Role of radiation therapy in brain metastases management.

The challenge of the management of brain metastases has not finished yet. Although new diagnosis-specific prognostic assessment classifications and guidelines for patients with brain metastases help to guide treatment more appropriately, and even if the development of modern technologies in imaging and radiation treatment, as well as improved new systemic therapies, allow to reduce cognitive side effects and make retreatment or multiple and combined treatment possible, several questions remain unanswered. However, tailoring the treatment to the patient and his expectations is still essential; in other words, patients with a poor prognosis should not be over-treated, and those with a favorable prognosis may not be subtracted to the best treatment option. Some ongoing trials with appropriate endpoints could better inform our choices. Finally, a case-by-case inter-disciplinary discussion remains essential.

Anatomical and functional MR imaging to define tumoral boundaries and characterize lesions in neuro-oncology.

Neuroimaging and especially MRI has emerged as a necessary imaging modality to detect, measure, characterize and monitor brain tumours. Advanced MRI sequences such as perfusion MRI, diffusion MRI and spectroscopy as well as new post-processing techniques such as automatic segmentation of tumours and radiomics play a crucial role in characterization and follow up of brain tumours. The purpose of this review is to provide an overview on anatomical and functional MRI use for brain tumours boundaries determination and tumour characterization in the specific context of radiotherapy. The usefulness of anatomical and functional MRI on particular challenges posed by radiotherapy such as pseudo progression and pseudo esponse and new treatment strategies such as dose painting is also described.

Expression-based intrinsic glioma subtypes are prognostic in low-grade gliomas of the EORTC22033-26033 clinical trial.

INTRODUCTION: The European Organisation for Research and Treatment of Cancer (EORTC) 22033-26033 clinical trial (NCT00182819) investigated whether initial temozolomide (TMZ) chemotherapy confers survival advantage compared with radiotherapy (RT) in low-grade glioma (LGG) patients. In this study, we performed gene expression profiling on tissues from this trial to identify markers associated with progression-free survival (PFS) and treatment response. METHODS: Gene expression profiling, performed on 195 samples, was used to assign tumours to one of six intrinsic glioma subtypes (IGSs; molecularly similar tumours as previously defined using unsupervised expression analysis) and to determine the composition of immune infiltrate. DNA copy number changes were determined using OncoScan arrays. RESULTS: We confirm that IGSs are prognostic in the EORTC22033-26033 clinical trial. Specific genetic changes segregate in distinct IGSs: most samples assigned to IGS-9 have IDH-mutations and 1p19q codeletion, samples assigned to IGS-17 have IDH-mutations without 1p19q codeletion and samples assigned to other intrinsic subtypes often are IDH-wildtype. A trend towards benefit from RT was observed for samples assigned to IGS-9 (hazard ratio [HR] for TMZ is 1.90, P = 0.065) but not for samples assigned to IGS-17 (HR 0.87, P = 0.62). We did not identify genes significantly associated with PFS within intrinsic subtypes, although follow-up time is limited. We also show that LGGs and glioblastomas differ in their immune infiltrate, which suggests that LGGs are less amenable to checkpoint inhibitor-type immune therapies. Gene expression analysis also allows identification of relatively rare subtypes. Indeed, one patient with a pilocytic astrocytoma was identified. CONCLUSION: IGSs are prognostic for PFS in EORTC22033-26033 clinical trial samples.

Reirradiation with concurrent bevacizumab for recurrent high-grade gliomas in adult patients.

PURPOSE: To analyse feasibility, prognostic factors and patterns of recurrence after concurrent reirradiation and bevacizumab for recurrent high-grade gliomas. PATIENTS AND METHODS: Between 2009 and 2015, 35 patients (median 57-year-old; 21 men, 14 women) with WHO grade III (n=11) or grade IV (n=24) gliomas were included in this retrospective and consecutive single-centre study. All patients received bevacizumab (median number of treatments: 12) concomitant with reirradiation (median dose: 45Gy, median number of fractions: 18) for recurrence with median 22 months (range: 5.6-123.7 months) from first irradiation (median dose: 60Gy). RESULTS: The median follow-up was 9.2 months from reirradiation. The median overall survival from reirradiation was 10.5 months (95% confidence interval [95% CI]: 4.9-16.1) and the progression-free survival from reirradiation was 6.7 months (95% CI: 2.9-10.5). The median overall survival from initial diagnosis was 44.6 months (95% CI: 32-57.1). No grade 3 toxicity or above was reported. Prognostic factors significantly correlated with better overall survival in univariate analysis were: age at least 55 (P=0.024), initial surgery (P=0.003), and 2Gy equivalent dose (EQD2) at least 50Gy at reirradiation (P=0.046). Twenty-two patients bevacizumab-naïve at time of reirradiation had a significantly increased overall survival from reirradiation compared to patients treated with reirradiation after bevacizumab failure (17.7 vs. 5.4 months, P<0.001) as well as overall survival from initial diagnosis (58.9 vs. 33.5 months, P=0.006). This outcome was similar in patients with initial glioblastomas (P=0.018) or anaplastic gliomas (P=0.021). There was no correlation between overall survival and gross tumour volume or planning target volume, frontal localization, or number of salvage therapies before reirradiation (P>0.05). CONCLUSIONS: Concomitant reirradiation with bevacizumab in high-grade recurrent gliomas shows encouraging results in terms of survival and toxicities. Our data suggest that reirradiation should be favoured at initiation of bevacizumab, with EQD2 at least 50Gy.

Combined irradiation and targeted therapy or immune checkpoint blockade in brain metastases: toxicities and efficacy.

BACKGROUND: Targeted therapies (TT) and immune checkpoint inhibitors (ICI) are currently modifying the landscape of metastatic cancer management and are increasingly used over the course of many cancers treatment. They allow long-term survival with controlled extra-cerebral disease, contributing to the increasing incidence of brain metastases (BMs). Radiation therapy remains the cornerstone of BMs treatment (either whole brain irradiation or stereotactic radiosurgery), and investigating the safety profile of radiation therapy combined with TT or ICI is of high interest. Discontinuing an efficient systemic therapy, when BMs irradiation is considered, might allow systemic disease progression and, on the other hand, the mechanisms of action of these two therapeutic modalities might lead to unexpected toxicities and/or greater efficacy, when combined. PATIENTS AND METHODS: We carried out a systematic literature review focusing on the safety profile and the efficacy of BMs radiation therapy combined with targeted agents or ICI, emphasizing on the role (if any) of the sequence of combination scheme (drug given before, during, and/or after radiation therapy). RESULTS: Whereas no relevant toxicity has been noticed with most of these drugs, the concomitant use of some other drugs with brain irradiation requires caution. CONCLUSION: Most of available studies appear to advocate for TT or ICI combination with radiation therapy, without altering the clinical safety profiles, allowing the maintenance of systemic treatments when stereotactic radiation therapy is considered. Cognitive functions, health-related quality of life and radiation necrosis risk remain to be assessed. The results of prospective studies are awaited in order to complete and validate the above discussed retrospective data.

[Repair and time-dose factor: The example of spinal cord irradiation]. / Réparation et facteur temps : l'exemple de l'irradiation médullaire.

The question whether a reirradiation is possible, with either curative of palliative intent, is a frequent issue and a true therapeutic challenge, in particular for a critical organ sensitive to cumulative dose, such as the spinal cord. Preclinical experimental data, based on debatable models that are hardly transferable to patients, suggest that there is a possibility of reirradiation, beyond the classical threshold for dose constraints, taking into account the "time-dose factor". Although the underlying biological mechanisms are however uncertain, scarce clinical data seem to confirm that the tolerance of spinal cord to reirradiation does exist, provided that a particular attention to total dose is given. In the context where modern stereotactic irradiation facilities expand therapeutic perspectives, we review the literature on possibilities of reirradiation, through the example of spinal cord reirradiation.

Recent advances in the management of atypical meningiomas.

Based on the 2007 WHO classification, the proportion of atypical meningiomas has steeply increased. Complete resection is usually considered curative, however, the recurrence rate remains high. The treatment of more aggressive meningiomas remains problematic. We performed a literature review via the PubMed database with specific attention to radiological, pathological, genetic and molecular aspects particular to WHO grade II meningiomas and current therapeutic strategies. We also reviewed the role of surgery and summarized the results of the principal studies dealing with adjuvant strategies based on the most recent evidence. Adjuvant radiotherapy, administered as stereotactic radiosurgery or conventional external beam irradiation, should be strongly considered in selected cases. Limited data exist regarding the role of hormonal treatment or chemotherapy as adjunct therapy. A target therapy modulating the altered molecular balance may be the key to revolutionize the prognosis of these patients.

Radionecrosis after stereotactic radiotherapy for brain metastases.

INTRODUCTION: Radionecrosis (RN) represents the main complication of stereotactic radiotherapy (SRT) for brain metastases. It may be observed in up to 34% of cases at 24 months after treatment and associated with significant morbidity in 10-17%. AREAS COVERED: Our aim is to discuss the results of original studies on RN related to SRT for brain metastases. Expert commentary: Although the development of RN is unpredictable, larger volume of the lesion, prior whole brain irradiation, and higher dose of radiation represent the major risk factors. RN appears on MRI as contrast-enhancing necrotic lesions, surrounded by edema, occurring at least 3 months after SRT, localized within fields of irradiation. No firm criteria are established. Surgery can provide symptomatic relief but is associated with a risk of complications. Corticosteroids are considered the standard of care treatment, despite limited efficacy and many adverse effects. Bevacizumab represents another interesting option that needs to be validated.

[Systemic treatment of melanoma brain metastases]. / Traitement systémique des métastases cérébrales de mélanome.

Melanomas have a high rate of brain metastases. Both the functional prognosis and the overall survival are poor in these patients. Until now, surgery and radiotherapy represented the two main modalities of treatment. Nevertheless, due to the improvement in the management of the extracerebral melanoma, the systemic treatment may be an option in patients with brain metastases. Immunotherapy with anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) - ipilimumab - or BRAF (serine/threonine-protein kinase B-raf) inhibitors - vemurafenib, dabrafenib - has shown efficacy in the management of brain metastases in a- or pauci-symptomatic patients. Studies are ongoing with anti-PD1 (programmed cell death 1) and combinations of targeted therapies associating anti-RAF (raf proto-oncogene, serine/threonine kinase) and anti-MEK (mitogen-activated protein kinase kinase).

[Brain metastases imaging]. / Imagerie des métastases cérébrales.

The therapeutic management of brain metastases depends upon their diagnosis and characteristics. It is therefore imperative that imaging provides accurate diagnosis, identification, size and localization information of intracranial lesions in patients with presumed cerebral metastatic disease. MRI exhibits superior sensitivity to CT for small lesions identification and to evaluate their precise anatomical location. The CT-scan will be made only in case of MRI's contraindication or if MRI cannot be obtained in an acceptable delay for the management of the patient. In clinical practice, the radiologic metastasis evaluation is based on visual image analyses. Thus, a particular attention is paid to the imaging protocol with the aim to optimize the diagnosis of small lesions and to evaluate their evolution. The MRI protocol must include: 1) non-contrast T1, 2) diffusion, 3) T2* or susceptibility-weighted imaging, 4) dynamic susceptibility contrast perfusion, 5) FLAIR with contrast injection, 6) T1 with contrast injection preferentially using the 3D spin echo images. The role of the nuclear medicine imaging is still limited in the diagnosis of brain metastasis. The Tc-sestamibi brain imaging or PET with amino acid tracers can differentiate local brain metastasis recurrence from radionecrosis but still to be evaluated.

[Global brain metastases management strategy: a multidisciplinary-based approach]. / Stratégie globale de prise en charge des métastases cérébrales: une approche multidisciplinaire.

Brain metastases management has evolved over the last fifteen years and may use varying strategies, including more or less aggressive treatments, sometimes combined, leading to an improvement in patient's survival and quality of life. The therapeutic decision is subject to a multidisciplinary analysis, taking into account established prognostic factors including patient's general condition, extracerebral disease status and clinical and radiological presentation of lesions. In this article, we propose a management strategy based on the state of current knowledge and available therapeutic resources.

[Stereotactic radiotherapy in brain metastases]. / Radiothérapie en conditions stéréotaxiques des métastases cérébrales.

Stereotactic radiotherapy of brain metastases is increasingly proposed after polydisciplinary debates among experts. Its definition and modalities of prescription, indications and clinical interest regarding the balance between efficacy versus toxicity need to be discussed. Stereotactic radiotherapy is a 'high precision' irradiation technique (within 1mm), using different machines (with invasive contention or frameless, photons X or gamma) delivering high doses (4 to 25Gy) in a limited number of fractions (usually 1 to 5, ten maximum) with a high dose gradient. Dose prescription will depend on materials, dose constraints to organs at risk varying with fractionation. Stereotactic radiotherapy may be proposed: (1) in combination with whole brain radiotherapy with the goal of increasing (modestly) overall survival of patients with a good performance status, 1 to 3 brain metastases and a controlled extracranial disease; (2) for recurrence of 1-3 brain metastases after whole brain radiotherapy; (3) after complete resection of a large and/or symptomatic brain metastases; (4) after diagnosis of 3-5 asymptomatic new or progressing brain metastases during systemic therapy, with the aim of delaying whole brain radiotherapy (avoiding its potential neurotoxicity) and maintaining a high focal control rate. Only a strict follow-up with clinical and MRI every 3 months will permit to deliver iterative stereotactic radiotherapies without jeopardizing survival. Simultaneous delivering of stereotactic radiotherapy with targeted medicines should be carefully discussed.

[ANOCEF guidelines for the management of brain metastases]. / Recommandations de l'Anocef pour la prise en charge des métastases cérébrales.

The incidence of brain metastases is increasing because of the use of new therapeutic agents, which allow an improvement of overall survival, but with only a poor penetration into the central nervous system brain barriers. The management of brain metastases has changed due to a better knowledge of immunohistochemical data and molecular biological data, the development of new surgical, radiotherapeutic approaches and improvement of systemic treatments. Most of the time, the prognosis is still limited to several months, nevertheless, prolonged survival may be now observed in some sub-groups of patients. The main prognostic factors include the type and subtype of the primitive, age, general status of the patient, number and location of brain metastases, extracerebral disease. The multidisciplinary discussion should take into account all of these parameters. We should notice also that treatments including surgery or radiotherapy may be proposed in a symptomatic goal in advanced phases of the disease underlying the multidisciplinary approach until late in the evolution of the disease. This article reports on the ANOCEF (French neuro-oncology association) guidelines. The management of brain metastases of breast cancers and lung cancers are discussed in the same chapter, while the management of melanoma brain metastases is reported in a separate chapter due to different responses to the brain radiotherapy.

[Whole brain radiation therapy for brain metastases: Advantages and controversies]. / Radiothérapie encéphalique en totalité des métastases cérébrales : intérêts et controverses dans le cadre d'un référentiel.

Whole brain radiation therapy is the angular stone of the brain metastasis radiation therapy. This treatment allows reaching two goals, potentially curative for in place metastasis and prophylactic in the rest of brain tissue. However, these two advantages can be disputed and in light of the same data opposite conclusions could be drawn.

[Radiotherapy for brain tumors: which margins should we apply?]. / Radiothérapie des tumeurs cérébrales : quelles marges ?

Radiotherapy is a major modality in the treatment of brain tumours. The target volumes definition has to be precise for the radiation planification. The gross target volume (GTV) is most of the time delineated within the fusion of the planning CT scan with the appropriated MRI sequences. The clinical target volume (CTV) definition is more complex: it varies in time following the evolution of scientific knowledge and also depending of the school of thought. This article offers a review of the literature about the margins applied in brain tumours radiotherapy for gliomas (high grade, anaplastic, low grade and brain stem gliomas), embryologic tumours (medulloblastomas and primitive neuroectodermal tumours [PNET]), ependymomas, atypical teratoid rahbdoid tumours (ATRT), craniopharyngiomas, pineal gland tumours, primary central nervous cell lymphomas, meningiomas and schwannomas. New imaging modalities such as diffusion-weighted imaging, dynamic contrast enhanced, spectroscopic MRI and PET scan will allow us to delineate more precisely the target volumes and to realise dose-painting by adapting the dose to the tumour metabolism.

[Medulloblastomas: review]. / Les médulloblastomes: revue générale.

INTRODUCTION: The term of "medulloblastoma" refers to cerebellar tumors belonging to the family of primitive neuro-ectodermic tumors (PNET). Medulloblastomas represent 40% of cerebellar tumors, 15 to 20% of brain tumors and the first cause of malignant brain tumors in childhood. Seventy to 80% of cases are diagnosed in children versus 20 to 30% in adults. UPDATED KNOWLEDGE: Diagnosis is based on clinical and radiological exams, and proved on pathological analysis in association with molecular biology. Treatment comprises surgery, craniospinal radiotherapy except for children under five years of age and chemotherapy according to age and high-risk criteria. Medulloblastoma is a rare case of a central nervous system tumor which is radio- and chemo-sensitive. Treatment goals are, on one hand, to improve the survival rates and, on the other hand, to avoid late neurocognitive, neuroendocrine and orthopedic side effects related to radiation therapy, notably in children. The prognosis is relatively good, with a five year survival rate over 75% after complete resection of a localized tumor although sequelae may still compromise outcome. PERSPECTIVES AND CONCLUSION: Management of patients with medulloblastoma implies a multidisciplinary approach combining the contributions of neurosurgery, neuroradiology, pediatric oncology, neuro-oncology and radiotherapy teams.

[Role of perfusion, vascular permeability and anatomic MR imaging in radiation therapy for gliomas]. / IRM de perfusion, de perméabilité et morphologique : application en radiothérapie neuro-oncologique.

There is no clear consensus for tumour volume definition in radiotherapy of brain tumours, particularly for high-grade gliomas (HGG). They are infiltrative and heterogeneous, sub-populations of low and high grade can coexist inside one tumour volume, and peritumoral oedema is partly due to a vasogenic mechanism but also to a microscopic extension of sparse tumour cells. All these characteristics are not directly detectable using a conventional MR imaging (MRI). Complementary to the anatomical sequences (T1/T2), still always mandatory, functional maps using the dynamic MRI with a T2* weighted sequence reflect micro-vessel perfusion and permeability, more on a quantitative aspect and a qualitative one, respectively. These parameters better appreciate neo-vascularity of gliomas and areas associated with a higher value of perfusion are clearly correlated with a higher grade. Even a low-grade glioma but with detectable areas of high permeability presents a two-fold risk of recurrence versus another one with the same anatomical characteristics and treatment, but without any micro-vascular leakage. For high-grade gliomas, a high level of tissue perfusion seems to be better predictive for the risk of recurrence than histology itself. The exact co-registration of anatomic and vascular maps is currently available in clinical practice and can be incorporated during the dedicated brain MRI for radiotherapy. Its potential for better predicting the exact sites of recurrence after treatment has to be prospectively evaluated and a strong interest for a dose-escalating study is evident. Finally, T2* dynamic MRI has the ability to differentiate post-treatment modifications from recurrence better than conventional imaging.