[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.

[Re-irradiation of head and neck cancers: Target volumes, technical evolutions and prospects]. / Réirradiation des tumeurs de la tête et du cou : volumes cibles, évolutions techniques et perspectives.

Malignant tumors of the head and neck have a predominantly regional recurrence pattern, with most deaths resulting from this progression. Optimization of re-radiation in recurrence setting is a major objective for these patients. Extensive research has been carried out with the PubMed search engine to find publications dealing with this topic. The first attempts to reirradiate the ORL sphere date back to the 1980s and the first to be performed by intensity modulation conformational radiotherapy (IMRT) date back to the late 1990s. Compared to 3 dimensional conformal radiotherapy, IMRT improves clinical outcomes and reduces toxicity. In IMRT series, associated or not with concomitant chemotherapy, the locoregional control obtained at 2 years was of the order of 45 to 65% and the overall survival of 15 to 60%, depending on predictive factors. Grade 3 acute toxicity occurred on the order of 10 to 30% and late-grade 3 toxicity on the order of 15 to 50%. In a selected population with low volumes tumors, stereotactic re-irradiation at a minimum dose of 35Gy obtained outcome comparable to IMRT. Re-irradiation of head and neck tumors by proton therapy is rare. The toxicity rate appears to be lower than that usually seen after photon therapy. However, we do not have a long follow-up. This technique therefore remains reserved for search protocols and represents a future perspective in these situations.

[French organization of paediatric radiation treatment: Results of a survey conducted by the radiotherapy Committee of the French Society of Paediatric Cancers (SFCE)]. / Organisation française de la radiothérapie pédiatrique : résultats d'une enquête du comité radiothérapie de la Société française des cancers de l'enfant (SFCE).

PURPOSE: Radiotherapy is a rare indication in paediatric oncology, with 800 to 900 children in treatment per year in France. Child cancers represent approximately 1% of cancers in France and half occur before the age of 5 years. Paediatric radiation requires appropriate tools, local, time and specific training. In France, in 2015, 18 centres are accredited by the French National Cancer Institute (INCa) for this activity. MATERIAL AND METHODS: Survey conducted in February 2015 on the care of children (0 to 18 years) in radiotherapy departments in France. The survey was sent to the radiation oncologists involved in the 18 centres. The questions concerned the qualitative and quantitative aspect, medical and organizational aspects, and the involvement of assistant practitioners in the management of this activity. RESULTS: Seventeen centres responded. In 2014, 889 children under 18 were treated in radiotherapy departments. These departments are working together with one to four paediatric oncology departments. Regarding access to general anaesthesia: three centres perform one to seven treatment(s) under anaesthesia per year, three centres eight to ten treatments under anaesthesia per year, three centres ten to 24 treatments under anaesthesia per year and nine centres out of 17 use hypnosis techniques. In terms of human resources, in 2015, 29 radiation therapists have a paediatric radiotherapy activity. Involvement of assistant practitioners is growing and specific training are desired. Regarding treatment preparation and delivery, 13 centres have specific paediatric contentions, 14 of 16 centres employ radiation intensity modulated if dosimetry is more satisfying with 11 regularly to the craniospinal irradiation. Radiotherapy on moving areas with respiratory gating or hypofractionation is under developed. CONCLUSION: Paediatric radiation therapy is a specific activity requiring a dedicated management, both in human, organizational, medical and scientific aspects.

[French experience in paediatric total body irradiation: A study from the radiotherapy committee of the Société française des cancers de l'enfant (SFCE)]. / Expérience française de l'irradiation corporelle totale en pédiatrie : étude du comité de radiothérapie de la Société française des cancers de l'enfant (SFCE).

A survey was conducted in 2015 in France on the care of children in radiotherapy services. We present the results for total body irradiation in children, a specific technique of radiation treatment, which needs dedicated controls for this particular population. Of the 17 centres interviewed, 16 responded, and 13 practiced total body irradiation. Patients are positioned in lateral decubitus in 11 centres and supine/prone in two centres. Doses used for total body irradiation in myeloablative bone marrow transplantation are the same in all centres (12Gy); treatments are always fractionated. Lung shielding is positioned to limit the dose at an average of 8Gy with extremes ranging from 6 to 10Gy. The shape of the shieldings varies depending on departments' protocol, with a smaller size in case of mediastinal mass. Four centres have experience of total body irradiation under general anaesthesia, despite twice-daily fractions. In total, practice is relatively homogeneous throughout France and is inspired by the knowledge obtained in adults.

Paediatric brain tumours: A review of radiotherapy, state of the art and challenges for the future regarding protontherapy and carbontherapy.

BACKGROUND AND PURPOSE: Brain tumours are the most frequent solid tumours in children and the most frequent radiotherapy indications in paediatrics, with frequent late effects: cognitive, osseous, visual, auditory and hormonal. A better protection of healthy tissues by improved beam ballistics, with particle therapy, is expected to decrease significantly late effects without decreasing local control and survival. This article reviews the scientific literature to advocate indications of protontherapy and carbon ion therapy for childhood central nervous system cancer, and estimate the expected therapeutic benefits. MATERIALS AND METHODS: A systematic review was performed on paediatric brain tumour treatments using Medline (from 1966 to March of 2014). To be included, clinical trials had to meet the following criteria: age of patients 18 years or younger, treated with radiation, and report of survival. Studies were also selected according to the evidence level. A secondary search of cited references found other studies about cognitive functions, quality of life, the comparison of photon and proton dosimetry showing potential dose escalation and/or sparing of organs at risk with protontherapy; and studies on dosimetric and technical issues related to protontherapy. RESULTS: A total of 7051 primary references published were retrieved, among which 40 clinical studies and 60 papers about quality of life, dose distribution and dosimetry were analysed, as well as the ongoing clinical trials. These papers have been summarized and reported in a specific document made available to the participants of a final 1-day workshop. Tumours of the meningeal envelop and bony cranial structures were excluded from the analysis. Protontherapy allows outstanding ballistics to target the tumour area, while substantially decreasing radiation dose to the normal tissues. There are many indications of protontherapy for paediatric brain tumours in curative intent, either for localized treatment of ependymomas, germ-cell tumours, craniopharyngiomas, low-grade gliomas; or panventricular irradiation of pure non-secreting germinoma; or craniospinal irradiation of medulloblastomas and metastatic pure germinomas. Carbon ion therapy is just emerging and may be studied for highly aggressive and radioresistant tumours, as an initial treatment for diffuse brainstem gliomas, and for relapse of high-grade gliomas. CONCLUSION: Both protontherapy and carbon ion therapy are promising for paediatric brain tumours. The benefit of decreasing late effects without altering survival has been described for most paediatric brain tumours with protontherapy and is currently assessed in ongoing clinical trials with up-to-date proton devices. Unfortunately, in 2015, only a minority of paediatric patients in France can receive protontherapy due to the lack of equipment.

[Current situation and perspectives of proton therapy]. / État des lieux et perspectives de la protonthérapie.

Proton beam therapy is indicated as a treatment for some rare tumours and paediatric tumours because the technique allows a good local control with minimal toxicity; the growing number of centres that use proton beam therapy is associated with an increase of dosimetric and clinical data for other malignant tumours as well. This paper reviews potential indications of proton beam therapy. A systematic review on Medline was performed with the following keywords proton beam therapy, cancer, heavy particle, charged particle. No phase III trial has been published using proton beam therapy in comparison with the best photon therapy, but numerous retrospective and dosimetric studies have revealed an advantage of proton beam therapy compared to photons, above all in tumours next to parallel organs at risk (thoracic and abdominal tumours). This could be accompanied with a better safety profile and/or a better tumoural control; numerous phase 0, I, II, III and IV studies are ongoing to examine these hypotheses in more common cancers. Use of proton beam therapy is growing for common cancers within clinical trials but some indications could be applied sooner since in silico analysis showed major advantages with this technique.

Use of gEUD for predicting ear and pituitary gland damage following proton and photon radiation therapy.

OBJECTIVE: To determine the relationship between the dose to the inner ear or pituitary gland and radiation-induced late effects of skull base radiation therapy. METHODS: 140 patients treated between 2000 and 2008 were considered for this study. Hearing loss and endocrine dysfunction were retrospectively reviewed on pre- and post-radiation therapy audiometry or endocrine assessments. Two normal tissue complication probability (NTCP) models were considered (Lyman-Kutcher-Burman and log-logistic) whose parameters were fitted to patient data using receiver operating characteristics and maximum likelihood analysis. The method provided an estimation of the parameters of a generalized equivalent uniform dose (gEUD)-based NTCP after conversion of dose-volume histograms to equivalent doses. RESULTS: All 140 patients had a minimum follow up of 26 months. 26% and 44% of patients experienced mild hearing loss and endocrine dysfunction, respectively. The fitted values for TD50 and γ50 ranged from 53.6 to 60.7 Gy and from 1.9 to 2.9 for the inner ear and were equal to 60.6 Gy and 4.9 for the pituitary gland, respectively. All models were ranked equal according to Akaike's information criterion. CONCLUSION: Mean dose and gEUD may be used as predictive factors for late ear and pituitary gland late complications after skull base proton and photon radiation therapy. ADVANCES IN KNOWLEDGE: In this study, we have reported mean dose effects and dose-response relationship of small organs at risk (partial volumes of the inner ear and pituitary gland), which could be useful to define optimal dose constraints resulting in an improved therapeutic ratio.

[Update of clinical programs using hadrontherapy 2008-2012]. / Évolution des indications cliniques en hadronthérapie 2008-2012.

Hadrontherapy, a type of radiation therapy dealing with heavy charged particles, has become for the past decade one of the most sophisticated and attractive approach in the management of cancer. This is related with major technological innovations that have made available, at a relatively cheap cost, compact proton accelerators equipped with rotational gantries. The implementation of pencil beam scanning should also make treatment planning and delivery much easier and faster than conventional approaches. Until now, approximately 100,000 patients have been treated with protons worldwide. Due to more complex technological and biological challenges, light ion therapy - mainly carbon ions - has developed at a lower pace, except in Japan where most of the 15,000 treated patients have been enrolled. Current indications for protons include firstly, locally aggressive tumours non or incompletely resected, that are located close to critical normal structures: ocular melanomas, skull base and spinal canal low grade sarcomas, selected ENT carcinomas (like adenoid cystic); secondly, improvement of tolerance to radiations: delayed, mainly in paediatric malignancies, due to the exquisite sensitivity of organs under development (including to carcinogenesis); immediate, on bone marrow, mucosae… mainly in concomitant radiation-chemotherapy interactions (tested in esophagus, and lung). Most promising indications for carbon ions include inoperable highly radioresistant primaries, such as mucosal melanomas, high grade bone and soft part sarcomas, and pancreatic carcinomas. Altered fractionations are also of interests that could translate in clinical and economical benefits. Controversies have risen whether more common indications, like prostate, should also be explored.

Quality-of-life, mood and executive functioning after childhood craniopharyngioma treated with surgery and proton beam therapy.

PRIMARY OBJECTIVE: Childhood craniopharyngioma, a benign tumour with a good survival rate, is associated with important neurocognitive and psychological morbidity, reducing quality-of-life (QoL). METHOD: This retrospective study analysed QoL, mood disorders, everyday executive functioning and disease's impact on family life in 29 patients (mean age at diagnosis 7 years 10 months (SD = 4.1); mean follow-up period 6 years 2 months (SD = 4.5)) treated for childhood craniopharyngioma by surgery combined with radiotherapy using proton beam. Assessment included a semi-structured interview and standardized scales evaluating self-report of QoL (Kidscreen 52) and depression (MDI-C) and proxy-reports of QoL (Kidscreen 52), executive functioning (BRIEF) and disease's impact (Hoare and Russel Questionnaire). RESULTS: Twenty-three families answered the questionnaires completely. Overall QoL self-report was within the normal range. QoL proxy-report was lower than self-report. Eleven patients reported depression; 24-38% had dysexecutive symptoms. A majority of families felt 'very concerned' by the disease. Depression and low parental educational level were associated with lower QoL and higher levels of executive dysfunction. CONCLUSION: Given the high morbidity of childhood craniopharyngioma, screening for psychosocial outcome, cognitive functioning, including executive functions, mood and QoL should be systematic and specific interventions should be developed and implemented.

[Protontherapy: basis, indications and new technologies]. / La protonthérapie : bases, indications et nouvelles technologies.

With over 70,000 patients treated worldwide, protontherapy has an evolution on their clinical applications and technological developments. The ballistic advantage of the Bragg peak gives the possibility of getting a high conformation of the dose distribution to the target volume. Protontherapy has accumulated a considerable experience in the management of selected rare malignancies such as uveal melanomas and base of the skull chordomas and chondrosarcomas. The growing interest for exploring new and more common conditions, such as prostate, lung, liver, ENT, breast carcinomas, as well as the implementation of large pediatric programs advocated by many experts has been challenged up to now by the limited access to operational proton facilities, and by the relatively slow pace of technical developments in terms of ion production, beam shaping and modelling, on-line verification etc. One challenge today is to deliver dynamic techniques with intensity modulation in clinical facilities as a standard treatment. We concentrate in this paper on the evolution of clinical indications as well as the potentialities of new technological concepts on ion production, such as dielectric walls and laser-plasma interactions. While these concepts could sooner or later translate into prototypes of highly compact equipments that would make easier the implantation of cost-effective hospital-based facilities, the feasibility of their clinical use must still be proved.

[Normal tissue tolerance to external beam radiation therapy: spinal cord]. / Tolérance à l'irradiation des tissus sains: moelle épinière.

Radiation myelopathy is one of the most dreadful complications of radiation therapy. Despite multiple animal experiments and human autopsic series, its pathogenesis remains largely unknown. In most instances, the classical aspect of myelomalacy combines glial and vascular injuries in various sequences. Recent studies point out the role of oligodendrocytes and their precusors, as well as of intercellular mediators (cytokines and stress molecules). The clinical presentation comprises a spectrum of non specific neurological symptoms whose evolution is sometimes regressive but more commonly progressive and life-threatening. Usually, it occurs following a latent period of six months to two years after irradiation of the cervical, thoracic or upper lumbar spine to a dose in excess of 50 Gy, conventionally fractionated. Nonetheless, these typical features can be altered by extrinsic factors, such as hypofractionation/acceleration of the dose, multiple surgical procedures, chemotherapy especially megatherapy, or neurotoxic drugs. Conversely, hyperfractionated regimens that take into account protracted half-time repair of sublethal damages to the CNS, as well as sophisticated estimates of the dose to the cord and QA programs during the treatment course minimize such risks.

[Is proton beam therapy the future of radiotherapy? Part I: clinical aspects]. / La protonthérapie: avenir de la radiothérapie? Première partie: aspects cliniques.

Proton beam therapy uses positively charged particles, protons, whose physical properties improve dose-distribution (Bragg peak characterized by a sharp distal and lateral penumbra) compared with conventional photon-based radiation therapy (X-ray). These ballistic advantages apply to the treatment of deep-sited tumours located close to critical structures and requiring high-dose levels. [60-250 MeV] proton-beam therapy is now widely accepted as the "gold standard" in specific indications in adults--ocular melanoma, chordoma and chondrosarcoma of the base of skull --and is regarded as a highly promising treatment modality in the treatment of paediatric malignancies (brain tumours, sarcomas…). This includes the relative sparing of surrounding normal organs from low and mid-doses that can cause deleterious side-effects such as radiation-induced secondary malignancies. Other clinical studies are currently testing proton beam in dose-escalation evaluations, in prostate, lung, hepatocellular cancers, etc. Clinical validation of these new indications appears necessary. To date, over 60,000 patients worldwide have received part or all of their radiation therapy program by proton beams, in approximately 30 treatment facilities.

[Proton beam therapy in pediatric radiotherapy]. / La protonthérapie en radiothérapie pédiatrique.

Pediatric tumors still represent a formidable challenge despite the considerable therapeutical advances that have been reported for the past 30 years. This is largely related with the untowards side-effects of local therapy that are still acknowledged as the "price for cure". In this setting, Proton therapy a sophisticated radiotherapeutical modality seems to represent a real breakthrough due to its unique ability to spare close and distant normal organs compared with modern photons techniques. We summarize in this paper current clinical and dosimetrical evidences including an update of the Orsay series on 108 children.

[An original contention system for hadron therapy]. / Un système de contention original applicable à l'hadronthérapie.

In hadron therapy centers that have only fixed horizontal beams (i.e. most carbon ions centers and protons centers of first generation), the angulations of the beam remain technically limited, especially for the treatment of children under general anaesthesia with posterior-oblique (40 degrees or so) beams in supine position. We have been developing recently an original positioning system allowing for treatment with posterior-oblique beams, either from right or left directions, by keeping the child in the adequate position.

[Giant cell tumor of the base of the skull: a report of two cases and review of the literature]. / Les tumeurs à cellules géantes de la base du crâne: revue de la littérature à partir de deux cas.

Giant cell tumors of the skull base are rare neoplasms. This report reviews two cases of patients presenting with aggressive giant cell tumors that were irradiated by a combination of photons and protons. Two females 29 and 14 years old were initially managed with one and three extensive surgical resections respectively. Radiation therapy was recommended in respect to tumor aggressiveness. Combined proton and photon radiation therapy was performed based on a three-dimensional planning, and delivered a total dose of 59.4 CGE to 65.2 CGE respectively, administered in 5 sessions per week of 1.8-2 Gy/CGE (Cobalt Gray Equivalent). With 8 and 83 months follow-up, respectively, the youngest patient relapsed marginally 4 months post irradiation, while the second remained with NED. No complication developed in any of them. In conclusion, we have reviewed a total of 116 cases (114 previously published cases+2 new cases) and discuss the role and modalities of radiation therapy in the management of giant cell skull base tumors.

High-dose busulfan and thiotepa followed by autologous stem cell transplantation (ASCT) in previously irradiated medulloblastoma patients: high toxicity and lack of efficacy.

We previously demonstrated that Busulfan-Thiotepa (Bu-Thio) and ASCT effectively treated patients with locally relapsed medulloblastoma after surgery and conventional chemotherapy. We thus evaluated the administration of Bu-Thio in patients relapsing after conventional CNS irradiation. Patients were scheduled to receive Busulfan (600 mg/m(2)) and Thiotepa (900 mg/m(2)) and ASCT. Resection of residual tumour and additional irradiation were performed if necessary and feasible after Bu-Thio. Toxicity was compared to that observed in 35 patients treated without previous CNS irradiation. From 5/88 to 3/02, 15 patients were treated according to this strategy. Toxicity was significantly higher than that observed in unirradiated patients: thrombocytopenia <50,000/mm(3) lasting 56 days (13-732) (P=0.02) and 30 days (4-124), respectively, HVOD (10/15 and 12/35 patients, respectively) (P=0.06), neurological toxicity (8/15 vs 3/35 patients) (P=0.01). Tumour response was assessable in seven patients and consisted in two CR, three PR and two NR. Currently, two of 15 patients are alive with no evidence of disease. In conclusion, the toxicity of Bu-Thio was significantly more severe in previously irradiated patients. In spite of a high response rate, this strategy failed to improve the prognosis of previously irradiated patients with a relapse from a medulloblastoma.

[Chordomas of the base of the skull and upper cervical spine. 100 patients irradiated by a 3D conformal technique combining photon and proton beams]. / Les chordomes de la base du crâne et du rachis cervical haut. A propos d'une série de 100 patients irradiés selon une technique conformationnelle 3D par une association de faisceaux de photons et de protons.

OBJECTIVE: To define prognostic factors for local control and survival in 100 consecutive patients treated by fractionated photon and proton radiation for chordoma of the skull base and upper cervical spine. PATIENTS AND METHODS: Between December 1995 and August 2002, 100 patients (median age: 53 years, range: 8-85, M/F sex-ratio: 3/2), were treated by a combination of high-energy photons and protons. The proton component was delivered by the 201 MeV proton beam of the Centre de Protonthérapie d'Orsay (CPO). The median total dose delivered to the gross tumour volume was 67 Cobalt Gray Equivalent (CGE) (range: 60-71). A complete surgery, incomplete surgery or a biopsy was performed before the radiotherapy in 16, 75 and 9 cases, respectively. RESULTS: With a median follow-up of 31 months (range: 1-87), 25 tumours failed locally. The 2 and 4-year local control rates were 86.3% (+/-3.9%) and 53.8% (+/-7.5%), respectively. According to multivariate analysis, less than 95% of the tumour volume encompassed by the 95% isodose line (P=0.048; RR: 3.4 IC95% [1.01-11.8]) and a minimal dose less than 56 CGE (p=0.042; RR: 2.3 IC95% [1.03-5.2]) were independent prognostic factors of local control. Ten patients died. The 2 and 5-year overall survival rates were 94.3% (+/-2.5%) and 80.5% (+/-7.2%). According to multivariate analysis, a controlled tumour (P=0.005; RR: 21 IC95% [2.2-200]) was the lonely independent favourable prognostic factor for overall survival. CONCLUSION: In chordomas of the skull base and upper cervical spine treated by surgical resection followed by high-dose photon and proton irradiation, local control is mainly dependent on the quality of radiation, especially dose-uniformity within the gross tumour volume. Special attention must be paid to minimise underdosed areas due to the close proximity of critical structures and possibly escalate dose-constraints to tumour targets in future studies, in view of the low toxicity observed to date.

Outcome of flat bone sarcomas (other than Ewing's) in children and adolescents: a study of 25 cases.

We analysed the clinical features and outcome of young patients with non-Ewing's flat bone sarcoma treated during the era of contemporary chemotherapy. The characteristics and outcome of 25 patients (15 males and 10 females) with primary or radiation-related flat bone sarcoma treated in the Pediatrics Department at the Institut Gustave Roussy from 1981 to 1999 were reviewed. In all, 20 patients had osteosarcoma, four chondrosarcoma and one malignant fibrous histiocytoma. The age at diagnosis ranged from 2 to 23 years (median, 15 years). Nine tumours were located in the craniofacial bones, 11 in the pelvis and five in flat bones at other sites. Four patients had metastatic disease at diagnosis. Radiation-associated flat bone osteosarcoma was diagnosed in 10 out of 25 cases. The projected overall survival and event-free survival (EFS) rates at 5 years were 45.1 and 34.3% for all the 25 patients. The EFS rate of patients with second bone sarcoma was similar to that of patients with de novo flat bone sarcoma (P=0.1). The aim of treatment was curative for 24 patients, 23 of whom were treated with intensive chemotherapy regimens and 19 with surgery. Significant adverse prognostic factors on survival included incomplete surgical resection (P=0.001) and use of regimens without pre- and postoperative chemotherapy (P=0.007). Nine of the 25 patients were treated with pre- and postoperative chemotherapy and complete surgical resection. Among them, eight are alive with no disease. Radical surgical resection is the overriding prognostic factor for flat bone sarcomas in young patients. Nevertheless, our results suggest a more favourable outcome since the advent of intensive chemotherapy.