Therapy of breast cancer brain metastases: challenges, emerging treatments and perspectives.

Brain metastases are the most common central nervous system tumors in adults, and incidence of brain metastases is increasing due to both improved diagnostic techniques (e.g. magnetic resonance imaging) and increased cancer patient survival through advanced systemic treatments. Outcomes of patients remain disappointing and treatment options are limited, usually involving multimodality approaches. Brain metastases represent an unmet medical need in solid tumor care, especially in breast cancer, where brain metastases are frequent and result in impaired quality of life and death. Challenges in the management of brain metastases have been highlighted in this review. Innovative research and treatment strategies, including prevention approaches and emerging systemic treatment options for brain metastases of breast cancer, are further discussed.

Acute skin allergy to thermoplastic mask used for patient immobilization during radiation therapy: a case report.

BACKGROUND: Radiosurgical treatments of brain tumors, vascular malformations, and functional disorders are more and more frequently used. Gamma Knife irradiation with the Icon system necessitates the use of a thermoplastic mask for head immobilization during treatment. Acute cutaneous allergy to thermoplastic masks has never been reported. CASE PRESENTATION: A 71-year-old Caucasian woman treated radiosurgically for a sphenoidal meningioma using the Icon Gamma Knife system developed an acute allergic skin reaction to the thermoplastic mask used for head immobilization. Corticoids and antihistamine drugs were needed to continue the radiosurgical procedure to its end. CONCLUSION: Allergic reaction of the skin during radiosurgery with a thermoplastic mask for head fixation can develop due to cutaneous contact of the face with the mask.

[Early postsurgical temozolomide treatment in newly diagnosed bad prognosis glioblastoma patients: Feasibility study]. / Administration précoce de témozolomide après chirurgie chez des patients ayant un glioblastome de mauvais pronostic : étude de faisabilité.

INTRODUCTION: Despite the combined adjuvant treatment of radiotherapy plus chemotherapy with temozolomide (TMZ) followed by 6 cycles of temozolomide after surgery, the prognosis of patients with glioblastoma remains poor. We conducted a monocentric prospective study to explore the tolerance and potential efficacy of an early temozolomide cycle after surgery. METHOD: Patients with newly diagnosed glioblastoma (unmutated IDH1) and of poor prognosis (age>50 years, biopsy or partial resection or unmethylated MGMT promoter) were prospectively included from June 2014 to 2017. They all received a cycle of 5 days of temozolomide between surgery and the combined adjuvant treatment. RESULTS: Twelve patients of median age 64.5 years (45-73) were included in the study. The median doses of temozolomide administered were respectively 265mg (225-300) for the early cycle; 130mg (110-150) for the concomitant treatment and 310mg (225-400) for the adjuvant one. Side effects during treatment were grade III lymphopenia, grade III neutropenia, fatigue and nausea/vomiting respectively in 4, 1, 7 and 5 patients. Progression-free survival and overall survival were respectively 90% and 91.7% at 6 months; 58.3 and 71.3% at 12 months; 31.1 and 71.3% at 18 months. CONCLUSION: Early postsurgical temozolomide treatment prior to standard adjuvant therapy for poor prognosis glioblastoma patients in our small prospective series presents toxicity and survival similar to those published in the literature for the general population of glioblastoma. These encouraging results should be confirmed by a multicentric study comparing this regiment with the standard treatment.

Management of supratentorial recurrent low-grade glioma: A multidisciplinary experience in 35 adult patients.

The management of recurrent diffuse low-grade gliomas (LGGs) is controversial. In the present study, the multidisciplinary management of 35 patients with recurrent LGGs was retrospectively analyzed. Tumor progression or recurrence was defined by clinical, radiological and/or metabolic pejorative evolution. All patients were regularly followed up by a multidisciplinary neuro-oncological group at Hôpital Erasme. Patients with histologically confirmed supratentorial LGGs (7 astrocytoma, 22 oligodendrogliomas and 6 oligoastrocytomas) who had undergone surgery between August 2004 and November 2010 were included. A total of 3 patients exhibited no tumor progression (median follow-up (FU), 81 months; range, 68-108 months). Tumor recurrence occurred in the 32 remaining patients [progression-free survival (PFS), 26 months; range, 2-104 months]. In addition, 25/29 (86%) patients who received surgery alone underwent reoperation at the time of tumor recurrence, and high-grade transformation occurred in 6 of these patients (24%). Furthermore, 4/29 (14%) patients were treated with adjuvant therapy alone (3 chemotherapy and 1 radiotherapy). In the 19 patients with no high-grade transformation at reintervention, 3 received adjuvant therapy and 16 were regularly followed up through multimodal imaging. The PFS time of the patients who underwent reoperation with close FU (n=16) and for the patients receiving adjuvant therapy with or without surgery (n=7) at first recurrence was 10 and 24 months (P=0.005), respectively. However, no significant difference was observed for overall survival (P=0.403). At the time of this study, 22 of the 35 patients included were alive following a median FU time of 109 months (range, 55-136). The results of the present study could change the multidisciplinary approach used into a more aggressive approach with adjuvant therapy, with or without surgery, for the treatment of a select subpopulation of patients with LGGs at the first instance of tumor recurrence.

Testicular germ cell tumor: Short and long-term side effects of treatment among survivors.

Long-term prognosis of germ cell tumor (GCT) types is excellent, however, treatment is associated with non-negligible complication rates and a negative impact on quality of life. The present study described treatment results in terms of survival, both short and long-term toxicity, and paternity rates in a cohort of patients treated at Jules Bordet Institute, University ULB of Brussels (Brussels, Belgium). The present study analyzed the data of a cohort of patients with GCT types. Pre-operative patient and tumor characteristics were described. Performance status, pulmonary function tests and renal clearance prior to chemotherapy were noted. Chemotherapeutic regimens and their associated toxicities were analyzed. The duration to event-free, cancer-specific and overall survivals were estimated using Kaplan-Meier curves. A total of 115 patients (median age, 31-years-old) were treated for a GCT at Jules Bordet Institute. At a median follow-up of 6-years, 11 (10%) patients had relapsed and 2 (2%) developed a second malignant neoplasm. At the final follow-up, 97 (89%) and 6 (5.5%) patients exhibited complete and partial remission, respectively. A total of 6% of patients exhibited a progressive disease. In terms of short-term toxicity, 11% of patients presented with febrile neutropenia. The 10-year overall survival rate and relapse-free survival rate were 93.4 and 89.8%, respectively. The paternity rate post-treatment was 27%. Testicular GCT survivors suffered from short- and long-term treatment-associated side effects on both a physical and psychological level. A long-term close follow-up is necessary in order to assist the patient with these treatment-induced complications.

Repeat Gamma Knife surgery for vestibular schwannomas.

BACKGROUND: Gamma Knife (GK) surgery is a recognized treatment option for the management of small to medium-sized vestibular schwannoma (VS) associated with high-tumor control and low morbidity. When a radiosurgical treatment fails to stop tumor growth, repeat GK surgery can be proposed in selected cases. METHODS: A series of 27 GK retreatments was performed in 25 patients with VS; 2 patients underwent three procedures. The median time interval between GK treatments was 45 months. The median margin dose used for the first, second, and third GK treatments was 12 Gy, 12 Gy, and 14 Gy, respectively. Six patients (4 patients for the second irradiation and 2 patients for the third irradiation) with partial tumor regrowth were treated only on the growing part of the tumor using a median margin dose of 13 Gy. The median tumor volume was 0.9, 2.3, and 0.7 cc for the first, second, and third treatments, respectively. Stereotactic positron emission tomography (PET) guidance was used for dose planning in 6 cases. RESULTS: Mean follow-up duration was 46 months (range 24-110). At the last follow-up, 85% of schwannomas were controlled. The tumor volume decreased, remained unchanged, or increased after retreatment in 15, 8, and 4 cases, respectively. Four patients had PET during follow-up, and all showed a significant metabolic decrease of the tumor. Hearing was not preserved after retreatment in any patients. New facial or trigeminal palsy did not occur after retreatment. CONCLUSIONS: Our results support the long-term efficacy and low morbidity of repeat GK treatment for selected patients with tumor growth after initial treatment.

Five-fraction Gamma Knife radiosurgery using the Extend relocatable system for benign neoplasms close to optic pathways.

PURPOSE: To evaluate the precision of hypofractionated radiosurgery using the Gamma Knife Extend relocatable system in patients with benign neoplasms located close to the optic pathways. METHODS AND MATERIALS: A series of 59 irradiation procedures with the Extend system were performed on 12 patients. We treated 11 meningiomas and 1 craniopharyngioma. All patients except 1 were treated with 5 daily fractions of a 5-Gy margin dose; 1 patient was treated with 4 fractions of 6 Gy. The deviations on the X, Y, and Z axes were calculated as the mean value of all measures performed on each plate of the reposition check tool. An estimation of the patient's head motion during treatment was calculated as the difference between the radial deviations measured before and after each irradiation procedure. RESULTS: The maximum deviation of all measures was 0.9 mm for the 59 procedures. The mean deviations in the X, Y, and Z axes were 0.23 mm (standard deviation [SD], 0.17; maximum, 0.85), 0.31 mm (SD, 0.21; maximum, 0.90), and 0.27 mm (SD, 0.20; maximum, 0.80), respectively. The mean radial intrafraction difference was 0.16 mm (SD 0.14) and the maximum intrafraction deviation was of 0.7 mm. The mean follow-up duration was 19.3 months (range, 6-32 months). The visual status remained stable for 11 patients and improved in 1 patient; the tumor volume remained stable for 4 patients and decreased for 8 patients. From a clinical point of view, no new symptoms were recorded and no vision deterioration occurred. CONCLUSIONS: The Extend system provides good repositioning accuracy and adequate immobilization of the patient's head for multisession treatment. The clinical and radiological outcomes of a series of 12 patients who underwent 59 irradiation fractions were excellent.

Long-term tumor control of benign intracranial tumors after Gamma Knife radiosurgery in 280 patients followed more than 5 years.

The objective of the study was to assess the long-term radiological outcome of benign intracranial tumors (BIT) after Gamma Knife radiosurgery. We report the radiological outcome of 280 patients who underwent radiosurgical irradiation for BIT in a single center. Our series included 120 meningiomas, 139 vestibular schwannomas, 12 other schwannomas and 9 pituitary adenomas. Serial imaging studies were performed after irradiation for at least 5 years for all patients. The median tumor volume was 1.9 cc, and the median margin dose was 12 Gy. After a median follow-up of 6.8 years, the tumor control rate was 92.1%: tumor decreased in 176 cases (62.9%), remained unchanged in 82 lesions (29.3%) and increased in 22 cases (7.9%). The actuarial tumor control rate was 93.2% at 5 years, 92.3% at 7.5 years and 91.0% at 10 years. No atypical or malignant transformation of irradiated tumors occured during the follow-up period. Gamma Knife radiosurgery provides a high rate of tumor control for BIT even in the medium to long-term.

Dosimetric and clinical analysis of spatial distribution of the radiation dose in gamma knife radiosurgery for vestibular schwannoma.

OBJECTIVES: We investigated variations in the distribution of radiation dose inside (dose inhomogeneity) and outside (dose falloff) the target volume during Gamma Knife (GK) irradiation of vestibular schwannoma (VS). We analyzed the relationship between some parameters of dose distribution and the clinical and radiological outcome of patients. METHODS AND MATERIALS: Data from dose plans of 203 patients treated for a vestibular schwannoma by GK C using same prescription dose (12 Gy at the 50% isodose) were collected. Four different dosimetric indexes were defined and calculated retrospectively in all plannings on the basis of dose-volume histograms: Paddick conformity index (PI), gradient index (GI), homogeneity index (HI), and unit isocenter (UI). The different measures related to distribution of the radiation dose were compared with hearing and tumor outcome of 203 patients with clinical and radiological follow-up of minimum 2 years. RESULTS: Mean, median, SD, and ranges of the four indexes of dose distribution analyzed were calculated; large variations were found between dose plans. We found a high correlation between the target volume and PI, GI, and UI. No significant association was found between the indexes of dose distribution calculated in this study and tumor control, tumor volume shrinkage, hearing worsening, loss of functional hearing, or complete hearing loss at last follow-up. CONCLUSIONS: Parameters of distribution of the radiation dose during GK radiosurgery for VS can be highly variable between dose plans. The tumor and hearing outcome of patients treated is not significantly related to these global indexes of dose distribution inside and around target volume. In GK radiosurgery for VS, the outcome seems more to be influenced by local radiation dose delivered to specific structures or volumes than by global dose gradients.

Gamma knife radiosurgery for intralabyrinthine schwannomas.

OBJECT: To analyze indications and technical specificities of treatment of intralabyrinthine schwannoma (ILS) by Gamma Knife radiosurgery. METHODS: Six patients were treated by Gamma Knife irradiation for a schwannoma arising from the cochleo-vestibular structures. Patients presented hearing worsening at different stages, tinnitus, imbalance and/or vertigo. RESULTS: ILS was intravestibular/intracochlear/intravestibulocochlear/ transmacular in respectively 2/1/2/1 patients. We cover the entire tumor volume with a margin prescription dose of 12-Gy. The tumor volume remained unchanged at last follow-up in all cases; for 4 patients with functional hearing still present before treatment, the audiological status remained stable in 2 patients, worsened moderately in 1 patientand worsened to cophosis in 1 patient. No patient experienced worsening of tinnitus, imbalance or vertigo after irradiation. CONCLUSIONS: Gamma Knife treatment of ILS is technically feasible without risk thanks to the precision of current robotized Gamma Knife devices. Patients treated radiosurgically avoid some of the risks of microsurgery, could in some cases maintain useful hearing and prevent further symptoms worsening.

Brain metastases in HER2-positive breast cancer: the evolving role of lapatinib.

Due to improvements in diagnosis and systemic therapy, brain metastases are an increasingly common cause of morbidity and mortality for patients with advanced breast cancer. The incidence of symptomatic brain metastases among women with metastatic breast cancer ranges from 10% to 16%. The HER2 receptor, which is overexpressed in approximately 25% of all breast cancers, is an important risk factor for the development of central nervous system metastases. Surgery and radiation therapy are the primary approaches to the treatment of brain metastases but new chemotherapy and biological agents promise to play an important role in the future management of central nervous system disease. This article reviews the epidemiology, current treatment options and recent advances in the field, with a focus on HER2-positive disease and the emerging role of lapatinib for the treatment and prevention of brain metastases.

Experimental analysis of radiation dose distribution in radiosurgery. II. Dose fall-off outside the target volume.

INTRODUCTION: The role of radiation dose delivered to surrounding tissues outside target is often minimized in radiosurgery. We study histopathological effects of dose fall-offs outside the target using an experimental model of trigeminal nerve irradiation in the rat. MATERIAL AND METHODS: Sixteen rats were irradiated with a Gamma Knife at the right trigeminal nerve using a 90-Gy dose and 4 different gradients of dose fall-off; the brainstem at the trigeminal nerve root entry was histologically analyzed 3 months after irradiation. RESULTS: Four specific histopathological reactions were found as a consequence of the irradiation. All these reactions were significantly related to the gradient of dose fall-off. CONCLUSIONS: Different dose distributions outside the target could produce various histological effects in the irradiated tissue that could influence the outcome of radiosurgical treatment. A more rapid fall-off of dose (higher selectivity) is associated with less risk of histological changes in tissues surrounding the target.

Experimental analysis of radiation dose distribution in radiosurgery: I. Dose hot spot inside target volume.

INTRODUCTION: Radiosurgery is currently performed with different systems of focused radiation providing different dose heterogeneities within the target volume. Here, we aimed to study histological consequences of different dose distributions inside the target area in an experimental model of Gamma Knife irradiation in the rat striatum. MATERIAL AND METHODS: Twelve rats were irradiated by Gamma Knife at the same volume in the right striatum; the same margin dose of 45 Gy was prescribed for all rats. Three different dose distributions inside the target volume were applied. Brain sections at the level of the target area were histologically analyzed 3 months after irradiation. RESULTS: Of the 7 histopathological reactions found as a consequence of the irradiation, 6 of them were significantly related to the gradient of dose heterogeneity within the target volume. CONCLUSIONS: Dose distribution inside the target volume could influence the histological effects of radiosurgical irradiation on tissue included in the target. A high dose in the target volume is more likely to lead to the desired radiobiological result.

Brain stem metastases treated with radiosurgery: prognostic factors of survival and life expectancy estimation.

BACKGROUND: The objective of this study is to study prognostic factors of survival and 3 stratification systems for life expectancy estimation in patients with brain stem metastases treated with radiosurgery. METHODS: Between December 1999 and November 2006, 25 patients with 27 brain stem metastases were treated with Gamma Knife radiosurgery. The lesions' mean volume was 0.6 mL (0.013-3.6 mL). The mean marginal dose was 20 Gy (15-24 Gy). Univariate and multivariate studies were done to identify prognostic factors, and 3 patient stratification systems were applied for survival estimation: RPA, SIR, and BSBM. RESULTS: The primary tumor location was in the lungs in 12 patients, breast in 8, and other in 5. Fourteen lesions were located in the pons, 9 in the midbrain, and 4 in the medulla. All patients were followed clinically. Radiologic follow-up was available in 21 lesions (78%). Tumor control was achieved in all but one followed lesion (95%). There were no complications related to treatment. Median survival of patients with brain stem metastases was 11.1 months. In multivariate analysis, KPS of 80 or more, control of the primary tumor, absence of radiotherapy, and a marginal dose higher than 18 Gy were associated with better survival. The BSBM in the univariate and multivariate analyses was the strongest predictor of survival (P < .0001). CONCLUSIONS: The BSBM was the most useful tool for estimating survival. Rather than the brain stem location of an intracranial metastasis, the patient integral clinical status seems to be more important in determining survival.

Three-dimensional Gaussian model to define brain metastasis limits on 11C-methionine PET.

PURPOSE: Since 11C-methionine (MET) heavily accumulates in brain tumors, PET with MET (MET-PET) is proposed for the image-guided planning of their targeted therapy. Determination of bulk tumor limits is therefore a crucial component of MET-PET image analysis. We aimed at validating a Gaussian model of tumor delineation on MET-PET. We choose MET-PET and MRI data obtained in brain metastases to adjust the model. Indeed, MRI limits of these non-infiltrative hypermetabolic brain lesions are efficiently used for their curative treatment. METHODS AND MATERIALS: We developed a three-dimensional (3D) Gaussian model that relates the tumor-limit-defining threshold to maximum and mean count values in the defined tumor volume and to mean count values in a reference region. To adjust the model to experimental data, we selected 25 brain metastases following these criteria: (i) no surgery or classical radiotherapy within 6 months, (ii) no previous radiosurgery, (iii) MET-PET and MRI acquired within a 48-h interval, (vi) necrosis representing less than 25% of tumor volume on MRI. We applied a progressive thresholding procedure on MET-PET so as to match tumor limits on contrast-enhanced co-registered MRI. RESULTS: In 22 tumors, a match could be reached between tumor margins on MET-PET and MRI. The relation between mean, maximum and threshold values closely fits the 3D-Gaussian model function. We found a quadratic relation between the mean-to-threshold ratio and the maximum-to-cerebellum activity ratio. CONCLUSIONS: A 3D-Gaussian model may describe the limits of MET uptake distribution within brain metastases, providing a simple method for metabolic tumor delineation.

Neurovascular compression anatomy and pain outcome in patients with classic trigeminal neuralgia treated by radiosurgery.

OBJECTIVE: To study the influence of the anatomy of neurovascular compression (NVC) on pain outcome in patients with classic trigeminal neuralgia treated by radiosurgery. METHODS: Analysis of the anatomy of the trigeminal nerve, brainstem, and vessels was performed in 89 consecutive patients treated by Leksell gamma knife (Elekta Instruments, Stockholm, Sweden) for classic trigeminal neuralgia. One-millimeter axial magnetic resonance imaging slices (T1-weighted, T1-weighted enhanced, and T2-weighted selected partial inversion recovery) with coronal, sagittal, and three-dimensional reconstructions were viewed. The end point for outcome was total pain remission and no medication. The follow-up period ranged between 6 and 42 months. RESULTS: In 82 patients (92%), a vascular structure in contact with the nerve was observed. In four patients, the NVC was produced by a large vessel (basilar or vertebral artery) and in 78 by a smaller vessel. The superior cerebellar artery was the cause of the NVC in 64 patients (78%). The NVC was proximal (<3 mm to the brainstem) in 34 patients (41%) and distal in 43 patients (52%). Nerve dislocation was present in 29 patients (33%), and nerve atrophy was present in 21 (24%) patients. Visualization of NVC on magnetic resonance imaging scans was not associated with outcome. The two variables associated with poor outcome were a large vessel contacting the nerve with brainstem deformation and proximal NVC. Nerve atrophy and nerve dislocation were not associated with outcome. CONCLUSION: The visualization of NVC, nerve atrophy, and nerve dislocation on magnetic resonance imaging scans was not associated with pain outcome. A large vessel compressing the nerve and deforming the brainstem and proximal NVC were associated with a lesser pain control.

Irradiation of cochlear structures during vestibular schwannoma radiosurgery and associated hearing outcome.

OBJECT: The purpose of this study was to measure the dose of radiation delivered to the cochlea during a Gamma knife surgery (GKS) procedure for treatment of patients with vestibular schwannomas (VSs), and to analyze the relationship between cochlear irradiation and the hearing outcome of these patients. METHODS: Eighty-two patients with VSs were treated with GKS using a marginal dose of 12 Gy. No patient had neurofibromatosis Type 2 disease, and all had a Gardner-Robertson hearing class of I to IV before treatment, and a radiological and audiological follow-up of at least 1-year after GKS. The dosimetric data of the volume of the cochlea were retrospectively analyzed and were correlated with the auditory outcome of patients. RESULTS: The mean radiation dose delivered to the cochlear volume ranged from 1.30 to 10.00 Gy (median 4.15 Gy). The cochlea received significantly higher radiation doses in patients with worsening of hearing after GKS. A highly significant association between the cochlear and the intracanalicular dose of radiation delivered during GKS was found. CONCLUSIONS: During GKS for VSs, relatively high doses of radiation can be delivered to the cochlea. Worsening of hearing after GKS can be the consequence of either radiation injury to the cochlea or the irradiation dose delivered into the auditory canal, or both.

Internal carotid occlusion following gamma knife radiosurgery for cavernous sinus meningioma.

Gamma knife radiosurgery is a safe and effective treatment for cavernous sinus meningioma, associated with a very low morbidity. However, a high dose of radiation could lead to modifications of the vascular wall such as in radiosurgical treatment of arteriovenous malformations. We present a patient treated by gamma knife radiosurgery for a left cavernous sinus meningioma using a margin dose of 13 Gy at the 50% isodose. A complete occlusion of the intracavernous segment of the ICA occurred during the follow-up, in combination with a regression of the meningioma volume. The patient sustained no neurological deficit. We found that a hot spot of dose was administered to the intracavernous segment of the internal carotid artery, with a maximum dose of 22.3 Gy. Dose heterogeneity inside the target volume can produce hot spots of dose inside the internal carotid artery that can lead to a vascular occlusion. Therefore, we recommend shifting the hot spot during the dosimetry planning in order to reduce the incidence of such vascular injury.

Clinical evaluation of targeting accuracy of gamma knife radiosurgery in trigeminal neuralgia.

PURPOSE: The efficiency of radiosurgery is related to its highly precise targeting. We assessed clinically the targeting accuracy of radiosurgical treatment with the Leksell Gamma Knife for trigeminal neuralgia. We also studied the applied radiation dose within the area of focal contrast enhancement on the trigeminal nerve root following radiosurgery. METHODS AND MATERIALS: From an initial group of 78 patients with trigeminal neuralgia treated with gamma knife radiosurgery using a 90-Gy dose, we analyzed a subgroup of 65 patients for whom 6-month follow-up MRI showed focal contrast enhancement of the trigeminal nerve. Follow-up MRI was spatially coregistered to the radiosurgical planning MRI. Target accuracy was assessed from deviation of the coordinates of the intended target compared with the center of enhancement on postoperative MRI. Radiation dose delivered at the borders of contrast enhancement was evaluated. RESULTS: The median deviation of the coordinates between the intended target and the center of contrast enhancement was 0.91 mm in Euclidean space. The radiation doses fitting within the borders of the contrast enhancement of the trigeminal nerve root ranged from 49 to 85 Gy (median value, 77 +/- 8.7 Gy). CONCLUSIONS: The median deviation found in clinical assessment of gamma knife treatment for trigeminal neuralgia is low and compatible with its high rate of efficiency. Focal enhancement of the trigeminal nerve after radiosurgery occurred in 83% of our patients and was not associated with clinical outcome. Focal enhancement borders along the nerve root fit with a median dose of 77 +/- 8.7 Gy.