignant gliomas.

J Clin Oncol 1995 Jul;13(7):1642-8
Stereotactic radiosurgery for recurrent malignant gliomas.

Hall W, University of Minnesota Hospital. The actuarial survival time for all patients was 21 months from diagnosis and 8 months from radiosurgery. Seven patients required surgical resection for increasing mass effect a mean of 4.0 months after radiosurgery, for an actuarial reoperation rate of 31%. Stereotactic radiosurgery appears to prolong survival for recurrent malignant gliomas and has a lower reoperative rate for symptomatic necrosis than does brachytherapy.

Neurosurgery
1997 Oct;41(4):776-83; discussion 783-5
Survival benefit of stereotactic radiosurgery for patients with malignant glial neoplasms.

Kondziolka D,University of Pittsburgh, Pennsylvania.  Of the entire series, the median survival time after initial diagnosis for patients with GBM was 26 months  and the median survival time after radiosurgery was 16 months. The 2-year survival rate was 51%. No survival benefit was identified for patients who underwent intravenously administered chemotherapy in addition to radiosurgery.Of the entire series, the median survival time after diagnosis for patients with anaplastic astrocytomas was 32 months and the median survival time after radiosurgery was 21 months. The 2-year survival rate was 67%. In comparison to historical controls, improved survival benefit after radiosurgery was identified for patients with GBM and patients with AA.

J Clin Oncol 1992 Sep;10(9):1379-85
Radiosurgery as part of the initial management of patients with malignant gliomas.

Loeffler J, Brigham and Women's Hospital.   Patients in the study group received external-beam radiotherapy that consisted of 5,940 cGy given in 33 fractions to partial brain fields that encompassed the primary tumor with a 3 to 4 cm margin. Radiosurgery, used as a technique for boosting the dose to any residual contrast-enhancing mass lesion, was given 2 to 4 weeks after the completion of conventional radiotherapy. Minimum radiosurgical doses ranged from 1,000 to 2,000 cGy (median, 1,200 cGy), whereas maximum doses ranged from 1,250 to 2,500 cGy (median, 1,500 cGy). The median tumor volume at the time of radiosurgery was 4.8 cm3 (range, 1.2 to 72 cm3). We conclude that radiosurgery is a useful adjunct to other modalities in the initial management of patients with small, radiographically well-defined malignant gliomas.
 
Int J Radiat Oncol Biol Phys 1994 Oct 15;30(3):541-9
Stereotactic radiosurgery for glioblastoma multiforme: report of a prospective study evaluating prognostic factors and analyzing long-term survival advantage.

Mehta MP, University of Wisconsin. in addition to 54 Gy in 1.8 Gy/fraction following biopsy (n = 12) or resection (n = 19). Eligibility required supratentorial glioblastoma, tumor not > 4 cm in > 1 axis, age > 18 years, and location > 1 cm from optic chiasm. and minimum and maximum tumor dose ranges were 10-20 (m = 12) and 15-35 Gy (m = 18.75). Median survival is 42 weeks. Twelve and 24-month actuarial survival are 38 and 28%. Comparison of the 2-year survival with previous Radiation Therapy Oncology Group patients was carried out using a nonparametric recursive partitioning technique and the observed vs. expected values are 28 vs. 9.7%. The improvement in median survival in broadly selected glioblastoma patients treated with radiosurgery is difficult to determine, but the 2-year survival may be superior. Future randomized trials of radiosurgery are recommended, and ad hoc use of this modality should be discouraged.

Int J Radiat Oncol Biol Phys 1999 Dec 1;45(5):1133-41

Single dose versus fractionated stereotactic radiotherapy for recurrent high-grade gliomas.

Cho KH, Hall WA, Gerbi BJ, Higgins PD, McGuire WA, Clark HB

Department of Therapeutic Radiology and Radiation Oncology, University of Minnesota Hospital and Clinic, Minneapolis 55455, USA. choxx006@tc.umn.edu

Between April 1991 and January 1998, 71 patients with recurrent high-grade gliomas were treated with SRT. Forty-six patients (65%) were treated with single dose radiosurgery (SRS) and 25 patients (35 %) with fractionated stereotactic radiotherapy (FSRT). For the SRS group, the median radiosurgical dose of 17 Gy was delivered to the median of 50% isodose surface (IDS) encompassing the target. For the FSRT group, the median dose of 37.5 Gy in 15 fractions was delivered to the median of 85% IDS. RESULTS: Actuarial median survival time was 11 months for the SRS group and 12 months for the FSRT group (p = 0.3, log-rank test). Late complications developed in 14 patients in the SRS group and 2 patients in the FSRT group (p<0.05). CONCLUSION: Given that FSRT patients had comparable survival to SRS patients, despite having poorer pretreatment prognostic factors and a lower risk of late complications, FSRT may be a better option for patients with larger tumors or tumors in eloquent structures. Since this is a nonrandomized study, further investigation is needed to confirm this and to determine an optimal dose/fractionation scheme.

J Neurosurg 2000 Dec;93 Suppl 3:42-6

Gamma knife radiosurgery for low-grade astrocytomas: results of long-term follow up.

Kida Y, Kobayashi T, Mori Y

Department of Neurosurgery, Komaki City Hospital, Japan.

Fifty-one patients with low-grade astrocytomas treated with GKS and followed for more than 24 months are reported. Of the 51 patients, 12 harbored Grade I astrocytomas in and around the visual pathways and hypothalamus. The remaining 39 harbored Grade II astrocytomas. The mean patient age at time of GKS was 9.8 years for patient with Grade I and 30.9 years for those with Grade II astrocytomas. The mean tumor diameter was 25.4 mm for Grade I and 23.7 mm for Grade II tumors. The mean margin dose was 12.5 Gy for Grade I and 15.7 Gy for Grade II tumors. In the mean follow-up period of 27.6 months, both Grade I and Grade II astrocytomas responded well to GKS. Grade I astrocytomas had a response rate of 50% and a control rate of 91.7%. Grade II astrocytomas had a 46.2% response rate and an 87.2% control rate. Statistical analyses concerning the efficacy and related factors showed a significantly better response for patients 10 years of age or older with Grade I and those with a follow-up period of more than 24 months. Complications included radiation-induced edema in 18 (35.3%) of 51 cases, cyst formation or enlargement in five (9.8%), and transient tumor enlargement in three (5.9%). CONCLUSIONS: Radiosurgery can play an important role in the treatment of low-grade astrocytomas, and complete cure of these tumors is expected in at least some of the cases.

Int J Radiat Oncol Biol Phys 2000 May 1;47(2):291-8

Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05.

Shaw E, Scott C, Souhami L, Dinapoli R, Kline R, Loeffler J, Farnan N

Department of Radiation Oncology, Wake Forest University School of Medicine, Winston Salem, NC 27157-1030, USA. eshaw@wfubmc.edu

PURPOSE: To determine the maximum tolerated dose of single fraction radiosurgery in patients with recurrent previously irradiated primary brain tumors and brain metastases. METHODS AND MATERIALS: Adults with cerebral or cerebellar solitary non-brainstem tumors </= 40 mm in maximum diameter were eligible. Initial radiosurgical doses were 18 Gy for tumors </= 20 mm, 15 Gy for those 21-30 mm, and 12 Gy for those 31-40 mm in maximum diameter. Dose was prescribed to the 50-90% isodose line. Doses were escalated in 3 Gy increments providing the incidence of irreversible grade 3 (severe) or any grade 4 (life threatening) or grade 5 (fatal) Radiation Therapy Oncology Group (RTOG) central nervous system (CNS) toxicity (unacceptable CNS toxicity) was < 20% within 3 months of radiosurgery. Chronic CNS toxicity was also assessed. RESULTS: Between 1990-1994, 156 analyzable patients were entered, 36% of whom had recurrent primary brain tumors (median prior dose 60 Gy) and 64% recurrent brain metastases (median prior dose 30 Gy). The maximum tolerated doses were 24 Gy, 18 Gy, and 15 Gy for tumors </= 20 mm, 21-30 mm, and 31-40 mm in maximum diameter, respectively. However, for tumors < 20 mm, investigators' reluctance to escalate to 27 Gy, rather than excessive toxicity, determined the maximum tolerated dose. In a multivariate analysis, maximum tumor diameter was one variable associated with a significantly increased risk of grade 3, 4, or 5 neurotoxicity. Tumors 21-40 mm were 7.3 to 16 times more likely to develop grade 3-5 neurotoxicity compared to tumors < 20 mm. Other variables significantly associated with grade 3-5 neurotoxicity were tumor dose and Karnofsky Performance Status. The actuarial incidence of radionecrosis was 5%, 8%, 9%, and 11% at 6, 12, 18, and 24 months following radiosurgery, respectively. Forty-eight percent of patients developed tumor progression within the radiosurgical target volume. A multivariate analysis revealed two variables that were significantly associated with an increased risk of local progression, i.e. progression in the radiosurgical target volume. Patients with primary brain tumors (versus brain metastases) had a 2.85 greater risk of local progression. Those treated on a linear accelerator (versus the Gamma Knife) had a 2.84 greater risk of local progression. Of note, 61 % of Gamma Knife treated patients had recurrent primary brain tumors compared to 30% of patients treated with a linear accelerator. CONCLUSIONS: The maximum tolerated doses of single fraction radiosurgery were defined for this population of patients as 24 Gy, 18 Gy, and 15 Gy for tumors </= 20 mm, 21-30 mm, and 31-40 mm in maximum diameter. Unacceptable CNS toxicity was more likely in patients with larger tumors, whereas local tumor control was most dependent on the type of recurrent tumor and the treatment unit

Gamma knife stereotactic radiosurgery for patients with glioblastoma multiforme.


Nwokedi EC, DiBiase SJ, Jabbour S, Herman J, Amin P, Chin LS.     Neurosurgery 2002 Jan;50(1):41-6

Department of Radiation Oncology, University of Maryland

OBJECTIVE: Stereotactic radiosurgery (SRS) has become an effective therapeutic modality for the treatment of patients with glioblastoma multiforme (GBM). This retrospective review evaluates the impact of SRS delivered on a gamma knife (GK) unit as an adjuvant therapy in the management of patients with GBM. METHODS: Between August 1993 and December 1998, 82 patients with pathologically confirmed GBM received external beam radiotherapy (EBRT) at the University of Maryland Medical Center. Of these 82 patients, 64 with a minimum follow-up duration of at least 1 month are the focus of this analysis. Of the 64 assessable patients, 33 patients were treated with EBRT alone (Group 1), and 31 patients received both EBRT plus a GK-SRS boost (Group 2). GK-SRS was administered to most patients within 6 weeks of the completion of EBRT. The median EBRT dose was 59.7 Gy (range, 28-070.2 Gy), and the median GK-SRS dose to the prescription volume was 17.1 Gy (range, 10-28 Gy). The median age of the study population was 50.4 years, and the median pretreatment Karnofsky performance status was 80. Patient-, tumor-, and treatment-related variables were analyzed by Cox regression analysis, and survival curves were generated by the Kaplan-Meier product limit. RESULTS: Median overall survival for the entire cohort was 16 months, and the actuarial survival rate at 1, 2, and 3 years were 67, 40, and 26%, respectively. When comparing age, Karnofsky performance status, extent of resection, and tumor volume, no statistical differences where discovered between Group 1 versus Group 2. When comparing the overall survival of Group 1 versus Group 2, the median survival was 13 months versus 25 months, respectively (P = 0.034). Age, Karnofsky performance status, and the addition of GK-SRS were all found to be significant predictors of overall survival via Cox regression analysis. No acute Grade 3 or Grade 4 toxicity was encountered. CONCLUSION: The addition of a GK-SRS boost in conjunction with surgery and EBRT significantly improved the overall survival time in this retrospective series of patients with GBM. A prospective, randomized validation of the benefit of SRS awaits the results of the recently completed Radiation Therapy Oncology Group's trial RTOG 93-05.

Stereotactic radiosurgery for glioblastoma: a final report of 31 patients.

Masciopinto JE,  J Neurosurg 1995 Apr;82(4):530-5

Department of Neurological Surgery, University of Wisconsin Hospital and Clinics, Madison.

From February 1989 to December 1992, 31 patients who presented with an initial pathological diagnosis of glioblastoma multiforme underwent tumor debulking or biopsy, stereotactic radiosurgery, and standard radiation therapy as part of their primary treatment. Presenting characteristics in the 22 men and nine women included a median age of 57 years, Karnofsky Performance Scale score median of 80, and median tumor volume of 16.4 cm3. Stereotactic radiosurgery delivered a central dose of 15 to 35 Gy with the isocenter location, collimator size, and beam paths individualized by means of three-dimensional software developed at the University of Wisconsin. The peripheral isodose line varied from 40% to 90% with a median of 72.5% and a mode of 80%. The mean follow-up period was 12.84 months with a median of 9.5 months. Statistical analysis was performed using Kaplan-Meier analysis and log-rank comparison of risk factor groups. The parameters of age, initial Karnofsky Performance Scale score, and biopsy were significantly different in patient survival from debulking; but no difference was noted between single and multiple isocenters and patterns of steroid requirement. Radiographic recurrences were divided by location into the following categories: central (within central stereotactic radiosurgery dose), 0; peripheral (within 2 cm of central dose), 19; and distant (> 2 cm), 4. There is no evidence of recurrence in five surviving patients. Actuarial 12-month survival was 37%, with a median survival of 9.5 months. These values are similar to previous results for surgery and standard radiotherapy alone. The results suggest that the curative value of radiosurgery is significantly limited by peripheral recurrences.

Comparison of stereotactic radiosurgery and brachytherapy in the treatment of recurrent glioblastoma multiforme.

Shrieve DC, Loeffler JS.   Neurosurgery 1995 Feb;36(2):275-82;

Brain Tumor Center, Brigham and Women's Hospital, Boston, Massachusetts, USA.

The purpose of this study was to compare the efficacy of stereotactic radiosurgery (SRS) and brachytherapy in the treatment of recurrent glioblastoma multiforme (GBM). The patients had either progressive GBM or pathologically proven GBM at recurrence after previous treatment for a lower grade astrocytoma. Thirty-two patients were treated with interstitial brachytherapy, and 86 received treatment with stereotactic radiosurgery (SRS). The patient characteristics were similar in the two groups. Those patients treated with SRS had a median tumor volume of 10.1 cm3 and received a median peripheral tumor dose of 13 Gy. Patients treated with brachytherapy had a median tumor volume of 29 cm3. Median dose to the periphery of the tumor volume was 50 Gy delivered at a median dose rate of 43 cGy/hour. Twenty-one patients (24%) treated with SRS were alive, with a median follow-up of 17.5 months. Median actuarial survival, measured from the time of treatment for recurrence, for all patients treated with SRS was 10.2 months, with survivals of 12 and 24 months being 45 and 19%, respectively. A younger age and a smaller tumor volume were predictive of better outcome. The tumor dose, the interval from initial diagnosis, and the need for reoperation were not predictive of outcome after SRS. Five patients (16%) treated with brachytherapy were alive, with a median follow-up of 43.3 months. The median actuarial survival for all patients treated with brachytherapy was 11.5 months. Survivals of 12 and 24 months were 44 and 17%, respectively