Role of radiotherapy in the management of brain oligometastases.

The management of patients with brain oligometastases is complex and relies on specific reasoning compared to extracranial oligometastases. The levels of evidence are still low because patients with brain oligometastases are frequently excluded from randomized clinical trials. Stereotactic radiotherapy should be preferred in this indication over whole brain irradiation, both for patients with metastases in place and for those who have undergone surgery. The decision of local treatment and its timing must be a multidisciplinary reflection taking into account the histological and molecular characteristics of the tumor as well as the intracranial efficacy of the prescribed systemic treatments. Great caution must be observed when using stereotactic radiotherapy and concomitant systemic treatments because interactions are still poorly documented. We present the recommendations of the French society of radiation oncology on the management of brain oligometastatic patients with radiotherapy.

Hypofractionated postoperative stereotactic radiotherapy for large resected brain metastases.

PURPOSE: The aim of the present retrospective study was to report outcomes after hypofractionated stereotactic radiotherapy (HSRT) for resected brain metastases (BM). PATIENTS AND METHODS: We reviewed results of patients with resected BM treated with postoperative HSRT (3×7.7Gy to the prescription isodose 70%) between May 2013 and June 2020. Local control (LC), distant brain control (DBC), overall survival (OS), leptomeningeal disease relapse (LMDR), and radiation necrosis (RN) occurrence were reported. RESULTS: Twenty-two patients with 23 brain cavities were included. Karnofsky Performance status (KPS) was≥70 in 77.3%. Median preoperative diameter was 37mm [21.0-75.0] and median planning target volume (PTV) was 23 cm3 [9.9-61.6]. Median time from surgery to SRT was 69 days [7-101] and 48% of patients had a local relapse on pre-SRT imaging. Median follow-up was 17.5 months [1.6-95.9]. One and two-year LC rates were 60.9 and 52.2% respectively. One and 2-year DBC rates were 45.5 and 40.9%. Median OS was 16.5 months. Four patients (18.2%) presented LMDR during follow-up. RN occurred in 6 patients (27.2%). Three factors were associated with OS: ECOG-PS (P=0.009), KPS (P=0.04), cystic or solid nature of the metastasis before surgery (P=0.037). Several factors were related to RN occurrence: PTV diameter and volume, Normal brain V21, V21 and V24 isodoses volumes. CONCLUSION: HSRT is the most widely used scheme for larger brain cavities after surgery. The optimal dose and scheme remain to be defined as well as the optimal delay between postoperative SRT and surgery. Dose escalation may be necessary, especially in case of subtotal resection.

Optic nerve motion and gaze direction: Their impact on intraorbital tumor radiotherapy.

PURPOSE: Management of inter- and intra-fraction movements of target volumes and organs at risk (OARs) during radiotherapy is essential. While there is little OAR or target volume movement, the movements and orientation of the eyes can be significant during radiotherapy and they can affect the position of the optic nerve. The objective of the present study was to assess the variations of the optic nerve position due to gaze direction and to discuss their clinical consequences on the radiation treatment of intraorbital tumors. MATERIAL AND METHODS: Three patients without a history of oculomotor nerve palsy underwent six CT acquisitions with a thermoplastic mask: eyes open with different gaze directions (straight ahead, left, right, up, down) and eyes closed. The acquisition with the straight-ahead gaze was chosen as the reference position. Left and right optic nerves were segmented on the six acquisitions, and total volumes and maximum amplitude motions were calculated in three dimensions. RESULTS: Maximum differences were observed while looking left and up, with a median maximum amplitude of 5 and 6mm [range: 2-7mm], respectively. These motions induced a position variation of more than 50% of the volume of the optic nerve (compared to the reference position). Greater variations of motion were observed for the anterior portion of the nerve. The gaze position with the fewest variations compared to the reference position was eyes closed. CONCLUSION: Optic nerve positions vary significantly due to the gaze direction, especially for the anterior portion of the nerve. These variations should be taken into account for the treatment of small intraorbital tumors involving the anterior third of the optic nerve.

Neurological side effects of radiation therapy.

Radiation therapy (RT) is one of the main treatments administered to patients with cancer. The development of technology has improved RT accuracy by allowing more precise delivery of high doses to the target volumes with reduced exposure of healthy tissue. Life expectancy has increased due to these therapeutic advancements and the patients' quality of life remains a major concern. The adverse events related to RT are quite various and most likely will impair essential neurological functions, e.g. cognitive status. This literature review aims to describe the physiopathological processes, the neurological symptoms as well as the local modifications observed in magnetic resonance imaging following RT. The specific therapeutic options and preventive actions will also be discussed.

Radiation guidelines for gliomas.

Gliomas are the most frequent primary brain tumour. The proximity of organs at risk, the infiltrating nature, and the radioresistance of gliomas have to be taken into account in the choice of prescribed dose and technique of radiotherapy. The management of glioma patients is based on clinical factors (age, KPS) and tumour characteristics (histology, molecular biology, tumour location), and strongly depends on available and associated treatments, such as surgery, radiation therapy, and chemotherapy. The knowledge of molecular biomarkers is currently essential, they are increasingly evolving as additional factors that facilitate diagnostics and therapeutic decision-making. We present the update of the recommendations of the French society for radiation oncology on the indications and the technical procedures for performing radiation therapy in patients with gliomas.

[New indications of protontherapy for adults intracranial tumours]. / Nouvelles indications de protonthérapie et essais cliniques en cours : tumeurs intracrâniennes.

Considering intracranial tumours, only few indications of protontherapy, such as chordoma, chondrosarcoma or uveal melanoma, are uniformly approved in the world. Other indications, excluding paediatric pathologies, are still debated. The aim of this article is to describe the rationale for the use of protonbeam irradiation for meningioma, pituitary adenoma, craniopharyngioma, paraganglioma, glioma, and schwannoma, and to inform the radiation oncologists if prospective studies or randomized studies are opened for inclusions. This article deals only with indications for adults.

Metallic implants and CT artefacts in the CTV area: Where are we in 2020?

Radiation therapy (RT) is one of the main modalities of cancer treatment worldwide with computed tomography (CT), as the most commonly used imaging method for treatment planning system (TPS). Image reconstruction errors may greatly affect all the radiation therapy planning process, such as target delineation, dose calculation and delivery, particularly with particle therapy. Metallic implants, such as hip and spinal implants, and dental filling significantly deteriorate image quality. These hardware structures are often very complex in geometry leading to geometric complex artefacts in the clinical target volume (CTV) area, rendering the delineation of CTV challenging. In our review, we focus on the methods to overcome artefact consequences on CTV delineation: 1- medical approaches anticipating issues associated with imaging artefacts during preoperative multidisciplinary discussions while following standard recommendations; 2- common metal artefact reduction (MAR) methods such as manually override artefact regions, ballistics avoiding beam paths through implanted materials, megavoltage-CT (MVCT); 3- prospects with radiolucent implants, MAR algorithms and various methods of dual energy computed tomography (DECT). Despite substantial and broad evidence for their benefits, there is still no universal solution for cases involving implanted metallic devices. There is still a high need for research efforts to adapt technologies to our issue: "how do I accurately delineate the ideal CTV in a metal artefact area?"

Radiotherapy of non-tumoral refractory neurological pathologies.

Intracranial radiotherapy has been improved, primarily because of the development of stereotactic approaches. While intracranial stereotactic body radiotherapy is mainly indicated for treatment of benign or malignant tumors, this procedure is also effective in the management of other neurological pathologies; it is delivered using GammaKnife® and linear accelerators. Thus, brain arteriovenous malformations in patients who are likely to experience permanent neurological sequelae can be managed by single session intracranial stereotactic body radiotherapy, or radiosurgery, in specific situations, with an advantageous benefit/risk ratio. Radiosurgery can be recommended for patients with disabling symptoms, which are poorly controlled by medication, such as trigeminal neuralgia, and tremors, whether they are essential or secondary to Parkinson's disease. This literature review aims at defining the place of intracranial stereotactic body radiotherapy in the management of patients suffering from non-tumoral refractory neurological pathologies. It is clear that the multidisciplinary collaboration of experienced teams from Neurosurgery, Neurology, Neuroradiology, Radiation Oncology and Medical Physics is needed for the procedures using high precision radiotherapy techniques, which deliver high doses to locations near functional brain areas.

Imaging issues specific to hadrontherapy (proton, carbon, helium therapy and other charged particles) for radiotherapy planning, setup, dose monitoring and tissue response assessment.

Imaging is critical to each step of precision radiation therapy, i.e. planning, setup, delivery and assessment of response. Hadrontherapy can be considered to deliver more precise dose distribution that may better spare normal tissues from intermediate low doses of radiation. In addition, hadrontherapy using high linear energy transfer ions may also be used for dose escalation on biological target volumes defined by functional imaging. However, the physical characteristics of hadrontherapy also make it more demanding in terms of imaging accuracy and image-based dose calculation. Some of the developments needed in imaging are specific to hadrontherapy. The current review addresses current status of imaging in proton therapy and the drawbacks of photon-based imaging for hadrons. It also addresses requirements in hadrontherapy planning with respect to multimodal imaging for proper target and organ at risk definition as well as to target putative radioresistant areas such as hypoxic ones, and with respect to dose calculation using dual energy CT, MR-proton therapy, proton radiography. Imaging modalities, such as those used in photon-based radiotherapy (intensity modulated and stereotactic radiotherapy), are somewhat already implemented or should be reaching "routine" hadrontherapy (at least proton therapy) practice in planning, repositioning and response evaluation optimizable within the next five years. Online monitoring imaging by PET, as currently developed for hadrontherapy, is already available. Its spatiotemporal limits restrict its use but similar to prompt gamma detection, represents an area of active research for the next 5 to 10 years. Because of the more demanding and specific dose deposit characteristics, developments image-guided hadrontherapy, such as specific proton imaging using tomography or ionoacoustics, as well as delivery with MR-proton therapy, may take another 10 years to reach the clinics in specific applications. Other aspects are briefly described such as range monitoring. Finally, the potential of imaging normal tissue changes and challenges to assess tumour response are discussed.

Dose distribution of the brain tissue associated with cognitive functions in high-grade glioma patients.

PURPOSE: The purpose of this prospective dosimetric study was to assess the dose distribution regarding the brain areas implied in cognitive functions using two approaches: volumetric modulated arc therapy (VMAT) and helical tomotherapy (HT). PATIENTS AND METHODS: Thirty-seven patients were treated using a dual-arc VMAT approach for supratentorial glioblastoma between 2016 and 2018. The total dose of 60Gy in 30 daily fractions was administered to the planning target volume (PTV). The brain structures that play an important role in cognitive physiology, such as the hippocampi, corpus callosum, cerebellum, subventricular zones (SVZ), were delineated. For each patient, a new treatment plan in HT was determined by a second medical physicist in a blindly fashion according to the same dose constraints and priorities. Statistical analyses were performed using the Wilcoxon-signed rank test. RESULTS: Conformity indexes remained similar with both techniques. The mean values were 0.96 (0.19-1.00) for VMAT and 0.98 (range, 0.84-1.00) for HT, respectively (P=0.73). Significant D50% reductions were observed with VMAT compared to HT: 14.6Gy (3.8-28.0) versus 17.4Gy (12.1-25.0) for the normal brain (P=0.014); 32.5Gy (10.3-60.0) versus 35.6Gy (17.1-58.0) for the corpus callosum (P=0.038); 8.1Gy (0.4-34.0) versus 12.8Gy (0.8-27.0) for the cerebellum (P<0.001), respectively. CONCLUSION: The VMAT approach seemed to improve the sparing of the key brain areas implied in cognitive functions without jeopardizing PTV coverage.

[Proton therapy in France in 2019]. / État des lieux de la protonthérapie en France en 2019.

Among over 100 proton therapy centres worldwide in operation or under construction, French proton therapy is coming to full maturity with the recent opening of the Nice (1991, upgrade in 2016) and Caen (2018) facilities next to the Orsay (1991, upgrade in 2010) centre. Proton therapy is a national priority for children and young adults in all three centres. The patient-related activity of the three French centres is coordinated via the Protonshare portal to optimise referral by type of indication and available expertise in coordination with the French society of radiation oncology SFRO and French radiotherapy centres. The centres are recognised by the French Health Care excellence initiative, promoted by the ministry of Foreign Affairs. The three centres collaborate structurally in terms of clinical research and are engaged at the international level in the participation to European databases and research initiatives. Concerted actions are now also promoted in preclinical research via the Radiotransnet network. Ongoing French developments in proton therapy are well presented in international hadron therapy meetings, including European Proton Therapy Network and Particle Therapy Cooperative Oncology Group. Proton therapy teaching in France is offered at several levels and is open to colleagues from all radiation oncology centres, so that they are fully informed, involved and trained to facility recognition of possible indications and thereby to contribute to appropriate patient referral. This close collaboration between all actors in French radiation oncology facilitates the work to demonstrate the required level of medical and scientific evidence for current and emerging indications for particle therapy. Based on that, the future might entail a possible creation of more proton therapy facilities in France.

Whole brain radiotherapy with concurrent temozolomide in multifocal and/or multicentric newly diagnosed glioblastoma.

The standard medical care of glioblastoma (GBM) patients with good performance status is based on focal brain radiotherapy (40-60 Gy) with concurrent temozolomide (TMZ) followed by adjuvant TMZ. Newly diagnosed multifocal and/or multicentric GBM (M/M GBM) cases are usually treated with TMZ alone: whole brain chemoradiotherapy (CRT) is avoided for safety reasons. To our knowledge, no study has investigated the safety and efficacy of whole-brain radiotherapy (WBRT) with concurrent TMZ in M/M GBM patients. This retrospective study sought to assess the role of WBRT associated with concurrent TMZ followed by TMZ alone in this population. Eleven patients with pathologically proven M/M GBM (≥3 lobes) were treated with WBRT between April 2009 and September 2017. The median age was 50 years [34-74]. The median dose of radiotherapy was 45 Gy at 1.8 Gy per fraction over 37 days [29-41], with concurrent daily TMZ at the dose of 75 mg/m2. This treatment was followed by adjuvant monthly TMZ (150 mg/m2-D1-D5). All pathology slides and radiology images were reviewed. The median overall and progression-free survival times for all patients were 10 months [4-25] and 5 months [3-21], respectively. There was no grade 3-4 toxicity due to radiotherapy. One patient stopped the TMZ during the radiochemotherapy period and 9 patients received adjuvant TMZ with a median number of 5 cycles [2-8]. Our study supports the safety and the efficacy of WBRT with TMZ in newly diagnosed M/M GBM. Larger prospective studies are needed to support our results.

[Boost in proton for locally advanced nasopharyngeal carcinoma: A Curie Institute experience]. / Complément de dose de protons pour les cancers du nasopharynx localement évolués : une expérience de l'institut Curie.

PURPOSE: The aim of this study was to assess the treatment outcome and toxicity for patients with locally advanced nasopharyngeal carcinoma treated with a complementary dose with proton. PATIENTS AND METHODS: Between November 1999 and September 2016, 17 patients have been treated for a stage III-IVa nasopharyngeal carcinoma in the proton therapy centre of Curie Institute. Bilateral lymph node in the neck (I-V levels) received from 40 to 54Gy with photon beam. The primary tumor volume including microscopically extensions received a complementary dose with proton in order to reach the dose of 70 to 78Gy. All the patients received a concomitant chemotherapy. The end-points of the study were loco-regional control, survival, and treatment-related toxicity. RESULTS: Patients characteristics were: median age 49, 71 % male, 88% stage IVa, with a majority (82%) of T4N0M0. The median follow-up was 99 months. The 2-, 5- and 10-year actuarial locoregional free survival and overall survival were 94% and 88%, 86% and 74%, and 86% and 66%, respectively. The grade≥3 late adverse events were sphenoid bone radionecrosis (5.9%) and hearing loss (23.5%). CONCLUSION: This study showed that a complementary dose with proton seems to be a good option for the treatment of locally advanced nasopharyngeal carcinoma, particularly for T4N0M0.

Three-year results after radiotherapy for locally advanced sinonasal adenoid cystic carcinoma, using highly conformational radiotherapy techniques proton therapy and/or Tomotherapy.

PURPOSE: We report the patient outcomes of a treatment combining proton therapy and Tomotherapy in sinonasal adenoid cystic carcinoma involving skull base. MATERIALS AND METHODS: We included patients treated at Curie Institute, Paris, France, between March 2010 and February 2014 for an advanced adenoid cystic carcinoma involving skull base. Patients received Tomotherapy, proton therapy or both. We evaluated treatment toxicity (according to CTCAE V4), local control, distant metastasis-free survival and overall survival. RESULTS: Thirteen patients were included, with a median follow-up of 34 months. Radiation therapy followed surgery for 77% of the patients and margins were positive in all those cases. Median dose was 73.8Gy. Local control, distant metastasis-free survival and overall survival at 3 years were respectively 60%, 48% and 60%. One-sided grade 3 hearing impairment occurred in 46% of the patients. CONCLUSION: Combining high-dose proton therapy and Tomotherapy is effective and has moderate toxicity in the treatment of T4 sinonasal adenoid cystic carcinoma involving skull base.

Protontherapy of head and neck paragangliomas: A monocentric study.

PURPOSE: The aim of this study was to assess efficacy and safety of proton beam therapy of paragangliomas of the head and neck, rare benign tumours developed close to crucial structures such as cranial nerves and vascular tissues. PATIENTS AND METHODS: Ten patients with a paraganglioma of the head and neck were treated from 2001 to 2014 with image-guided proton therapy. Neurological and ear nose throat symptoms were collected in addition to audiometric testing, before and after the treatment. Acute and late toxicities were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) v4. RESULTS: Median age at diagnosis was 52.6years (range: 18.2-65.8years). Proton therapy was the exclusive treatment in six patients and four patients had a postoperative radiotherapy. Median dose was 50.4Gy relative biological effectiveness (RBE; range: 45.0-67.0Gy). With a median follow-up of 24.6months (range: 6.7-46.2 months), local tumour control rate was 100% (stable, n=10). No upper grade 2 acute toxicity was reported. To the latest news, seven patients had controlled symptoms (improved, n=1, stabilized, n=6). One patient out of seven with initial tinnitus had a decrease in his symptoms, while the six other patients had a sustained stabilization. CONCLUSION: Proton beam therapy is an effective and well-tolerated treatment modality of skull base paragangliomas, with documented functional benefit. A longer follow-up is planned in order to assess local control and long-term toxicities.

[Radiotherapy for brain metastases]. / Radiothérapie des métastases cérébrales.

Radiotherapy for brain metastases has become more multifaceted. Indeed, with the improvement of the patient's life expectancy, side effects must be undeniably avoided and the retreatments or multiple treatments are common. The cognitive side effects should be warned and the most modern techniques of radiation therapy are used regularly to reach this goal. The new classifications of patients with brain metastases help guiding treatment more appropriately. Stereotactic radiotherapy has supplanted whole brain radiation therapy both for patients with metastases in place and for those who underwent surgery. Hippocampus protection is possible with intensity-modulated radiotherapy. Its relevance in terms of cognitive functioning should be more clearly demonstrated but the requirement, for using it, is increasingly strong. While addressing patients in palliative phase, the treatment of brain metastases is one of the localisations where technical thinking is the most challenging.

[Guidelines for the radiotherapy of gliomas]. / Référentiels d'irradiation des gliomes.

Gliomas are the most frequent primary brain tumours. Treating these tumours is difficult because of the proximity of organs at risk, infiltrating nature, and radioresistance. Clinical prognostic factors such as age, Karnofsky performance status, tumour location, and treatments such as surgery, radiation therapy, and chemotherapy have long been recognized in the management of patients with gliomas. Molecular biomarkers are increasingly evolving as additional factors that facilitate diagnosis and therapeutic decision-making. These practice guidelines aim at helping in choosing the best treatment, in particular radiation therapy.

Prognostic and therapeutic factors of gliosarcoma from a multi-institutional series.

The aims of this multicentre retrospective study were to identify prognostic or therapeutic factors impacting on overall survival in patients with gliosarcoma. The analysis included all patients treated for gliosarcoma between 1998 and 2014 in seven French academic centres. Seventy-five patients with a median age of 60 years (range from 23 to 79 years) were treated with a combination of surgery (n = 66), radiotherapy (adjuvant for 64 patients and exclusive for 8 patients) and temozolomide based chemotherapy (n = 58). Median follow-up was 12 months (range from 2 to 71 months). Two-year overall survival (OS) and disease free survival rates were 12 % (95 % CI 4-20 %) and 2 % (95 % CI 0-6 %), respectively. The median OS was 13 months. Treatment at recurrence consisted of chemotherapy (n = 38) (bevazicumab for 18 patients, repeat temozolomide for 10 patients), salvage surgery (n = 8) and radiochemotherapy (n = 1). In univariate analysis, younger age, higher total dose of radiotherapy, longer time to recurrence and treatment at recurrence significantly increased OS. In multivariate analysis, high total dose of radiotherapy (HR = 0.97, p = 0.007) and treatment at recurrence (HR = 0.28, p < 0.001) were favourable prognostic factors of OS. Radiotherapy at a minimum dose of 54 Gy and salvage treatment increased OS of gliosarcoma. Unlike glioblastoma, in our analysis, TMZ based chemotherapy was not associated with an improvement in OS compared to patients who received radiation therapy only.

[Current use and prospects for hadron therapy in 2015]. / Hadronthérapie : quelle place et quelles perspectives en 2015 ?

Hadron therapy (including protons and ions) is still expanding worldwide, although still limited by the cost and thus the number of available facilities. If the historical indications remain eye melanomas, skull base tumours and paediatric tumours for protontherapy; and salivary glands, paranasal sinus and nasal cavity tumours, and soft tissue sarcomas for carbon ions, no conclusion can be drawn about the role of these modalities for other tumours, such as prostate, lung cancers. Since 2013, more than 100 clinical trials are on-going, including comparisons between advanced photons modalities, protontherapy and carbon ions therapy. An important technological and scientific (physics, radiobiology) effort has been made in parallel in order to reduce the cost of the facilities and to fully take advantages of the beam properties: standardization of beam scanning, image guided treatment, robust and 4D planning. Furthermore, the increasing number of facilities, the development of hypofractionation and the selection of indications will contribute to find the true place of particle therapy, despite the "screening effect" of the cost. The long term effects assessment on large patient cohorts will allow or not to correlate adverse effects and dosimetric data, always evoked.

Iris metastasis from prostate carcinoma: a case report and review of the literature.

Despite the high incidence of prostate carcinoma, metastases of the uvea are very rare and the iris localization is even more. Only a few cases worldwide have been described so far. We report here the case of a 66-year-old man diagnosed with a metastatic prostate carcinoma. Nine months later, he developed brain and skin metastases. A couple of weeks later, the metastatic lesion appeared on his left iris. He has received whole brain radiation therapy including the iris lesion in the radiation fields. Through this case report and a literature review, we discuss the incidence, the different clinical presentations and the impact on the survival prognosis of this uncommon metastatic site.