Two fractions staged Gammaknife radiosurgery for "large" cerebral metastases.

BACKGROUND: Gammaknife radiosurgery (GKRS) is a valuable option to control cerebral metastases. However, the risk (adverse radiation effect (ARE))-benefit (local control (LC)) ratio switches when the target is too large. OBJECTIVE: In order to balance this ratio, two fractions staged GKRS protocol was conducted for "large" cerebral metastases. The aim of this study is to evaluate the outcome (LC, ARE). METHODS: A total of 39 large cerebral metastases in 35 patients were treated. The initial mean tumor volume was 14.6 cc [6.1; 35.8]. The prescription margin dose was 12 Gy on the 50% isodose line, with 2 weeks between them. A majority of primary cancer were from lung (43%), melanoma (20%) or breast (17%) origin. The mean age was 63 years old (31-89). Mean Graded Prognostic Assessment (GPA) was 2. RESULTS: At the second fraction, mean tumor volume was 10.3 cc [1.9-27.4]. The mean percentage of volume variation for decreasing lesions was 29%. At last follow-up, mean tumor volume was 7.4 cc [0-25.2]; 34 lesions decreased volume (mean 35%). A decreased volume of more than 45% after first stage GKRS was able to predict a long-term local response to staged GKRS treatment. Local control rate at 6 months and 1 year was 87.3% and 75% respectively. The rate of ARE was 7.7%. No predictive factor of local control or ARE was found in a univariate analysis. CONCLUSION: The new 2-fractions-dose-staged GKRS concept seems to be a well-tolerated and effective treatment option for large cerebral metastases.

Nidus Compacity Determined by Semi-Automated Segmentation is a Strong Quantitative Predictor of Brain Arterio-Venous Malformation Cure.

BACKGROUND AND OBJECTIVE: A compact nidus is a well-known feature of good outcome after treatment in brain arteriovenous malformations (bAVM). This item, included in the "Supplementary AVM grading system" by Lawton, is subjectively evaluated on DSA. The present study aimed to assess whether quantitative nidus compacity along with other angio-architectural bAVM features were predictive of angiographic cure or the occurrence of procedure-related complications. MATERIALS AND METHODS: Retrospective analysis of 83 patients prospectively collected data base between 2003 to 2018 having underwent digital subtraction 3D rotation angiography (3D-RA) for pre-therapeutic assessment of bAVM. Angio-architectural features were analyzed. Nidus compacity was measured with a dedicated segmentation tool. Univariate and multivariate analyses were performed to test the association between these factors and complete obliteration or complication. RESULTS: Compacity was the only significant factor associated with complete obliteration in our predictive model using logistic multivariate regression; the area under the curve for compacity predicting complete obliteration was excellent (0.82; 95% CI 0.71-0.90; p < 0.0001). The threshold value maximizing the Youden index was a compacity > 23% (sensitivity 97%; specificity 52%; 95% CI 85.1-99.9; p = 0.055). No angio-architectural factor was associated with the occurrence of a complication. CONCLUSION: Nidus high compacity quantitatively measured on 3D-RA, using a dedicated segmentation tool is predictive of bAVM cure. Further investigation and prospective studies are warranted to confirm these preliminary results.

Efficacy of Large Use of Combined Hypofractionated Radiotherapy in a Cohort of Anti-PD-1 Monotherapy-Treated Melanoma Patients.

To assess the role of radiotherapy in anti-PD-1-treated melanoma patients, we studied retrospectively a cohort of 206 consecutive anti-PD-1 monotherapy-treated advanced melanoma patients (59% M1c/d, 50% ≥ 3 metastasis sites, 33% ECOG PS ≥ 1, 33% > 1st line, 32% elevated serum LDH) having widely (49%) received concurrent radiotherapy, with RECIST 1.1 evaluation of radiated and non-radiated lesions. Overall (OS) and progression-free (PFS) survivals were calculated using Kaplan−Meier. Radiotherapy was performed early (39 patients) or after 3 months (61 patients with confirmed anti-PD-1 failure). The first radiotherapy was hypofractionated extracranial radiotherapy to 1−2 targets (26 Gy-4 weekly sessions, 68 patients), intracranial radiosurgery (25 patients), or palliative. Globally, 67 (32.5% [95% CI: 26.1−38.9]) patients achieved complete response (CR), with 25 CR patients having been radiated. In patients failing anti-PD-1, PFS and OS from anti-PD-1 initiation were 16.8 [13.4−26.6] and 37.0 months [24.6−NA], respectively, in radiated patients, and 2.2 [1.5−2.6] and 4.3 months [2.6−7.1], respectively, in non-radiated patients (p < 0.001). Abscopal response was observed in 31.5% of evaluable patients who radiated late. No factors associated with response in radiated patients were found. No unusual adverse event was seen. High-dose radiotherapy may enhance CR rate above the 6−25% reported in anti-PD-1 monotherapy or ipilimumab + nivolumab combo studies in melanoma patients.

Clinical Characteristics, Angioarchitecture and Management of Tectum Mesencephali Arteriovenous Malformations : A Retrospective Case Series.

PURPOSE: Tectum mesencephali arteriovenous malformations (TM-AVMs) are rare lesions deeply located close to eloquent structures making them challenging to treat. We aimed to present clinical presentation, angiographic features and treatment strategies of TM-AVMs through a single center retrospective case series. METHODS: A TM-AVMs is defined as a nidus located in the parenchyma or on the pia mater of the posterior midbrain. Records of consecutive patients admitted with TM-AVMs over a 21-year period were retrospectively analyzed. Vascular anatomy of the region is also reviewed. RESULTS: In this study 13 patients (1.63% of the complete cohort; 10 males), mean age 48 years, were included. All patients presented with intracranial hemorrhage and two patients (15%) died after an early recurrent bleeding. Mean size of the TM-AVMs was 10.1 ± 5 mm. Multiple arterial feeders were noted in every cases. Of the patients 11 underwent an exclusion treatment, 8 via embolization (6 via arterial access and 2 via venous access) and 4 via stereotactic radiosurgery (SRS) (1 patient received both). Overall success treatment rate was 7/11 patients (64% overall; 63% in the embolization group, 25% in the SRS group). Two hemorrhagic events led to a worsened outcome, one during embolization and one several years after SRS. All other patients remained clinically stable or improved. CONCLUSION: The TM-AVMs are rare but stereotypic lesions found in a hemorrhagic context. Multiple arterial feeders are always present. Endovascular treatment seems to be an effective technique with relatively low morbidity; SRS had a low success rate but was only use in a limited number of patients.

Dosimetric study between a single isocenter dynamic conformal arc therapy technique and Gamma Knife radiosurgery for multiple brain metastases treatment: impact of target volume geometrical characteristics.

PURPOSE: To compare linac-based mono-isocentric radiosurgery with Brainlab Elements Multiple Brain Mets (MBM) SRS and the Gamma Knife using a specific statistical method and to analyze the dosimetric impact of the target volume geometric characteristics. A dose fall-off analysis allowed to evaluate the Gradient Index relevancy for the dose spillage characterization. MATERIAL AND METHODS: Treatments were planned on twenty patients with three to nine brain metastases with MBM 2.0 and GammaPlan 11.0. Ninety-five metastases ranging from 0.02 to 9.61 cc were included. Paddick Index (PI), Gradient Index (GI), dose fall-off, volume of healthy brain receiving more than 12 Gy (V12Gy) and DVH were used for the plan comparison according to target volume, major axis diameter and Sphericity Index (SI). The multivariate regression approach allowed to analyze the impact of each geometric characteristic keeping all the others unchanged. A parallel study was led to evaluate the impact of the isodose line (IDL) prescription on the MBM plan quality. RESULTS: For mono-isocentric linac-based radiosurgery, the IDL around 70-75% was the best compromise found. For both techniques, the GI and the dose fall-off decreased with the target volume. In comparison, PI was slightly improved with MBM for targets < 1 cc or SI > 0.78. GI was improved with GP for targets < 2.5 cc. The V12Gy was higher with MBM for lesions > 0.4 cc or SI < 0.84 and exceeded 10 cc for targets > 5 cc against 6.5 cc with GP. The presence of OAR close to the PTV had no impact on the dose fall off values. The dose fall-off was higher for volumes < 3.8 cc with GP which had the sharpest dose fall-off in the infero-superior direction up to 30%/mm. The mean beam-on time was 94 min with GP against 13 min with MBM. CONCLUSIONS: The dose fall-off and the V12Gy were more relevant indicators than the GI for the low dose spillage assessment. Both evaluated techniques have comparable plan qualities with a slightly improved selectivity with MBM for smaller lesions but with a healthy tissues sparing slightly favorable to GP at the expense of a considerably longer irradiation time. However, a higher healthy tissue exposure must be considered for large volumes in MBM plans.

Safety of radiosurgery concurrent with systemic therapy (chemotherapy, targeted therapy, and/or immunotherapy) in brain metastases: a systematic review.

Stereotactic radiosurgery (SRS) is a standard option for brain metastases (BM). There is lack of consensus when patients have a systemic treatment, if a washout is necessary. The aim of this review is to analyze the toxicity of SRS when it is concurrent with chemotherapies, immunotherapy, and/or targeted therapies. From Medline and Embase databases, we searched for English literature published up to April 2020 according to the PRISMA guidelines, using for key words the list of the main systemic therapies currently in use And "radiosurgery," "SRS," "GKRS," "Gamma Knife," "toxicity," "ARE," "radiation necrosis," "safety," "brain metastases." Studies reporting safety or toxicity with SRS concurrent with systemic treatment for BM were included. Of 852 abstracts recorded, 77 were included. The main cancers were melanoma, lung, breast, and renal carcinoma. These studies cumulate 6384 patients. The median SRS dose prescription was 20 Gy [12-30] .For some, they compared a concurrent arm with a non-concurrent or a SRS-alone arm. There were no skin toxicities, no clearly increased rate of bleeding, or radiation necrosis with significant clinical impact. SRS combined with systemic therapy appears to be safe, allowing the continuation of treatment when brain SRS is considered.

Stereotactic Radiation Therapy for Renal Cell Carcinoma Brain Metastases in the Tyrosine Kinase Inhibitors Era: Outcomes of 120 Patients.

BACKGROUND: The objective of the study was to evaluate the outcomes in terms of efficacy and safety of a large consecutive series of 362 patients with renal cell carcinoma (RCC) brain metastases treated using stereotactic radiosurgery (SRS) in the tyrosine kinase inhibitor (TKI) era. PATIENTS AND METHODS: From 2005 to 2015, 362 consecutive patients with brain metastases from RCC were treated using SRS in 1 fraction: 226 metastases (61 patients) using Gamma-Knife at a median of 18 Gy (50% isodose line); 136 metastases (63 patients) using linear accelerator at a median of 16 Gy (70% isodose line). The median patient age was 58 years. At the first SRS, 37 patients (31%) received a systemic treatment. Among systemic therapies, TKIs were the most common (65%). RESULTS: The local control rates were 94% and 92% at 12 and 36 months, respectively. In multivariate analysis, a minimal dose >17 Gy and concomitant TKI treatment were associated with higher rates of local control. The overall survival rates at 12 and 36 months were 52% and 29%, respectively. In multivariate analysis, factors associated with poor survival included age ≥65 years, lower score index for SRS, concomitant lung metastases, time between RCC diagnosis and first systemic metastasis ≤4 months, occurrence during treatment with a systemic therapy, no history of neurosurgery, and persistence or occurrence of neurological symptoms at 3 months after SRS. Seventeen patients had Grade III/IV adverse effects of whom 3 patients presented a symptomatic radionecrosis. CONCLUSION: SRS is highly effective in patients with brain metastases from RCC. Its association with TKIs does not suggest higher risk of neurologic toxicity.

Can anticancer chemotherapy promote the progression of brain metastases?

Brain metastases natural history from one primary tumor type might be accelerated or favored by using certain systemic chemotherapy. A great deal was described in mice and suggested in human with antiangiogenic drugs, but little is known about the metastatic progression generated by the perverse effect of anticancer drugs. A total of 413 patients who underwent treatment for brain metastasis (2013-2016) were included. The identification of all previous anticancer drugs received by patients from primary tumor diagnosis to brain metastases diagnosis was collated. The median value for the time of first appearance of brain metastasis in all patients was 13.1 months (SD 1.77). The values of brain metastasis-free survival (bMFS) for each primary cancer were: 50.9 months (SD 8.8) for breast, 28.5 months (SD 11.4) for digestive, 27.7 months (SD 18.3) for melanoma, 12.3 months (SD 8.3) for kidney, 1.5 months (SD 0.1) for lung and 26.9 months (SD 18.3) for others (p < 0.009). Through Cox multivariate proportional hazard model, we identified that the only independent factors associated with short bMFS were: lung primary tumor [odd ratio (OR) 0.234, CI 95% 0.16-0.42; p < 0.0001] and mitotic spindle inhibitor (taxanes) chemotherapy [OR 0.609, CI 95% 0.50-0.93; p < 0.001]. Contrariwise, breast primary tumor [odd ratio (OR) 2.372, CI 95% 1.29-4.3; p < 0.005] was an independent factor that proved a significantly longer bMFS. We suggest that anticancer drugs, especially taxane and its derivatives, could promote brain metastases, decreasing free survival. Mechanisms are discussed but still need to be determined.

Timeline metastatic progression: in the wake of the « seed and soil ¼ theory.

Little is known about the natural history of cancer and its evolution to metastasis. Paget was the first to postulate the important role played by microenvironment in metastasis progression. Since, the concept of his "seed and soil" theory has been supported and confirmed. Understanding the chronology and natural course that underlie metastasis is mandatory to deepen this concept and to progress in the development of novel therapeutic strategies. A total of 413 patients who underwent treatment for brain metastasis (2013-2016) were included. The identification of previous and newly diagnosed metastasis was made during the clinical and imaging follow-up. We identified 910 metastases in our series. The 2-, 5-, and 10-year survival estimates were 80% (SD 2), 59.1% (3), and 36% (4), respectively. The median time for first metastasis, referred as metastasis-free survival (MFS) was 15.2 months (SD 1.47). MFS were determined for each metastasis location and were as follows: 7.2 months (SD 8.0) for bone, adrenal 8.4 months (SD 9.4) for adrenal, 13.2 months (SD 1.7) for brain, 14.6 months (SD 5.4) for liver, 25.7 months (SD 11.7) for pleura, 27.7 months (SD 15.9) for peritoneum, 29.8 months (SD 7.2) for spine, 30.2 months (SD 5.2) for lungs, and 54.2 months (SD 12.4) for skin (p < 0.009 log rank). We identified a metastatic timeline process for breast cancer (p < 0.0001 log rank (Mantel-Cox)) and furthermore according to breast subtype cancer (p < 0.0001). We suggest that in addition to Paget's theory, a timeline and a natural history of metastasis exist in patients with cancer. We suppose that some, but not all, primary cancers follow chronological and scheduled metastatic processes to invade organs.

Grade II meningiomas and Gamma Knife radiosurgery: analysis of success and failure to improve treatment paradigm.

OBJECTIVE Grade II meningiomas, which currently account for 25% of all meningiomas, are subject to multiple recurrences throughout the course of the disease and represent a challenge for the neurosurgeon. Radiosurgery is increasingly performed for the treatment of Grade II meningiomas and is quite efficient in controlling relapses locally at the site of the lesion, but it cannot prevent margin relapses. The aim of this retrospective study was to analyze the technical parameters involved in producing marginal relapses and to optimize loco-marginal control to improve therapeutic strategy. METHODS Eighteen patients presenting 58 lesions were treated by Gamma Knife radiosurgery (GKRS) between 2010 and 2015 in Hopital de la Pitié-Salpêtrière. The median patient age was 68 years (25%-75% interval: 61-72 years), and the sex ratio (M/F) was 13:5. The median delay between surgery and first GKRS was 3 years. Patients were classified as having Grade II meningioma using World Health Organization (WHO) 2007 criteria. The tumor growth rate was computed by comparing 2 volumetric measurements before treatment. After GKRS, iterative MRI, performed every 6 months, detected a relapse if tumor volume increased by more than 20%. Patterns of relapse were defined as being local, marginal, or distal. Survival curves were estimated using the Kaplan-Meier method, and the relationship between criterion and potential risk factors was tested by the log-rank test and univariable Cox model. RESULTS The median follow-up was 36 months (range 8-57 months). During this period, 3 patients presented with a local relapse, 5 patients with a marginal relapse, and 7 patients with a distal relapse. Crude local control was 84.5%. The local control actuarial rate was 89% at 1 year and 71% at 3 years. The marginal control actuarial rate was 81% at 1 year and 74% at 2 years. The distal control actuarial rate was 100% at 1 year, 81% at 2 years, and 53% at 3 years. Median distal control was 38 months. Progression-free survival (PFS) was 71% at 1 year, 36% at 2 years, and 23% at 3 years. Median PFS was 18 months. Lesions treated with a minimum radiation dose of ≤ 12 Gy had significantly more local relapses than those treated with a dose > 12 Gy (p = 0.04) in univariate analysis. Marginal control was significantly influenced by tumor growth rate, with a lower growth rate being highly associated with improved marginal control (p = 0.002). There was a trend toward a relationship between dose and marginal control, but it was not significant (p = 0.09). PFS was significantly associated with delay between first surgery and GKRS (p = 0.03). The authors noticed few complications with no sequelae. CONCLUSIONS In order to optimize loco-marginal control, radiosurgical treatment should require a minimum dose of > 12 Gy and an extended target volume along the dural insertion. Ideally, these parameters should correspond to the aggressiveness of the lesion, based on genetic features of the tumor.

Predictors of Trigeminal Neuropathy After Radiosurgery for Vestibular Schwannomas.

PURPOSE: To analyze the relationship between dosimetric characteristics and symptoms related to trigeminal neuropathy (TN) observed after radiosurgery (RS) for vestibular schwannomas (VS); to propose guidelines to optimize planification in VS RS regarding TN preservation; and to detail the mechanism of TN impairment after VS RS. METHODS AND MATERIALS: One hundred seventy-nine patients treated between 2011 and 2013 for VS RS and without trigeminal impairment before RS were included in a retrospective study. Univariate and multivariate analyses were performed to determine predictors of TN among characteristics of the patients, the dosimetry, and the VS. RESULTS: There were 20 Koos grade 1, 99 grade 2, 57 grade 3, and 3 grade 4. Fourteen patients (7.8%) presented a transitory or permanent TN. Between the patients with and without TN after VS RS, there was no significant difference regarding dosimetry or VS volume itself. Significant differences (univariate analysis P<.05, Mann-Whitney test) were found for parameters related to the cisternal portion of the trigeminal nerve: total integrated dose, maximum dose, mean dose, volume of the Vth nerve (Volv), and volume of the Vth nerve receiving at least 11 Gy (VolVcist>11Gy), but also for maximal dose to the Vth nerve nucleus and intra-axial portion (Dose maxVax). After multivariate analysis, the best model predicting TN included VolVcist>11Gy (P=.0045), Dose maxVax (P=.0006), and Volv (P=.0058). The negative predictive value of this model was 97%. CONCLUSIONS: The parameters VolVcist>11Gy, Dose maxVax, and Volv should be checked when designing dosimetry for VS RS.

Patterns of relapse and growth kinetics of surgery- and radiation-refractory meningiomas.

Patients with surgery- and radiation-refractory meningiomas have a poor outcome. Due to our lack of knowledge concerning multi-recurrent meningioma natural history, their clinical course is poorly defined. This retrospective study aims at defining patterns of relapse in order to help in the definition of response criteria in future clinical trials. We performed a retrospective review of surgery- and radiotherapy-refractory meningioma cases with interpretable radiological follow-up treated in our department. Tumor volumes were measured on 3D T1 Gadolinium volumetric sequences using a semi-automated algorithm for tumor segmentation. Twenty nine patients with multi-treated meningioma (11 WHO Grade II, 5 de novo WHO Grade III and 13 transformed WHO Grade III), were evaluated. Median PFS was 16 months for patients with Grade II meningiomas. In patients with Grade III meningiomas, the de novo subgroup had a median PFS of 4 months compared with 7 months in patients with malignant transformation. Volumetric analysis of tumor growth concerned 95 tumor nodules in 50 relapses. The mean growth rate of tumor nodules was 10.4 cm(3)/year (95% CI 7.3-14.8 cm(3)/year). Three patterns of tumor growth were described: "classical" for 9 (31%) patients, "local multi-nodular" for 6 (21%) patients and "multi-nodular metastatic" for the last 14 (48%) patients. Considering all tumor nodules, median time to tumor progression (TTP) was 3.7 months. Progressing tumors represent the most frequent histological subgroup of surgery and radiation-refractory meningiomas while tumors with multi-nodular metastatic dissemination are the prominent radiological pattern of progression.

In memoriam Ladislau Steiner, neurosurgeon: some people from transylvania do live forever.

We review the extraordinary professional trajectory of Ladislau Steiner, a prolific neurosurgeon and radiosurgeon, who died earlier this year. Dr. Steiner trained and practiced as a neurosurgeon in his native Romania until he was 42, before moving to Stockholm. After 25 years at the Karolinska Institute, when most people consider retirement, he spent the following 25 years of his life as director of the Lars Leksell Center for Gamma Knife Radiosurgery at the University of Virginia, Charlottesville, Virginia. At 90, nostalgia for Europe made him accept the position of director of the Gamma Knife Center at the International Neuroscience Institute in Hannover, Germany. His life was dedicated to the 15,000 patients whose lives he saved in his lengthy career.

Minimized doses for linear accelerator radiosurgery of brainstem metastasis.

PURPOSE: Treatment of cerebral metastases located inside the brainstem remains a challenge, as the brainstem is considered to be a neurological organ at risk, whatever the treatment strategy. We report a retrospective study of 30 consecutive patients treated in our institution between 2005 and 2007 with micromultileaf linear accelerator (LINAC)-radiosurgery for brainstem metastases, with reduced doses compared to those usually reported in the literature. METHODS AND MATERIALS: Mean follow-up was 311 days (range, 41-1351). Median age was 57 years (range, 37-82), Mean Karnofsky Index (KI) was 80. Primary tumor site was lung (n = 13), breast (n = 4), kidney (n = 4), skin (melanoma; n = 3), and others (n = 6). Primary tumor was controlled in 17 cases; extracranial metastases were controlled in 12 cases. Mean number of metastases was 1.46 (one to three); median volume was 2.82 cc (0.06-18). Dose was delivered by a micromultileaf collimator 6-MV LINAC . RESULTS: Dose administered at the 70% isodose was 13.4 Gy (range, 8.2-15). Median survival was 10 months. Local control rates at 3, 6, and 12 months were 100%, 100%, and 79% respectively. Median neurological control duration was 5 months. Neurological control rates at 3, 6, and 12 months were 73%, 42%, and 25%, respectively. No parameter was found to significantly correlate with survival, local, or cerebral control. No patients had severe side effects (Grade III-IV), according to the Radiation Therapy Oncology Group (RTOG) scale. CONCLUSION: Lower doses than previously reported can achieve the same local control and survival rates in brain metastases, with minimal side effects.

Shunt dependence: myths and facts.

INTRODUCTION: Chronically shunted patients are believed to be unable to have a shunt-free life. Nevertheless, sometimes shunt removal is possible after an endoscopic third ventriculostomy, even after long periods of cerebral spinal fluid diversion. RESULTS AND DISCUSSION: We perform a literature review that leads to a discussion of this subject in the light of the current medical knowledge.

Linac stereotactic radiosurgery: an effective and safe treatment for elderly patients with brain metastases.

PURPOSE: To evaluate the outcomes of radiosurgery for brain metastases in patients 65 years or older. PATIENTS AND METHODS: Between January 1994 and January 2003, 117 patients (47 women, 70 men), median age 71 years (range, 65-86 years), received radiosurgery for 227 metastases. Sixty-one patients (55%) presented symptoms in relation to the brain metastases. Thirty-eight patients (32%) received whole-brain radiotherapy. Median metastasis diameter and volume were 21 mm (range, 0.5-75 mm) and 1.7 cc (range, 0.02-71 cc), respectively. RESULTS: Median follow-up was 7 months (range, 1-45 months), 9.5 months for alive patients (range, 1-45 months). Median minimum and maximum doses were 14.5 Gy (6.5 Gy, 19.5 Gy), and 20.4 Gy (13.2 Gy, 41.9 Gy), respectively. Median survival was 8 months from the date of radiosurgery. Overall survival rates at 6 and 24 months were 58% +/- 5% and 13% +/- 4%, respectively. According to multivariate analysis, a low Karnofsky performance status was an independent unfavorable prognostic factor for overall survival (p = 0.003; odds ratio [OR] = 0.28; 95% confidence interval [CI], 0.14-0.56). Median brain disease-free survival was 10 months. Brain disease-free survival rates at 6 and 24 months were 67% +/- 6% and 40% +/- 7%, respectively. According to multivariate analysis, a radiosensitive lesion was an independent favorable factor (p = 0.038; OR = 0.42; 95% CI, 0.18-0.95); more than two metastases and a low Karnofsky performance status were independent unfavorable factors for brain disease-free survival (p = 0.046; OR = 2.15; 95% CI, 1.01-4.58 and p = 0.003; OR = 30.4; 95% CI, 3.1-296, respectively). Local control rates were 98% +/- 2% and 91% +/- 8.5% at 6 and 24 months. Out of the 61 patients presenting symptoms before radiosurgery, complete symptomatic response was achieved in 12 patients (20%), partial improvement in 25 (41%), stabilization in 7 (11%), and worsening in 4 (6%) related to a progression of the irradiated metastasis. Seven cases of radionecrosis were described and were related to the margin dose (p = 0.03). CONCLUSION: Radiosurgery for elderly patients was effective and safe. Age alone should not be a criterion for denying radiosurgery to any patient with brain metastases.

LINAC radiosurgery for brain metastasis of renal cell carcinoma.

The purpose of the study was to evaluate the efficacy and toxicity of stereotactic radiotherapy in the treatment of the brain metastasis of renal cell carcinoma. From 1994 to 2001, 28 patients presenting with 65 metastases of renal cell cancer were treated by radiosurgery. Median age was 55 years (35-75), and median Karnofski performance status ranges between 50 and 100. Seven patients had received whole brain radiotherapy (WBRT) before radiosurgery. Twelve patients were treated by radiosurgery for 1 metastasis, 5 patients for two metastases and 6 for three, and 5 for more than three metastases. One procedure was performed in 22 patients and, 2 or 3 procedures for 6 patients. Median metastasis diameter was 19 mm (5-55 mm). Median metastasis volume was 1.28 cc (0.02-28 cc). Irradiation was delivered by linear accelerator. Median minimal dose (on the 70% isodose) was 14.7 Gy (10.8 Gy, 19.5 Gy), median maximal dose (at the isocenter) 20.5 Gy (14.3 Gy, 39.6 Gy). Median follow-up was 14 months (1-33). Two metastases progressed (3%), 2 and 12 months after radiosurgery. Overall, crude local control rate was 97% and 3-, 6- and 12-month local control rates were 98% +/- 2%, 98% +/- 2%, and 93% +/- 5%, respectively. In univariate analysis, no prognostic factor of local control was retrieved. Median brain disease-free survival was 25 months after RS. the 3-, 6- and 12-month distant brain control rates were 91% +/- 4%, 91% +/- 4%, and 70% +/- 12%, respectively. Median survival duration was 11 months. The 3-, 6-, 12- and 24-month overall survival rates were 82% +/- 7%, 67% +/- 9%, 48% +/- 10%, and 33% +/- 10%, respectively. According to univariate analysis, only site of metastasis was overall survival prognostic factor. Radiosurgery for brain metastasis of renal cell carcinoma is an effective and accurate treatment. The use of radiosurgery alone is an appropriate management strategy for many patients with brain metastasis of renal cell carcinoma. Radiosurgery is efficient even after development of new metastasis appearing after WBRT.

Three irradiation treatment options including radiosurgery for brain metastases from primary lung cancer.

PURPOSE: To determine local control and survival rates in 92 patients with 145 brain metastases treated with three options of radiotherapy including stereotactic radiosurgery (SR). METHODS: Between July 1994 and August 2002, 92 consecutive patients with 145 metastases were treated with a SR, 34 with initially SR alone, 22 initially with an association of whole-brain radiotherapy (WBRT) and 36 with SR alone for recurrent new brain metastasis after WBRT. At time of treatment, extracranial disease was controlled in 46 (50%) and uncontrolled in 46 (50%). Pathologies were adenocarcinoma in 54 cases (59%), squamous cell carcinoma in 14 cases (15%), small cell carcinoma in 10 cases (11%) and miscellaneous in 14 cases (15%). All patients underwent only one treatment fraction for 1 or 2 metastases in 73 cases (83%) and for more than 2 metastases for the others. RESULTS: The characteristics of patients and metastases in the group treated initially with SR alone and in the group treated initially with WBRT+SR were comparable. Median follow-up was 29 months (18-36). Overall, the median and the 1- and 2-year rates of overall survival were, respectively, 9 months, 37 and 20%. A controlled extracranial disease, a high Karnofsky index and a low number of metastasis were independent prognostic factor of overall survival, respectively, HR 0.53 (95% CI 0.31-0.90, P=0.01), HR 0.95 (95% CI 0.92-0.97, P=0.0002), and HR 0.48 (95% CI 0.25-0.90, P=0.02). Thirteen metastases were not controlled (9%). Six-month and 1-year local control rate were, respectively, 93 and 86%. High delivered dose was an independent prognostic factor of local control, HR 0.41 (95% CI 0.18-0.95, P=0.03). A controlled extracranial disease was favourable independent prognostic factor of brain free-disease free survival, HR 0.47 (95% CI 0.2-0.98, P=0.04). Although there was a trend of a better local control, overall and brain disease free survivals rates in the WBRT+SR group compared to SR alone one, the difference were not statistically different. CONCLUSION: Local control and survival rates are acceptable for a palliative treatment for the three option of treatment. In this series, the number of patients is not enough great to conclude to the necessity of the association of WBRT to SR. Re-irradiation is a safe treatment after new metastases appeared in previously irradiated area.

Radiosurgery for brain metastasis: impact of CTV on local control.

PURPOSE: The purpose of the present analysis was to assess whether adding a 1 mm margin to the gross tumour volume (GTV) improves the control rate of brain metastasis treated with radiosurgery (RS). PATIENTS AND METHODS: All the patients had one or two brain metastases, 30 mm or less in diameter, and only one isocentre was used for RS. There were 23 females and 38 males. The median age was 54 years (34-76). The median Karnofsky performance status was 80 (60-100). At the time of RS, 23 patients had no evidence of extracranial disease and 38 had a progressive systemic disease. Thirty-eight patients were treated up-front with only RS. Twenty-three patients were treated for relapse or progression more than 2 months after whole brain radiotherapy. From January 1994 to July 1995, clinical target volume (CTV) was equal to GTV without any margin (33 metastases). From August 1995 to August 2000, CTV was defined as GTV plus a 1 mm margin (45 metastases). A dose of 20Gy was prescribed to the isocentre and 14Gy at the margin of CTV. RESULTS: The median follow-up was 10.5 months (1-45). The mean minimum dose delivered to GTV was 14.6Gy in the group without a margin and 16.8Gy in the group with a 1 mm margin (P<0.0001). The response of 11 metastases was never assessed because patients died before the first follow-up. Ten metastases recurred, eight in the group treated without a margin and two in the group treated with a 1 mm margin (P=0.01). Two-year local control rates were 50.7+/-12.7% and 89.7+/-7.4% (P=0.008), respectively. Univariate analysis showed that the treatment group (P=0.008) and the tumour volume (P=0.009) were prognostic factors for local control. In multivariate analysis, only the treatment group with a 1 mm margin was an independent prognostic factor for local control (P=0.04, RR: 5.8, 95% CI [1.08-31.13]). There were no significant differences, either in overall survival rate or in early and late side effects, between the two groups. CONCLUSION: Adding a 1 mm margin to the GTV in patients treated with RS significantly improves the probability of metastasis control without increasing the side effects.

Predictive factors of radiation necrosis after radiosurgery for cerebral metastases.

The aim of this study was to determine if the risk of radiation necrosis after radiosurgery is related to the presence of normal tissue included in the prescription volume. Between 1994 and 2001, 377 patients representing 760 lesions were treated by radiosurgery in our center with a 10-MV LINAC. The median age of the patients was 57 years (range 30-86 years), median tumor volume was 4.9 cm(3), median peripheral dose (70%) was 15.6 Gy and median dose at the isocenter was 21.6 Gy. Karnofsky index, disease control and number of lesions were the only parameters significantly influencing survival (median 8.6 months), while disease-free survival was correlated with the number of isocenters. Seven percent of the patients presented severe complications, including nine episodes of radiation necrosis. The only parameter influencing the risk of radiation necrosis was the conformity index (p = 0.001). These findings emphasize the importance of reducing falsely irradiated normal tissue during radiosurgery to prevent radiation necrosis.