[Proposal for the delineation of postoperative primary clinical target volumes in maxillary sinus and nasal cavity cancers]. / Proposition de délinéation des volumes cibles anatomocliniques postopératoires de la tumeur primitive des cancers du sinus maxillaire et des cavités nasales.

In this article, we propose a consensus delineation of postoperative clinical target volumes for the primary tumour in maxillary sinus and nasal cavity cancers. These guidelines are developed based on radioanatomy and the natural history of those cancers. They require the fusion of the planning CT with preoperative imaging for accurate positioning of the initial GTV and the combined use of the geometric and anatomical concepts for the delineation of clinical target volume for the primary tumour. This article does not discuss the indications of external radiotherapy (nor concurrent systemic treatment) but focuses on target volumes when there is an indication for radiotherapy.

[Frameless trigeminal neuralgia radiosurgery with a dedicated linear accelerator: From equipment commissioning to initial clinical results]. / Radiochirurgie des névralgies trigéminales avec accélérateur linéaire dédié sans cadre invasif : de la mise en service de l'appareil aux premiers résultats cliniques.

PURPOSE: Radiosurgery for the treatment of trigeminal neuralgia delivers a very high dose in a single fraction, over a few millimeters, at a single isocenter placed along the nerve. We present here the different steps that have been performed to validate small beams by conical collimators, and report the clinical results of the first patients treated on Novalis Tx®, frameless. MATERIAL AND METHODS: First, the geometric accuracy of 4 and 6mm conical collimators was evaluated using Winston-Lutz tests; then dosimetric data acquisition was performed using high spatial resolution detectors (PTW 60019 microdiamond and a PTW 60017 E-diode). The corrective factors of the TRS 483 report were applied to calculate the collimator aperture factors. These dosimetric data were then compared with the data implemented in the iPlan® treatment planning system. Then end-to-end tests were performed to control the entire treatment process using an anthropomorphic phantom "STEEV". Between 2020 and 2022, 18 patients were treated for refractory trigeminal neuralgia on Novalis Tx®, frameless, with Exactrac® repositioning. A total of 17 patients were evaluated (one was lost to follow-up) using the BNI score for pain assessment and MRI with a median follow-up of 12 months. RESULTS: The quality criteria of geometric and dosimetric accuracy were met for the 6-mm cone but not for the 4-mm cone. All patients were treated with a 6-mm cone with a dose of 90Gy prescribed at the isocenter at the root entry zone. Initial pain control was obtained in 70.5% of our patients, and 53% maintained pain control with a median follow-up of 12 months. All recurrences occurred within 3 to 6 months after radiosurgery. No brainstem toxicity was observed. Six patients had non-disabling facial hypoesthesia, half of whom already had pretreatment hypoesthesia. CONCLUSION: The treatment of trigeminal neuralgia on a dedicated linear accelerator is a highly technical treatment whose accuracy and safety are paramount. The physical measurements allowed the commissioning of the technique with a 6mm cone. Our first clinical results are in accordance with the literature.

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.

Pembrolizumab versus cetuximab concurrent with radiotherapy in patients with locally advanced squamous cell carcinoma of head and neck unfit for cisplatin (GORTEC 2015-01 PembroRad): a multicenter, randomized, phase II trial.

BACKGROUND: To evaluate potential synergistic effect of pembrolizumab with radiotherapy (RT) compared with a standard-of-care (SOC) cetuximab-RT in patients with locally advanced-squamous cell carcinoma of head and neck (LA-SCCHN). PATIENTS AND METHODS: Patients with nonoperated stage III-IV SCC of oral cavity, oropharynx, hypopharynx, and larynx and unfit for receiving high-dose cisplatin were enrolled. Patients received once-daily RT up to 69.96 Gy in 33 fractions with weekly cetuximab (cetuximab-RT arm) or 200 mg Q3W pembrolizumab during RT (pembrolizumab-RT arm). The primary endpoint was locoregional control (LRC) rate 15 months after RT. To detect a difference between arms of 60%-80% in 15-month LRC, inclusion of 66 patients per arm was required to achieve a power of at least 0.85 at two-sided significance level of 0.20. RESULTS: Between May 2016 and October 2017, 133 patients were randomized to cetuximab-RT (n = 66) and pembrolizumab-RT (n = 67). Two patients (one in each arm) were not included in the analysis (a consent withdrawal and a progression before treatment start). The median age was 65 years (interquartile range 60-70 years), 92% were smokers, 60% were oropharynx (46% of oropharynx with p16+) and 75% were stage IV. Median follow-up was 25 months in both arms. The 15-month LRC rate was 59% with cetuximab-RT and 60% with pembrolizumab-RT ]odds ratio 1.05, 95% confidence interval (CI) 0.43-2.59; P = 0.91]. There was no significant difference between arms for progression-free survival (hazard ratio 0.85, 95% CI 0.55-1.32; P = 0.47) and for overall survival (hazard ratio 0.83, 95% CI 0.49-1.40; P = 0.49). Toxicity was lower in the pembrolizumab-RT arm than in the cetuximab-RT arm: 74% versus 92% patients with at least one grade ≥3 adverse events (P = 0.006), mainly due to mucositis, radiodermatitis, and rash. CONCLUSION: Compared with the SOC cetuximab-RT, pembrolizumab concomitant with RT did not improve the tumor control and survival but appeared less toxic in unfit patients with LA-SCCHN.

[Impact of HPV status on nutritional status during radio chemotherapy for oropharyngeal cancer]. / Impact du statut HPV sur l'évolution nutritionnelle au cours de la chimioradiothérapie des patients atteints d'un cancer de l'oropharynx.

PURPOSE: Patients with oropharyngeal cancer are at high nutritional risk before and during treatment. Little is known about the influence of human papillomavirus (HPV) infection on nutritional status and its evolution during treatment. MATERIALS AND METHODS: A single-center retrospective study was conducted between August 2017 and December 2020 including 48 patients (14 HPV-induced: HPV+ and 34 non-HPV-induced: HPV-) with oropharyngeal squamous cell carcinoma treated by radiotherapy±chemotherapy (RT/CT). Nutritional risk at the time of tumor assessment (TA) was assessed by weight loss, swallowing ability, and the presence of digestive disorders in 4 stages of increasing severity. Nutritional status was assessed by weight and nutrition risk index (NRI) at the time of TA, before the start and at 3 months from the end of RT±CT. During RT±CT, the NRI and the systemic inflammatory response index (SIRI=neutrophils * monocytes/lymphocytes) were assessed weekly. RESULTS: HPV+patients were at lower nutritional risk at TA (50% grade ≥2 vs 85%, P=0.02), lost more weight (6% of their body weight vs 3%, P=0.05), and increased their SIRI by 7.5 points more than HPV- patients (P=0.04) during RT/CT. CONCLUSION: HPV+ oropharyngeal cancer patients are at high nutritional risk even in the absence of undernutrition at the outset of management.

Histosurgical mapping of endoscopic endonasal surgery of sinonasal tumours to improve radiotherapy guidance.

PURPOSE: Endoscopic endonasal surgery (EES) is becoming a standard for most malignant sinonasal tumours. Margin analysis after piecemeal resection is complex and optimally relies on accurate histosurgical mapping. Postoperative radiotherapy may be adapted based on margin assessment mapping to reduce the dose to some sinonasal subvolumes. We assessed the use of histosurgical mapping by radiation oncologists (RO). MATERIAL AND METHODS: A French practice survey was performed across 29 ENT expert RO (2 did not answer) regarding integration of information on EES, as well as quality of operative and pathology reportsto refine radiotherapy planning after EES. This was assessed through an electronic questionnaire. RESULTS: EES was ubiquitously performed in France. Operative and pathology reports yielded accurate description of EES samples according to 66.7% of interviewed RO. Accuracy of margin assessment was however insufficient according to more than 40.0% of RO. Additional margins/biopsies of the operative bed were available in 55.2% (16/29) of the centres. In the absence of additional margins, quality of resection after EES was considered as microscopically incomplete in 48.3% or dubious in 48.3% of RO. As performed, histosurgical mapping allowed radiotherapy dose and volumes adaptation according to 26.3% of RO only. CONCLUSIONS: Standardized histosurgical mapping with margin and additional margin analysis could be more systematic. Advantages of accurate EES reporting could be dose painting radiotherapy to further decrease morbidity in sinonasal tumours.

Radiotherapy of benign intracranial tumours.

We present the updated recommendations of the French Society for Radiation Oncology on benign intracranial tumours. Most of them are meningiomas, vestibular schwannomas, pituitary adenomas, craniopharyngiomas, and glomus tumours. Some grow very slowly, and can be observed without specific treatment, especially if they are asymptomatic. Symptomatic or growing tumours are treated by surgery, which is the reference treatment. When surgery is not possible, due to the location of the lesion, or general conditions, radiotherapy can be applied, as it is if there is a postoperative growing residual tumour, or a local relapse. Indications have to be discussed at a multidisciplinary panel, with precise evaluation of the benefit and risks of the treatments. The techniques to be used are the most modern ones, as multimodal imaging and image-guided radiation therapy. Stereotactic treatments, using fractionated or single doses depending on the size or the location of the tumours, are commonly realized, to avoid as much a possible the occurrence of late side effects.

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.

Radiotherapy for nasopharyngeal cancer.

Nasopharyngeal cancers are a rarity in France. Radiotherapy is the cornerstone of treatment, frequently combined with chemotherapy. The technical modality of radiotherapy is complex in this disease, which is located in the vicinity of numerous organs at risk. In this article, we will present the updated guidelines of the French society for radiation oncology (Société française de radiothérapie oncologique, SFRO) on the indications, and technical details of radiotherapy in nasopharyngeal cancers.

Radiotherapy for hypopharynx cancers.

We present the update of the recommendations of the French society of oncological radiotherapy on radiotherapy for hypopharynx. Intensity-modulated radiotherapy is the gold standard treatment for hypopharynx cancers. Early T1 and T2 tumors could be treated by exclusive radiotherapy or surgery followed by postoperative radiotherapy in case of high recurrence risk. For locally advanced tumours requiring total pharyngolaryngectomy (T2 or T3) or with significant lymph nodes involvement, induction chemotherapy followed by exclusive radiotherapy or concurrent chemoradiotherapy were possible. For T4 tumour, surgery must be proposed. The treatment of lymph nodes is based on initial primary tumour treatment. In non-surgical procedure, for 35 fractions, curative dose is 70Gy (2Gy per fraction) and prophylactic dose are 50 to 56Gy (2Gy per fraction in case of sequential radiotherapy or 1.6Gy in case of integrated simultaneous boost) radiotherapy; for 33 fractions, curative dose is 69.96Gy (2.12Gy per fraction) and prophylactic dose is 52.8Gy (1.6Gy per fraction in integrated simultaneous boost radiotherapy or 54Gy in 1.64Gy per fraction); for 30 fractions, curative dose is 66Gy (2.2Gy per fraction) and prophylactic dose is 54Gy (1.8Gy per fraction in integrated simultaneous boost radiotherapy). Doses over 2Gy per fraction could be done when chemotherapy is not used regarding potential larynx toxicity. Postoperatively, radiotherapy is used in locally advanced cancer with dose levels based on pathologic criteria, 60 to 66Gy for R1 resection and 54 to 60Gy for complete resection in bed tumour; 50 to 66Gy in lymph nodes areas regarding extracapsular spread. Volume delineation were based on guidelines cited in this article.

Radiotherapy for laryngeal cancers.

We present the update of the recommendations of the French society of oncological radiotherapy on radiotherapy of laryngeal cancers. Intensity modulated radiotherapy is the standard of care radiotherapy for the management of laryngeal cancers. Early stage T1 or T2 tumours can be treated either by radiotherapy or conservative surgery. For tumours requiring total laryngectomy (T2 or T3), an organ preservation strategy by either induction chemotherapy followed by radiotherapy or chemoradiotherapy with cisplatin is recommended. For T4 tumours, a total laryngectomy followed by radiotherapy is recommended when feasible. Dose regimens for definitive and postoperative radiotherapy are detailed in this article, as well as the selection and delineation of tumour and lymph node target volumes.

Radiotherapy for oral cavity cancers.

Intensity modulated radiation therapy and brachytherapy are standard techniques of irradiation for the treatment of oral cavity cancers. These techniques are detailed in terms of indication, planning, delineation and selection of the volumes of interest, dosimetry and patients positioning control. This is an update of the guidelines of the French Society of Radiotherapy Correspondence.

Toxicity and time lapse between immunotherapy and stereotactic radiotherapy of brain metastases.

PURPOSE: Stereotactic radiotherapy (SRT) is the standard treatment for brain metastases of non-small-cell lung cancer (NSCLC) and melanoma, mostly in combination with immunotherapy. The objective was to retrospectively evaluate the influence of the time-lapse between immunotherapy and stereotactic radiotherapy on toxicity. PATIENTS AND METHODS: From 2016 to 2019, 59 patients treated with SRT for 103 brain metastases of NSCLC (60%) and melanoma (40%) in combination with concomitant immunotherapy (≤30 days) were included. The prescribed dose was 20Gy/1f or 33Gy/3f at the isocentre and 14Gy or 23.1Gy (70%) respectively at the PTV envelope (PTV=GTV+2mm). The mean tumour diameter was 14mm (4-52mm). The immunotherapies used were anti-PD1 and anti-PDL1. The 103 metastases were classified into 3 groups according to the time-lapse between instatement of immunotherapy and instatement of SRT for the patient concerned: 7 (7%) in group A (≤7 days), 38 (37%) in group B (7 to 14 days) and 58 (56%) in group C (14 to 30 days). RESULTS: The mean follow-up was 10.1 months. The median overall survival was 11.5 months for NSCLC and 12.5 months for melanoma. The percentage of local control (LC) at one year was 65.1% (93.6% for NSCLC and 26.5% for melanoma). The time-lapse between immunotherapy and SRT was not a significant predictor of LC (P=0.86), while the histology was (P<0.001). The proportion of grade≥3 toxicities was 5.1%, and that of radionecrosis was 9.7% (among these patients, 80% were non-symptomatic): 0%, 13.1% and 8.6% for groups A, B and C respectively. The time-lapse between immunotherapy and SRT was not a significant predictor of toxicity. Only tumour volume was a significant predictive factor (P=0.03). CONCLUSION: The time lapse between immunotherapy and SRT does not influence brain toxicity. The tumour volume remains the main factor.

[Predictive factors for mandibular osteoradionecrosis after irradiation of head and neck cancers]. / Facteurs prédictifs de l'ostéoradionécrose mandibulaire après irradiation des cancers des voies aérodigestives supérieures.

The identification of the different risk factors for mandibular osteoradionecrosis (ORN) must be done before and after the management of patients with head and neck cancer. Various clinical criteria for this severe radiation-induced complication are related to the patient (intrinsic radiosensitivity, malnutrition associated with thin weight loss, active smoking intoxication, microcapillary involvement, precarious oral status, hyposalivation) and/or related to the disease (oral cavity, large tumor size, tumor mandibular invasion). Therapeutic risk factors are also associated with a higher risk of ORN (primary tumor surgery, concomitant radio-chemotherapy, post-irradiation dental avulsion, preventive non-observance with the absence of stomatological follow-up and daily installation of gutters fluoride and, non-observance curative healing treatments). Finally, various dosimetric studies have specified the parameters in order to target the dose values distributed in the mandible, which increases the risk of ORN. An mean mandibular dose greater than 48-54Gy and high percentages of mandibular volume receiving 40 to 60Gy appear to be discriminating in the risk of developing an ORN.

Impact of the method chosen for the analysis of recurrences after radiotherapy for head and neck cancers: volume-based, point-based and combined methods.

Intensity modulated radiation therapy for head and neck is a complex technique. Inappropriate delineation and/or dose distribution can lead to recurrences. Analysis of these recurrences should lead to improve clinical practice. For several years, different methods of analysis have been described. The purpose of this review is to describe these different methods and to discuss their advantages and limitations. The first published methods used a volume-based approach studying the entire volume of recurrence according to initial target volumes, or dose distribution. The main limitation of these methods was that the volume of recurrence studied was dependent on the delay in diagnosis of that recurrence. Subsequently, other methods used point-based approaches, conceptualizing recurrence either as a spherical expansion from a core of radioresistant cells (center of mass of recurrence volume) or using a more clinical approach, taking into account tumor expansion pathways. More recently, more precise combined methods have been described, combining the different approaches. The choice of method is decisive for conclusions on the origin of recurrence.

[Proposal for the delineation of postoperative primary clinical target volumes in ethmoid cancers]. / Proposition de délinéation des volumes cibles anatomocliniques postopératoires de la tumeur primitive des cancers de l'ethmoïde.

It is proposed to delineate the anatomo-clinical target volumes of primary tumor (CTV-P) in ethmoid cancers treated with post-operative radiotherapy. This concept is based on the use of radioanatomy and the natural history of cancer. It is supported by the repositioning of the planning scanner with preoperative imaging for the replacement of the initial GTV and the creation of margins around it extended to the microscopic risk zones according to the anatomical concept. This article does not discuss the indications of external radiotherapy but specifies the volumes to be delineated if radiotherapy is considered.

[Intra and extra hepatic cholangiocarcinomas radiation therapy]. / Place de la radiothérapie des cholangiocarcinomes intra- et extrahépatiques.

Cholangiocarcinomas are digestive tumors whose incidence remains low and have poor prognosis. The benefits of adjuvant radiochemotherapy and radiotherapy have never been demonstrated in any phase III randomized controlled trial. Chemotherapy with capecitabine 6 months is the standard of care in adjuvant setting. Radiochemotherapy is validated in R1 patients. It is not recommended in neoadjuvant situations given the lack of evidence. Chemotherapy and radiochemotherapy are validated in adjuvant or locally advanced diseases. Stereotactic radiation therapy offers an interesting perspective, at the cost of significant digestive toxicities, requiring evaluation in randomized trials.

Phase 1 trial of ralimetinib (LY2228820) with radiotherapy plus concomitant temozolomide in the treatment of newly diagnosed glioblastoma.

BACKGROUND AND PURPOSE: This phase 1 trial aimed to determine the maximum tolerated dose (MTD; primary objective) of a p38-MAPK inhibitor, ralimetinib, with radiotherapy (RT) and chemotherapy (TMZ), in the treatment of newly diagnosed glioblastoma (GBM) patients. MATERIALS AND METHODS: The study was designed as an open-label dose-escalation study driven by a Tite-CRM design and followed by an expansion cohort. Ralimetinib was administered orally every 12 h, 7 days a week, for 2 cycles of 2 weeks at a dose of 100, 200 or 300 mg/12 h. Patients received ralimetinib added to standard concurrent RT (60 Gy in 30 fractions) with TMZ (75 mg/m2/day) and 6 cycles of adjuvant TMZ (150-200 mg/m2 on days 1-5 every 28 days). RESULTS: The MTD of ralimetinib was 100 mg/12 h with chemoradiotherapy. The three patients treated at 200 mg/12 h presented a dose-limiting toxicity: one patient had a grade 3 face edema, and two patients had a grade 3 rash and grade 3 hepatic cytolysis (66%). Of the 18 enrolled patients, 15 received the MTD of ralimetinib. At the MTD, the grade ≥ 3 adverse events during concomitant chemoradiotherapy were hepatic cytolysis (2/15 patients), dermatitis/rash (1/15), lymphopenia (1/15) and nausea/vomiting (1/15). No interaction of TMZ and ralimetinib when administrated concomitantly has been observed. Inhibition of pMAPKAP-K2 (-54%) was observed in peripheral blood mononuclear cells. CONCLUSION: This phase 1 trial is the first trial to study the combination of a p38-MAPK inhibitor, ralimetinib, with radiotherapy (RT) and chemotherapy (TMZ), in the treatment of newly diagnosed glioblastoma (GBM) patients. The MTD of ralimetinib was 100 mg/12 h. The most frequent dose-limiting toxicities were hepatic cytolysis and rash.

Hypofractionated stereotactic radiotherapy for large brain metastases: Optimizing the dosimetric parameters.

PURPOSE: Stereotactic radiotherapy plays a major role in the treatment of brain metastases (BM). We aimed to compare the dosimetric results of four plans for hypofractionated stereotactic radiotherapy (HFSRT) for large brain metastases. MATERIAL AND METHODS: Ten patients treated with upfront NovalisTx® non-coplanar multiple dynamic conformal arcs (DCA) HFSRT for≥25mm diameter single BM were included. Three other volumetric modulated arc therapy (VMAT) treatment plans were evaluated: with coplanar arcs (Eclipse®, Varian, VMATcEclipse®), with coplanar and non-coplanar arcs (VMATncEclipse®), and with non-coplanar arcs (Elements Cranial SRS®, Brainlab, VMATncElements®). The marginal dose prescribed for the PTV was 23.1Gy (isodose 70%) in three fractions. The mean GTV was 27mm3. RESULTS: Better conformity indices were found with all VMAT techniques compared to DCA (1.05 vs 1.28, P<0.05). Better gradient indices were found with VMATncElements® and DCA (2.43 vs 3.02, P<0.001). High-dose delivery in healthy brain was lower with all VMAT techniques compared to DCA (5.6 to 6.3 cc vs 9.4 cc, P<0.001). Low-dose delivery (V5Gy) was lower with VMATncEclipse® or VMATncElements® than with DCA (81 or 94 cc vs 110 cc, P=0.02). CONCLUSIONS: NovalisTx® VMAT HFSRT for≥25mm diameter brain metastases provides the best dosimetric compromise in terms of target coverage, sparing of healthy brain tissue and low-dose delivery compared to DCA.