Stereotactic radiosurgery for brainstem metastases.

Department of Neurological Surgery, and Center for Image-Guided Neurosurgery, University of Pittsburgh Medical Center, Pennsylvania 15213, USA.

OBJECT: Brainstem metastases portend a dismal prognosis. Surgical resection is not part of routine management and radiation therapy has offered little clinical benefit. Radiosurgery provides a safe and effective treatment for many patients with brain metastasis, but its role in the brainstem has not been evaluated. In this study the authors examine the role of radiosurgery in the treatment of brainstem metastases. METHODS: The authors reviewed the outcomes after stereotactic radiosurgery in 26 patients with 27 brainstem metastases. Tumor locations included the pons (21 tumors) and midbrain (six tumors): 14 patients had additional tumors in other locations. Twenty patients presented with brainstem signs. The median dose to the tumor margin was 16 Gy (range 12-20 Gy). Twenty-four patients received fractionated whole-brain radiation therapy (WBRT) and 12 underwent additional chemotherapy or immunotherapy. The median follow-up time in these patients was 9.5 months (range 1-43 months). After radiosurgery, the local control rate in brainstem tumors was 95%. In one patient in whom the tumor initially decreased in size, tumor enlargement was seen 7 months later. The median survival time was 11 months after diagnosis and 9 months after radiosurgery. Thirteen patients improved, 10 were stable, and three deteriorated. Eventually, 22 patients died, 18 of progression of their extracranial disease, three of new tumor growth (including one hemorrhage into a new brain metastasis), and one of extracranial disease plus new brain tumor growth. CONCLUSIONS: Although they have slightly lower than the expected survival rates of patients with nonbrainstem tumors, patients with brainstem metastases may achieve effective palliation after stereotactic radiosurgery and WBRT.

Brainstem metastases: management using gamma knife radiosurgery.

Fuentes. Neurosurgery. 2006 Jan;58(1):37-42; discussion 37-42.
OBJECTIVE: Brainstem metastasis is an uncommon complication of systemic cancer, generally considered to have a highly unfavorable prognosis. Surgical risks are high and standard radiation or chemotherapy have little effect. The purpose of this study is to evaluate our experience using Gamma Knife radiosurgery (GKRS) for the management of brainstem metastasis. METHODS: Between July 1992 and March 2001, we treated 28 patients with brainstem metastasis using GKRS. Lesions were located in the pons in 17 patients, midbrain in nine, and medulla oblongata in two. At time of the radiosurgery, eight patients presented with another supratentorial metastasis. The most frequent primary tumor site was the lung (13 cases) followed by the melanoma in four cases, the kidney in two, and other locations in six. Only six patients underwent fractionated whole-brain radiation therapy. Mean marginal radiation dose for GKRS was 19.6 Gy (range, 11-30). Mean maximum diameter was 17.2 mm (range, 10-30). RESULTS: No GKRS-related morbidity was observed. Local tumor control was achieved in 92% of patients. Twenty-six patients have died. Death was related to the progression of the brainstem lesion in two cases. Mean and median survival after GKRS were 10.2 and 12 months, respectively. Follow-up periods in the two surviving patients were 12 and 13 months. CONCLUSION: The results of this small series demonstrate that GKRS can be a valuable modality for safe and effective management of brain stem metastasis. Owing to the high risk of surgical resection and low efficacy of medical treatment, radiosurgery can be proposed upfront.

Radiother Oncol 2000 Nov;57(2):207-13

Solitary brain metastases treated with the Leksell gamma knife: prognostic factors for patients.

Simonova G, Liscak R, Novotny J Jr, Novotny J

Stereotactic and Radiation Neurosurgery Department, Hospital Na Homolce, Roentgenova 2, 151 19 5, Prague, Czech Republic.

Between 1992-1998, 237 patients were treated with solitary brain metastasis (SBM). The histological subtypes were as follows: 101 patients (42.6%) non small-cell lung cancer, 42 (17.7%) renal cell carcinoma, 36 (15.2%) breast carcinoma, 30 (12.7%) colorectal carcinomas and 28 (11.8%) melanoma. RESULTS: A complete or partial regression was observed in 193 (81.4%) patients, cessation of growth activity in 32 (13.5%) and local progression in 12 (5.1%). Local recurrence was observed in nine (4.7%) of 193 patients with complete or partial regression. Acute toxicity appeared in 24 (10%) patients (score 3.4), late complications (score 3.4) were observed in 13 patients (5.5%). Out of 237 patients, 182 patients died with a median survival of 6 months and 55 patients are still alive with a median survival 12 months and with a minimal follow up period of 10 months. The significant prognostic factors for longer survival in these series of patients were: Karnofsky performance status (70% or more), the extent of extra-cerebral disease (no extra-cerebral disease), pretreatment neurological symptoms neurological functional class (NFC 1), histology (renal cell and breast carcinomas) and the dose to the planning target volume (20 Gy and higher). CONCLUSIONS: Radiosurgery provides an effective local control for 90% of treated patients with low morbidity. Several significant prognostic factors were detected for patients' survival. These factors can help to predict better patients' survival after the LGK treatment.

Stereotact Funct Neurosurg 2000;74(1):37-51

Gamma knife radiosurgery for the treatment of brain metastases.

Sansur CA, Chin LS, Ames JW, Banegura AT, Aggarwal S, Ballesteros M, Amin P, Simard JM, Eisenberg H

Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201-1595, USA.

One hundred and ninety-three patients with brain metastases from various primary sites received Gamma Knife radiosurgery (GKR) from July 1992 to August 1997 and were reviewed to evaluate their clinical outcome. Survival follow-up was available on 173 patients. Whole-brain radiation therapy was also administered to 148 of these patients. The median survival was 13.1 months from initial detection of brain metastases, and 7.5 months from GKR. Univariate and multivariate analyses were performed to determine prognostic factors that influenced survival following GKR. Enhanced survival is observed in patients with radiosensitive tumor types, supratentorial tumor, history of brain tumor resection, controlled primary site, and absent extracranial metastases. Local lesion control was obtained in 82% of the patients according to their last follow-up MRI scan. GKR is an effective means of treating patients with brain metastases.

Int J Radiat Oncol Biol Phys 1994 Mar 1;28(4):797-802

A multi-institutional experience with stereotactic radiosurgery for solitary brain metastasis.

Flickinger JC, Kondziolka D, Lunsford LD, Coffey RJ, Goodman ML, Shaw EG, Hudgins WR, Weiner R, Harsh GR 4th, Sneed PK, et al

University of Pittsburgh School of Medicine, PA.

A review of 116 patients with solitary brain metastases who underwent gamma knife stereotactic radiosurgery at five institutions was performed. The median follow-up was 7 months following radiosurgery and 12 months following diagnosis. Minimum tumor doses varied from 8-30 Gy (mean, 17.5 Gy). Forty-five patients failed prior radiotherapy and 71 had no prior brain irradiation. Fifty-one patients had radiosurgery alone and 65 underwent combined radiosurgery with fractionated large-field radiotherapy (mean dose, 33.8 Gy). RESULTS: Median survival was 11 months after radiosurgery and 20 months after diagnosis. Follow-up documented local tumor control in 99 patients (85%), tumor recurrence in 17 (15%), and documented radiation necrosis in one (1%). The 2-year actuarial tumor control rate was 67 +/- 8%. Tumor histology affected survival (better for breast cancer, p = .004) and local control (better for melanoma and renal cell, p = .0003) in multivariate analyses. Combined fractionated radiotherapy and radiosurgery improved local control (p = 0.111), but not survival in multivariate testing. CONCLUSION: Radiosurgery is effective in controlling solitary brain metastases with low morbidity. Further study is needed to better define optimum treatment parameters for radiosurgery.

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

Neurosurgery 2000 Aug;47(2):268-79; discussion 279-81

Stereotactic radiosurgery in the treatment of metastatic disease to the brain.

Chen JC, Petrovich Z, O'Day S, Morton D, Essner R, Giannotta SL, Yu C, Apuzzo ML

Department of Neurological Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, USA. josephcc@hsc.usc.edu

We reviewed our series of patients with metastatic tumors treated using gamma knife stereotactic radiosurgery from August 1994 to February 1999. This study included 190 patients harboring 431 lesions who were treated in 263 treatment sessions. The median follow-up after radiosurgery was 36 weeks for all patients. The median actuarial survival from the time of radiosurgery in all patients was 34 weeks. When patients were stratified according to tumor histology, those without melanoma had a median survival of 39 weeks, and those with melanoma had a median survival of 28 weeks. The cause of death could be determined in 122 (92%) of the patients known to have died during the data capture period. For patients harboring melanoma, death was attributable to systemic disease in 31 (47%), to central nervous system-related processes in 29 (44%), and to unknown causes in 6 (9%). For non-melanoma patients, death was attributable to systemic disease in 45 (68%), to central nervous system-related processes in 17 (26%), and to unknown causes in 4 (6%). Significantly improved survival (P = 0.002) was observed in patients with controlled systemic disease. No significant difference in survival could be ascertained for patients presenting with up to four lesions, although patients with a total tumor volume greater than 9 cc had shortened survival. No survival benefit could be demonstrated for whole-brain radiotherapy administered either concomitantly or after radiosurgery.

J Neurosurg 1999 Jul;91(1):35-43

Surgery and radiotherapy compared with gamma knife radiosurgery in the treatment of solitary cerebral metastases of small diameter.

Muacevic A, Kreth FW, Horstmann GA, Schmid-Elsaesser R, Wowra B, Steiger HJ, Reulen HJ

Department of Neurosurgery, Ludwig-Maximilians University, Klinikum Grosshadern, and Gamma Knife Center, Munich, Germany. Alexander.Muacevic@nc.med.uni-muenchen.de

OBJECT: The aim of this retrospective study was to compare treatment results of surgery plus whole-brain radiation therapy (WBRT) with gamma knife radiosurgery alone as the primary treatment for solitary cerebral metastases suitable for radiosurgical treatment. METHODS: Patients who had a single circumscribed tumor that was 3.5 cm or smaller in diameter were included. Treatment results were compared between microsurgery plus WBRT (52 patients, median tumor dose 50 Gy) and radiosurgery alone (56 patients, median prescribed tumor dose 22 Gy).  Patients who suffered from larger lesions underwent surgery (p < 0.01). The 1-year survival rate (median survival) was 53% (68 weeks) in the surgical group and 43% (35 weeks) in the radiosurgical group (p = 0.19). The 1-year local tumor control rates after surgery and radiosurgery were 75% and 83%, respectively (p = 0.49), and the 1-year neurological death rates in these groups were 37% and 39% (p = 0.8). Shorter overall survival time in the radiosurgery group was related to higher systemic death rates. A pretreatment KPS score of less than 70 was a predictor of unfavorable survival. Perioperative morbidity and mortality rates were 7.7% and 1.6% in the resection group, and 8.9% and 1.2% in the radiosurgery group, respectively. Four patients presented with transient radiogenic complications after radiosurgery. CONCLUSIONS: Radiosurgery alone can result in local tumor control rates as good as those for surgery plus WBRT in selected patients. Radiosurgery should not be routinely combined with radiotherapy.

Int J Radiat Oncol Biol Phys 2000 Jul 1;47(4):993-9

Application of recursive partitioning analysis and evaluation of the use of whole brain radiation among patients treated with stereotactic radiosurgery for newly diagnosed brain metastases.

Chidel MA, Suh JH, Reddy CA, Chao ST, Lundbeck MF, Barnett GH

Departments of Radiation Oncology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.

To evaluate the usefulness of whole brain radiotherapy (WBRT) and of the Radiation Therapy Oncology Group recursive partitioning analysis (RPA) for brain metastases among patients receiving stereotactic radiosurgery (SRS). METHODS AND MATERIALS: A retrospective analysis was performed on 135 patients who underwent linear accelerator (Linac) (n = 73) or Gamma Knife (n = 62) SRS for newly diagnosed brain metastases at the Cleveland Clinic Foundation between 8/89 and 12/98.  The median survival for all patients was 7.9 months (range: 1.1-90.1), and was 11.2 months for RPA class I compared to 6. 9 months for RPA classes II-III (p = 0.016). Median survival was 10. 5 months following SRS alone compared to 6.4 months following SRS and WBRT (p = 0.07). On univariate analysis, KPS >/= 80% (p = 0.002) and absence of systemic disease (p = 0.013) were also associated with longer survival, whereas control of the primary, DFI, and number of brain metastases did not have an impact. Multivariate analysis revealed only RPA class (p = 0.023) to be an independent predictor for overall survival, whereas treatment group (p = 0.079) was only marginally significant. At 2 years, immediate WBRT improved control at the original site of metastases (80% vs. 52%, p = 0.03) and prevention of new metastatic sites within the brain, 74% vs. 48% (p = 0.06). The 2-year intracranial disease-free survival was 60% following SRS and WBRT compared to only 34% following SRS alone (p = 0.03). CONCLUSIONS: Despite the inherent biases to select more favorable patients for SRS, the RPA class retains its prognostic value. Omission of WBRT from the initial management was not detrimental in terms of overall survival; however, progressive disease occurred in over 50% of patients treated in this manner. Further studies are required to determine which, if any, patients should be considered for SRS with WBRT held in reserve.

J Neurosurg 1996 May;84(5):748-54

Surgery versus radiosurgery in the treatment of brain metastasis.

Bindal AK, Bindal RK, Hess KR, Shiu A, Hassenbusch SJ, Shi WM, Sawaya R

Department of Neurosurgery, University of Texas M. D. Anderson Cancer Center, Houston, USA.

Surgery and radiosurgery are effective treatment modalities for brain metastasis. To compare the results of these treatment modalities, the authors followed 13 patients treated by radiosurgery and 62 patients treated by surgery who were retrospectively matched. For patients treated by radiosurgery, the median size of the treated lesion was 1.96 cm3 (range 0.41-8.25 cm3) and the median dose was 20 Gy (range 12-22 Gy). The median survival was 7.5 months for patients treated by radiosurgery and 16.4 months for those treated by surgery; this difference was found to be statistically significant using both univariate (p = 0.0018) and multivariate (p = 0.0009) analyses. On the basis of their data, the authors conclude that surgery is superior to radiosurgery in the treatment of brain metastasis. Patients who undergo surgical treatment survive longer and have a better local control. The data lead the authors to suggest that the indications for radiosurgery should be limited to surgically inaccessible metastatic tumors or patients in poor medical condition. Surgery should remain the treatment of choice whenever possible.

Cancer J 2000 Mar-Apr;6(2):88-92

Gamma knife radiosurgery in the treatment of patients with single and multiple brain metastases from carcinoma of the breast.

Amendola BE, Wolf AL, Coy SR, Amendola M, Bloch L

Miami Neuroscience Center Coral Gables, Florida, USA.

From December 1993 to July 1998, 68 women with breast carcinoma metastatic to the brain were treated with gamma knife radiosurgery at Miami Neuroscience Center in Coral Gables, Florida. Thirty-eight patients had previously received conventional modalities of treatment for brain metastases including whole-brain irradiation. A total of 110 treatments were given to the 68 women to an average of eight tumor sites per patient. Minimum doses ranged from 6 to 25 Gy to the 35% to 85% isodose line, with 95% of the prescribed minimum doses ranging from 15 to 24 Gy. Patients were treated for one to three lesions (n = 26), four to seven lesions (n = 18), and eight or more lesions (n = 24). RESULTS: The median overall actuarial survival for the entire group was 7.8 months. The actuarial survival was 32% at 1 year. The median follow-up was 7.8 months. Overall local control by lesion was 94% (485/518 lesions), and average tumor volume was 3.3 cm3. Twenty-seven (40%) of 68 eligible patients survived 1 year, nine (13%) survived 2 years, and two (3%) survived more than 3 years. Fifty-one of 56 documented deaths (91%) were unrelated to brain metastases. In a subgroup of 15 patients with single brain metastases, the average tumor volume was 16.6 cm3, and local control was 73% (11/15 lesions). The 15 patients who died had a median survival of 7.7 months (range, 3 to 45.7 months). CONCLUSIONS: Gamma knife radiosurgical treatment of patients with brain metastases from carcinoma of the breast has shifted the question of survival to that of systemic control. There was no radiation-induced dementia, and a remarkably low incidence of local failure was seen. Survival has been found to be independent of the number of lesions treated.

J Clin Oncol 1998 Nov;16(11):3563-9

Radiosurgery alone or in combination with whole-brain radiotherapy for brain metastases.

Pirzkall A

Department of Radiation Oncology, University of Heidelberg, Germany. a.pirzkall@dkfz-heidelberg.de

PURPOSE: Evaluation of the treatment outcome after radiosurgery (RS) alone or in combination with whole-brain radiotherapy (WBRT) with special attention to prescribed dose and its influence on local control and survival. PATIENTS AND METHODS: Between September 1984 and January 1997, 236 patients with 311 brain metastases treated with radiosurgery met the following inclusion criteria: one to three brain metastases per patient; no previous WBRT; and Kamofsky performance status (KPS) > or = 50%. One hundred fifty-eight patients treated only with RS received a median dose of 20 Gy prescribed to the 80% isodose line; 78 patients received RS with a median dose of 15 Gy/80% and an additional course of WBRT. RESULTS: For the entire series, overall median survival was 5.5 months, with control of CNS disease achieved in 92% of the treated brain metastases; the results were not significantly different between patients treated by RS with or without WBRT. However, in patients without evidence of extracranial disease, median survival was increased for patients who received WBRT (15.4 vs 8.3 months; P=.08). Additionally, there was a suggestion that increased doses for patients treated with RS only resulted in improved outcome. Four lesions were suspicious for radiation necrosis by magnetic resonance imaging (MRI); in one of the four lesions, radiation necrosis was confirmed histologically. The incidence of transient low-grade toxicity was 18%; symptoms could be treated by the temporary administration of steroids. CONCLUSION: RS is an effective, noninvasive means of controlling brain metastases when used alone or in combination with WBRT. There is a trend for superior local control and especially in patients without extracranial disease for superior survival when RS is used in conjunction with WBRT. Randomized trials would seem to be warranted, comparing the benefit of RS with or without additional WBRT.

Int J Radiat Oncol Biol Phys 2000 Mar 15;46(5):1155-61

Radiosurgery for brain metastases: a score index for predicting prognosis.

Weltman E,

Department of Radiation Oncology, Hospital Israelita Albert Einstein, Sao Paulo, Brazil. eweltman@einstein.br

PURPOSE: To analyze a prognostic score index for patients with brain metastases submitted to stereotactic radiosurgery (the Score Index for Radiosurgery in Brain Metastases [SIR]). Actuarial survival of 65 brain metastases patients treated with radiosurgery between July 1993 and December 1997 was retrospectively analyzed. Prognostic factors included age, Karnofsky performance status (KPS), extracranial disease status, number of brain lesions, largest brain lesion volume, lesions site, and receiving or not whole brain irradiation. The SIR was obtained through summation of the previously noted first five prognostic factors. Kaplan-Meier actuarial survival curves for all prognostic factors, SIR, and recursive partitioning analysis (RPA) (RTOG prognostic score) were calculated. Survival curves of subsets were compared by log-rank test. Application of the Cox model was utilized to identify any correlation between prognostic factors, prognostic scores, and survival. RESULTS: Median overall survival from radiosurgery was 6.8 months. Utilizing univariate analysis, extracranial disease status, KPS, number of brain lesions, largest brain lesion volume, RPA, and SIR were significantly correlated with prognosis. Median survival for the RPA classes 1, 2, and 3 was 20.19 months, 7.75 months, and 3. 38 months respectively (p = 0.0131). Median survival for patients, grouped under SIR from 1 to 3, 4 to 7, and 8 to 10, was 2.91 months, 7.00 months, and 31.38 months respectively (p = 0.0001). Using the Cox model, extracranial disease status and KPS demonstrated significant correlation with prognosis (p = 0.0001 and 0.0004 respectively). Systemic disease status, KPS, SIR, and RPA are reliable prognostic factors for patients with brain metastases submitted to radiosurgery. Applying SIR and RPA classifications to our patients' data, SIR demonstrated better accuracy in predicting prognosis. SIR should be further tested with larger patient accrual and for all patients with brain metastases subjected or not to stereotactic radiosurgery.

Int J Radiat Oncol Biol Phys 1999 Nov 1;45(4):931-9

Dose optimization and indication of Linac radiosurgery for brain metastases.

Matsuo T

Department of Neurosurgery, Nagasaki University School of Medicine, Japan. takayuki-m@odn.pop12.ne.jp

Median survival time was 11 months. In univariate analysis, extracranial tumor activity (p<0.001) and Karnofsky Performance Status (KPS) (p = 0.036) were two significant predictors of survival. In multivariate analysis, the status of an extracranial tumor was the single significant predictor of survival (p = 0.005). Minimum dose was the single most significant predictor of local recurrence in univariate, multivariate, and matched-pairs analyses (p<0.05). As to the appearance of new lesions, activity of extracranial tumors was a significant predictor (p<0.05). Side effects due to radiosurgery were experienced in 4 of 92 cases (4.3%). CONCLUSIONS: We concluded that brain metastases patients should be irradiated with > or =25 Gy, when extracranial lesions are stable and longer survival is expected. Combined surgery and conventional radiation may have little advantage over radiosurgery alone when metastatic brain tumors are small and extracranial tumors are well controlled. When extracranial tumors are progressive, the rate of appearance of new lesions in other nonirradiated locations becomes higher. In such cases, careful follow-up is required and a combination with whole brain irradiation should be considered.