Radiosurgery for brain metastases: the Tuebingen experience.

PURPOSE: To retrospectively investigate the effectiveness of linear accelerator based radiosurgery (RS) in the treatment of brain metastases (BM). MATERIAL AND METHODS: Of 55 patients with a total of 72 BM, 41 patients had a single brain metastasis and 14 patients had two or three metastases. Median tumour dose of 15Gy (range 8-20Gy) was prescribed to a median isodose surface of 90% (range 70-100%) encompassing the target volume. RESULTS: The median survival time (MST) for all 55 patients was 7 months [95% confidence interval (CI), 5-10 months] and 2-year survival is 18%. There was no significant difference between patients who had one brain metastasis and those with either two or three metastases (log rank P=0.7565). Multivariate analysis in patients with a single BM showed that interval between primary diagnosis (PD) to BM, maximum size of metastasis, and histology (renal cell carcinoma and melanoma versus others) were independent prognostic factors influencing survival. Local control was obtained in 66/72 (92%) metastases. Actuarial local control at 24 months was 52%. Only age (50 years) and histology (renal cell versus others) influenced local control in the univariate analysis in patients with a single BM. In multivariate analysis, size, histology (renal cell and melanoma versus others), activity of extracranial metastatic disease, age, interval from PD to BM and location (midline versus other) independently influenced local control, while the dose was not significant for our patient group. Only one patient developed radiographically suspected RS-induced necrosis after previous whole brain RT. CONCLUSION: RS was effective and little toxic in BM. Identification of prognostic factors must be performed to gain knowledge on patients most likely to benefit from this procedure.     

Radiosurgery for re-irradiation of brain metastasis: results in 54 patients.

PURPOSE: To evaluate in terms of probabilities of local-regional control and survival, as well as of treatment-related toxicity, results of radiosurgery for brain metastasis arising in previously irradiated territory. PATIENTS AND METHODS: Between January 1994 and March 2000, 54 consecutive patients presenting with 97 metastases relapsing after whole brain radiotherapy (WBRT) were treated with stereotactic radiotherapy. Median interval between the end of WBRT and radiosurgery was 9 months (range 2-70). Median age was 53 years (24-80), and median Karnofski performance status (KPS) 70 (60-100). Forty-seven patients had one radiosurgery, five had two and two had three. Median metastasis diameter and volume were 21 mm (6-59) and 1.2 cc (0.1-95.2), respectively. A Leksell stereotactic head frame (Leksell Model G, Elektra, Instrument, Tucker, GA) was applied under local anesthesia. Irradiation was delivered by a gantry mounted linear accelerator (linacs) (Saturne, General Electric). Median minimal dose delivered to the gross disease was 16.2 Gy (11.8-23), and median maximal dose 21.2 Gy (14- 42). RESULTS: Median follow-up was 9 months (1-57). Five metastases recurred. One- and 2-year metastasis local control rates were 91.3 and 84% and 1- and 2-year brain control rates were 65 and 57%, respectively. Six patients died of brain metastasis evolution, and three of leptomeningeal carcinomatosis. One- and 2-year overall survival rates were 31 and 28%, respectively. According to univariate analysis, KPS, RPA class, SIR score and interval between WBRT and radiosurgery were prognostic factors of overall survival and brain free-disease survival. According to multivariate analysis, RPA was an independent factor of overall survival and brain free-disease survival, and the interval between WBRT and radiosurgery longer than 14 months was associated with longer brain free-disease survival. Side effects were minimal, with only two cases of headaches and two of grade 2 alopecia. CONCLUSION: Salvage radiosurgery of metastasis recurring after whole brain irradiation is an effective and accurate treatment which could be proposed to patients with a KPS>70 and a primary tumour controlled or indolent. We recommend that a dose not exceeding 14 Gy should be delivered to an isodose representing 70% of the maximal dose since local control observed rate was similar to that previously published in literature with upper dose and side effects were minimal.     

Observations on pulmonary metastases in patients after single doses and multiple fractions of fast neutrons and cobalt-60 gamma rays

Pulmonary metastases have been irradiated with single and fractionated doses of fast neutrons and cobalt-60 gamma rays. The response to radiation was measured on volume changes of the lesions and thus RBE values could be derived. A correlation was found between grading of the tumour and volume doubling time and also between RBE and volume doubling time. This suggests an advantage for high LET radiation of slowly growing, well differentiated tumours. Furthermore the RBE for multiple fractions tends to be higher than for single doses. Calculation of the N exponent of the Ellis formula indicated that hardly any shoulder exists when neutrons are applied.     

Radiosurgery versus surgery, both with adjuvant whole brain radiotherapy, for solitary brain metastases: a randomised controlled trial

Aims

This randomised non-inferiority trial was designed to assess whether radiosurgery plus adjuvant whole brain radiotherapy (RS + WBRT) is as effective as surgery plus whole brain radiotherapy (S + WBRT) for cancer patients with a solitary brain metastasis, with respect to overall survival and quality of life.

Materials and methods

Major inclusion criteria were a history of systemic cancer within 5 years and enhanced magnetic resonance imaging-confirmed solitary brain metastasis suitable for both radiosurgery and surgery. All patients were to receive WBRT (30 Gy in 10 fractions). Between February 2003 and April 2009, 40 patients were considered eligible, 22 consented to randomisation and 21 were analysed (11 RS + WBRT, 10 S + WBRT). The trial was closed early due to slow accrual.

Results

The estimated median overall survival times for RS + WBRT and S + WBRT patients were 6.2 and 2.8 months, respectively (hazard ratio 0.53, 95% confidence interval 0.20–1.43, P = 0.20). Corresponding median failure-free survival times were 3.1 and 1.7 months (P = 0.20). For 19 ‘per protocol’ patients, 2/10 in the RS + WBRT arm had distant intracranial failure (one also had local failure) and 3/9 S + WBRT patients had distant intracranial failure (no local failures). There were no grade 3–4 late radiation toxicities. Two months after starting treatment there were no significant differences in quality of life between the arms.

Conclusion

This randomised trial encountered the accrual difficulties and consequent low statistical power commonly associated with interdisciplinary studies drawing from a small eligible population, but can contribute to future overviews on the management of solitary brain metastases.     

Radiosurgery for brain metastases: a score index for predicting prognosis

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]).

Methods and Materials: 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). Multivariate analysis also demonstrated significance for SIR and RPA when tested individually (p = 0.0001 and 0.0040 respectively). Applying the Cox Model to both SIR and RPA, only SIR reached independent significance (p = 0.0004).

Conclusions: 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.     

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

PURPOSE: To analyze treatment results, complications, prognostic factors and their statistical significance in surviving patients treated with the Leksell gamma knife (LGK) for solitary brain metastases. MATERIALS AND METHODS: 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.     

Radiosurgery for treatment of brain metastases: estimation of patient eligibility using three stratification systems

PURPOSE: To compare three patient stratification systems predicting survival: recursive partitioning analysis (RPA), score index for radiosurgery in brain metastases (SIR), and a proposed basic score for brain metastases (BS-BM). METHODS AND MATERIALS: We analyzed the outcome of 110 patients treated with Leksell Gamma Knife radiosurgery between December 1999 and January 2003. The BS-BM was calculated by evaluating three main prognostic factors: Karnofsky performance status, primary tumor control, and presence of extracranial metastases. RESULTS: The median survival was 27.6 months for RPA Class I, 10.7 months for RPA Class II, and 2.8 months for RPA Class III (p <0.0001). Using the SIR, the median survival was 27.7, 10.8, 4.6, and 2.4 months for a score of 8-10, 5-7, 4, and 0-3, respectively (p <0.0001). The median survival was undefined in patients with a BS-BM of 3 (55% at 32 months) and was 13.1 months for a BS-BM of 2, 3.3 months for a BS-BM of 1, and 1.9 months for a BS-BM of 0 (p <0.0001). The backward elimination model in multivariate Cox analysis identified SIR and BS-BM as the only two variables significantly associated with survival (p = 0.031 and p = 0.043, respectively). CONCLUSION: SIR and BS-BM were the most accurate for estimating survival. They were specific enough to identify patients with short survival (SIR 0-3 and BS-BM 0). Because of it simplicity, BS-BM is easier to use.     

Radiosurgery for brain metastases at the Royal Adelaide Hospital: Are we treating the right patients?

Although non‐randomized data strongly suggest improved outcome from radiosurgery (RS) for brain metastases relative to whole brain radiotherapy (WBRT) alone, selection factors account for much of the observed differences. This retrospective review of the 16 brain metastases patients treated so far with RS at the Royal Adelaide Hospital confirms a median survival of 10.1 months, consistent with recent multi‐institutional pooled results and significantly longer than the median survival of 3?6 months typically reported for WBRT alone. The emerging randomized trials comparing surgery, RS and WBRT for brain metastases are reviewed in the context of the Radiation Therapy Oncology Group Recursive Partitioning Analysis prognostic Class concept in order to assess whether we are using this resource intensive technique to treat the ‘right’ patients. We conclude that it is reasonable to continue our current policy of considering RS primarily for patients of good performance status with solitary brain metastases. We have a flexible approach to adjuvant WBRT which appears to decrease brain relapse, but not improve survival.     

Radiosurgery and whole brain therapy in the treatment of brainstem metastases

Purpose  

The incidence of brainstem metastasis (BSM) accounts for 1–3% of brain metastases (BM). They are often associated with multiple BM and produce significant neurological symptoms. We retrospectively analyse the results of treatment with stereotactic radiosurgery (SRS).     

Outcome of three-fraction gamma knife radiosurgery for brain metastases according to fractionation scheme: preliminary results

Journal of Neuro-Oncology - Chordoma is a rare refractory neoplasm that arises from the embryological remnants of the notochord, which is incurable using any multimodality therapy. Vascular...     

Radiosurgery for patients with brain metastases: a multi-institutional analysis, stratified by the RTOG recursive partitioning analysis method

PURPOSE: To estimate the potential improvement in survival for patients with brain metastases, stratified by the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) class and treated with radiosurgery (RS) plus whole brain radiotherapy (WBRT). METHODS AND MATERIALS: An analysis of the RS databases of 10 institutions identified patients with brain metastates treated with RS and WBRT. Patients were stratified into 1 of 3 RPA classes. Survival was evaluated using Kaplan-Meier estimates and proportional hazard regression analysis. A comparison of survival by class was carried out with the RTOG results in similar patients receiving WBRT alone. RESULTS: Five hundred two patients were eligible (261 men and 241 women, median age 59 years, range 26-83). The overall median survival was 10.7 months. A higher Karnofsky performance status (p = 0.0001), a controlled primary (median survival = 11.6 vs. 8.8 months, p = 0.0023), absence of extracranial metastases (median survival 13.4 vs. 9.1 months, p = 0.0001), and lower RPA class (median survival 16.1 months for class I vs. 10.3 months for class II vs. 8.7 months for class III, p = 0.000007) predicted for improved survival. Gender, age, primary site, radiosurgery technique, and institution were not prognostic. The addition of RS boosted results in median survival (16.1, 10.3, and 8.7 months for classes I, II, and III, respectively) compared with the median survival (7.1, 4.2, and 2.3 months, p <0.05) observed in the RTOG RPA analysis for patients treated with WBRT alone. CONCLUSION: In the absence of randomized data, these results suggest that RS may improve survival in patients with BM. The improvement in survival does not appear to be restricted by class for well-selected patients.     

Differentiating solitary pulmonary metastases in patients with extrapulmonary neoplasmas using FDG-PET

The purpose of this preliminary study is to evaluate the characteristics of solitary pulmonary lesions in patients using extrapulmonary neoplasmas with 18F-fluoro-2-deoxyglucose positron emission tomography (FDG-PET). Thirty-two patients with extrapulmonary neoplasmas who had solitary pulmonary lesions and were suspected for pulmonary metastasis underwent an oncological survey with FDG-PET. Standard uptake value (SUV) and the ratio of lesion-to-background (L/B ratio) were used as parameters to differentiate and characterize the solitary pulmonary lesions. Using SUV > 2.5 or L/B ratio > 3 as the cutoff to diagnose malignancy, FDG-PET correctly identified 29 true-positive cases. However, FDG-PET failed to interpret two false-positive and one false-negative cases. The accuracy of FDG-PET was 91%. We concluded that FDG-PET is an accurate modality to differentiate solitary pulmonary lesions in patients with extrapulmonary neoplasmas.     

Stereotactic radiosurgery for brain metastases: results and prognostic factors

This study was conducted to determine prognostic factors for tumor response and patient survival after stereotactic radiosurgery (SRS) for brain metastasis. Eighty-four patients with brain metastasis underwent SRS at a single institution. After fixation of the head with a stereotactic frame, computed tomography treatment planning was performed. The metastatic lesion was treated with multiple arcs to a median dose of 19 Gy. Forty-seven patients (56%) had a solitary brain lesion. Fifty-nine patients (70%) had evidence of extracranial disease at the time of SRS. The median survival duration from SRS was 7 months. Sixty-three percent of the patients had an objective radiographic response to SRS, which in turn was associated with superior central nervous system control. Age, collimator size, number of arcs, tumor location, and histology did not influence objective response rates. Patients who had a solitary lesion or who received treatment within 2 weeks after diagnosis were more likely to have an objective response than were those who did not (P < 0.05). Progressive brain disease accounted for 37% of the deaths. Nineteen patients (23%) had an in-field relapse. Four severe complications were attributed to SRS. This study confirms the role of SRS as an acceptable treatment option for patients with solitary or limited brain metastases. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 157-162 (2000).     

Radiosurgery and brain tolerance: an analysis of neurodiagnostic imaging changes after gamma knife radiosurgery for arteriovenous malformations.

In order to analyze complications and the factors responsible for the development of serial imaging changes after stereotactic radiosurgery for intracranial arteriovenous malformations, we reviewed serial post-treatment magnetic resonance imaging scans in 72 patients. Median follow-up was 23 months (range 12 to 35 months). Twenty patients developed post-radiosurgical imaging changes consisting of new regions of increased T2 signal on magnetic resonance imaging in brain surrounding the arteriovenous malformation (two year actuarial incidence of 31%). Imaging changes were associated with headache or new neurological deficits in nine of these 20 (45%) and remained asymptomatic in 11 (55%). Symptoms developed in three of 13 patients with imaging changes in the cerebral cortex or cerebellum, in contrast to six of seven patients who had symptoms with imaging changes in the brainstem (p = .028). The onset of imaging changes varied from five to 18 months after radiosurgery (median, 12 months). Serial follow-up scans four to 25 months after the onset of imaging changes were available for review in 16 patients. Post-radiosurgical imaging changes completely resolved within 4 to 19 months in ten patients and have not yet completely resolved after 6 to 25 months in six patients. The projected actuarial rate for resolution of imaging changes was 88%, 19 months after onset; the median time for resolution was 14 months. Univariate analysis revealed that the development of imaging changes was significantly associated with treatment volume (p = .025), the risk predicted from the integrated logistic formula (p = .042), and the number of isocenters treated (p = .042). In multivariate analysis, volume was the only factor significantly associated with the development of imaging changes.     

Radiosurgery/stereotactic radiotherapy in combination with immunotherapy and targeted agents for melanoma brain metastases

Introduction: The clinical landscape of advanced melanoma drastically changed after the introduction of both targeted therapies and immunotherapy. This rapid development in systemic therapies led to a change in the management of patients with brain metastases, with the subsequent need to re-assess the role of local therapies, in particular stereotactic radiosurgery (SRS).

Areas covered: In this non-systematic review, we report on the current knowledge on the use of SRS in combination with immunotherapy and BRAF/MEK inhibitors for patients with melanoma brain metastases, as well as ongoing trials in this field.

Expert commentary: It is now more common to observe patients with melanoma brain metastases with better performance status and prolonged life expectancy. A combination of targeted therapy and immunotherapy, in different sequences, has been shown to be feasible and well tolerable, on the basis of retrospective reports. Additional data from ongoing prospective trials are however needed to confirm or not these findings and better explore the efficacy of the combination.     

Leptomeningeal seeding in patients with brain metastases treated by gamma knife radiosurgery

To characterize the development of leptomeningeal seeding (LMS) in patients with brain metastases after gamma knife radiosurgery (GKRS). Eight hundred and twenty-seven patients that underwent GKRS as a part of an initial treatment plan for brain metastases between January 2002 and December 2010 were included in the study. Six hundred and fifty patients were treated with GKRS alone and 177 patients received GKRS combined with upfront whole brain radiation therapy (WBRT). Actuarial curves for overall survival (OS) and the development of LMS were plotted using the Kaplan-Meier method. Median overall survival for all patients was 55?weeks (95 % CI, 47.8-62.2), and the overall incidence of LMS was 5.3 %. The actuarial rates for LMS at 6 and 12 months were 3.1 and 5.8, respectively. Uni- and multivariate analysis suggested that breast cancer and a large number of metastases (n ≥ 4) are significant risk factors of LMS (P < 0.05). Regarding treatment modalities, the addition of WBRT was found to have a significant impact on lowering the risk of LMS by multivariate analysis (P = 0.045). LMS is an important pattern of CNS failure. The risk of LMS following GKRS may be associated with multiple lesions, breast cancer, and the omission of WBRT. Additional data from large-scale, randomized controlled trials are required to identify risk factors associated with the LMS more accurately.     

Topotecan chemotherapy in patients with breast cancer and brain metastases: results of a pilot study.

BACKGROUND: Symptomatic brain metastases occur in approximately 10-15% of patients suffering from breast cancer and are linked to a clear deterioration of the patient's condition. Although radiotherapy is recommended as a primary therapy, the optimal management remains controversial. To evaluate the role of topotecan as a primary chemotherapy for brain metastases, we performed a pilot study in patients with metastatic breast cancer. PATIENTS AND METHODS: 24 patients with newly diagnosed, bidimensionally measurable brain metastases received topotecan, 1.5 mg/m(2) day, 30-min infusion for 5 days every 3 weeks. A total of 93 courses of therapy were administered (range 1-11, median 3 courses per patient). Prior radiotherapy was excluded. Most of the patients had received prior adjuvant or palliative chemotherapy. RESULTS: 3/24 patients were withdrawn from the study for various reasons, 16/24 patients could be evaluated in terms of their response to therapy; 1 and 5 patients showed complete and partial response to therapy, respectively, and 5 patients had a stable condition. The median time of survival was 6.25 months. Hematologic toxicity was the major side effect, nonhematologic side effects occurred rarely and were tolerable. CONCLUSIONS: Our results demonstrate that primary chemotherapy with topotecan is an effective and well-tolerated treatment for patients with breast cancer and CNS metastases. Based on this pilot study, future clinical protocols should be developed including multimodal treatment strategies (i.e. radiotherapy).