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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., (Copyright © 2019. Published by Elsevier Masson SAS.)

Introduction: The depth-dose distribution of a proton beam, materialized by the Bragg peak makes it an attractive radiation modality as it reduces exposure of healthy tissues to radiations, compared with photon therapy Prominent indications, based on a long-standing experience are: intraocular melanomas, low-grade skull-base and spinal canal malignancies. However, many others potential indications are under investigations such as the benign morbid conditions that are compatible with an extended life-expectancy: low grade meningiomas, paragangliomas, pituitary adenomas, neurinomas craniopharyngioma or recurrent pleomorphic adenomas., Materials: Given the radiation-induced risk of secondary cancer and the potential neurocognitive and functional alteration with photonic radiotherapy, we systematically analyzed the existing clinical literature about the use of proton therapy as an irradiation modality for cervical or intracranial benign tumors. The aim of this review was to report clinical outcomes of adult patients with benign intracranial or cervical tumors treated with proton therapy and to discuss about potential advantages of proton therapy over intensity modulated radiotherapy or radiosurgery., Results: Twenty-four studies were included. There was no randomized studies. Most studies dealt with low grade meningiomas (n = 9). Studies concerning neurinoma (n = 4), pituitary adenoma (n = 5), paraganglioma (n = 5), or craniopharyngioma (n = 1) were fewer. Whatever the indication, long term local control was systematically higher than 90% and equivalent to series with conventional radiotherapy., Conclusion: Proton-therapy for treatment of adult benign intracranial and cervical tumors is safe. Randomized or prospective cohorts with long term cognitive evaluations are needed to assess the real place of proton-therapy in the treatment of adults benign head and neck tumors., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background and Purpose: To evaluate clinical results and safety of a dose adaptive protocol based on tumor volume coverage and critical structure constraints, for the treatment of skull base chordomas., Material and Methods: Between May 2006 and October 2012, 106 patients with skull base chordoma were treated by combined photon and proton irradiation. Prescribed dose levels were 68.4, 70.2, 72 and 73.8 Gy(RBE) in once daily fractionation of 1.8 Gy(RBE). Dose level and dosimetric constraints to organs at risk depended on postoperative residual Gross Tumor Volume (GTV) coverage. Local control (LC) and overall survival (OS) were evaluated using the Kaplan-Meier method., Results: With a median follow-up of 61 months, the 2-year, 4-year, and 5-year LC rates were 88.6%, 78.3%, and 75.1%, respectively. GTV > 25 mL (p = 0.034, HR = 2.22; 95%CI 1.06-4.62) was an independent unfavorable prognostic factor of LC. The 2-year, 4-year, and 5-year OS rates were 99%, 90.2%, and 88.3%, respectively. Grade 3-5 late toxicity was observed in 7 patients, resulting in 93% 5-year freedom from high-grade toxicity., Conclusions: This study suggests that the probability of LC of skull base chordomas depends on postoperative GTV. The dose adaptive protocol achieves acceptable local control. Future studies should investigate whether further dose escalation to doses in excess of 74 Gy(RBE) would achieve better results., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Radiotherapy plays an important role in the management of childhood cancer, with the primary aim of achieving the highest likelihood of cure with the lowest risk of radiation-induced morbidity. Proton therapy (PT) provides an undisputable advantage by reducing the radiation 'bath' dose delivered to non-target structures/volume while optimally covering the tumor with tumoricidal dose. This treatment modality comes, however, with an additional costs compared to conventional radiotherapy that could put substantial financial pressure to the health care systems with societal implications. In this review we assess the data available to the oncology community of PT delivered to children with cancer, discuss on the urgency to develop high-quality data. Additionally, we look at the advantage of combining systemic agents with protons and look at the cost-effectiveness data published so far., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Proton therapy is a radiotherapy, based on the use of protons, charged subatomic particles that stop at a given depth depending on their initial energy (pristine Bragg peak), avoiding any output beam, unlike the photons used in most of the other modalities of radiotherapy. Proton therapy has been used for 60 years, but has only become ubiquitous in the last decade because of recent major advances in particle accelerator technology. This article reviews the history of clinical implementation of protons, the nature of the technological advances that now allows its expansion at a lower cost. It also addresses the technical and physical specificities of proton therapy and the clinical situations for which proton therapy may be relevant but requires evidence. Different proton therapy techniques are possible. These are explained in terms of their clinical potential by explaining the current terminology (such as cyclotrons, synchrotrons or synchrocyclotrons, using superconducting magnets, fixed line or arm rotary with passive diffusion delivery or active by scanning) in basic words. The requirements associated with proton therapy are increased due to the precision of the depth dose deposit. The learning curve of proton therapy requires that clinical indications be prioritized according to their associated uncertainties (such as range uncertainties and movement in lung tumors). Many clinical indications potentially fall under proton therapy ultimately. Clinical strategies are explained in a paralleled manuscript., (Copyright © 2018 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Background: Radiation therapy plays a major role in the management of adjuvant breast cancer with nodal involvement, with an iatrogenic increase of cardio-vascular risk. Photon therapy, even with intensity modulation, has the downsides of high mean heart dose and heterogeneous target coverage, particularly in the case of internal mammary irradiation. This systematic review of the literature aims to evaluate proton therapy in locally advanced breast cancer., Material and Methods: PubMed was searched for original full-text articles with the following search terms: «Proton Therapy» and «Breast Cancer». On-going trials were collected using the words "Breast Cancer" and "Protons"., Results: 13 articles met the criteria: 6 with passive proton therapy (Double Scattering), 5 with Pencil Beam Scanning (PBS) and 2 with a combination of both. Proton therapy offered a better target coverage than photons, even compared with intensity modulation radiation therapy (including static or rotational IMRT or tomotherapy). With proton therapy, volumes receiving 95% of the dose were around 98%, with low volumes receiving 105% of the dose. Proton therapy often decreased mean heart dose by a factor of 2 or 3, i.e. 1 Gy with proton therapy versus 3 Gy with conventional 3D, and 6 Gy for IMRT. Lungs were better spared with proton therapy than with photon therapy. Cutaneous toxicity observed with double scattering is improved with PBS., Conclusion: Proton therapy reduces mean heart dose in breast cancer irradiation, probably reducing late cardio-vascular toxicity. Large clinical studies will likely confirm a clinical benefit of proton therapy., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: Chondrosarcoma is a rare malignant tumor of the cartilage affecting young adults. Surgery, followed by charged-particle irradiation, is considered the reference standard for the treatment of patients with grade I to II skull base chondrosarcoma. The present study was conducted to assess the effect of the quality of surgery and radiation therapy parameters on local control (LC) and overall survival (OS)., Methods and Materials: From 1996 to 2013, 159 patients (median age 40 years, range 12-83) were treated with either protons alone or a combination of protons and photons. The median total dose delivered was 70.2 Gy (relative biologic effectiveness [RBE]; range 67-71). Debulking and biopsy were performed in 133 and 13 patients, respectively., Results: With a median follow-up of 77 months (range 2-214), 5 tumors relapsed based on the initial gross tumor volume. The 5- and 10-year LC rates were 96.4% and 93.5%, respectively, and the 5- and 10-year OS rates were 94.9% and 87%, respectively. A total of 16 patients died (13 of intercurrent disease, 3 of disease progression). On multivariate analysis, age <40 years and primary disease status were independent favorable prognostic factors for progression-free survival and OS, and local tumor control was an independent favorable predictor of OS. In contrast, the extent of surgery, dosimetric parameters, and adjacent organs at risk were not prognostic factors for LC or OS., Conclusions: Systematic high-dose postoperative proton therapy for skull base chondrosarcoma can achieve a high LC rate with a low toxicity profile. Maximal safe surgery, followed by high-dose conformal proton therapy, is therefore recommended., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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., (Copyright © 2015. Published by Elsevier SAS.)

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.

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., (Copyright © 2010 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

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.

Purpose: To evaluate retrospectively the efficacy of conformal fractionated radiotherapy combining proton and photon beams after primary surgery for treatment of atypical and malignant meningiomas., Patients and Methods: Between September 1999 and October 2006, 24 patients (12 male, 12 female) with histopathologically proven meningioma (atypical 19, malignant 5) received postoperative combined radiotherapy with a 201-MeV proton beam at the Centre Protontherapie d'Orsay and a high-energy photon beam. Six patients underwent gross total resection and 18 a subtotal resection. Median gross tumor volume and clinical target volume were 44.7 cm(3) and 153.3 cm(3), respectively. Mean total irradiation dose was 65.01 CGE (cobalt gray equivalent), with a mean proton total dose of 34.05 CGE and a mean photon total dose 30.96 CGE., Results: The median (range) follow-up interval was 32.2 (1-72) months. The overall mean local relapse-free interval was 27.2 (10-50) months, 28.3 (10-50) months for atypical meningioma and 23 (13-33) months for malignant meningioma. Ten tumors recurred locally. One-, 2-, 3-, 4-, 5-, and 8- year local control rates for the entire group of patients were 82.9% +/- 7.8%, 82.9% +/- 7.8%, 61.3% +/- 11%, 61.3% +/- 11%, 46.7% +/- 12.3%, and 46.7% +/- 12.3%, respectively. One-, 2-, 3-, 4-, 5-, and 8- year overall survival rates were 100%, 95.5% +/- 4.4%, 80.4% +/- 8.8%, 65.3% +/- 10.6%, 53.2% +/- 11.6%, and 42.6% +/- 13%, respectively. Survival was significantly associated with total dose. There was no acute morbidity of radiotherapy. One patient developed radiation necrosis 16 months after treatment., Conclusions: Postoperative combination of conformal radiotherapy with protons and photons for atypical and malignant meningiomas is a well-tolerated treatment producing long-term tumor stabilization.

Purpose: To evaluate outcomes and tolerance of high-dose photon and proton therapy in the management of skull base and cervical canal primary bony malignancies in children., Patients and Methods: Thirty children were treated postoperatively with high-dose photon-proton (29 patients) or protons-only (1 patient) radiotherapy. Twenty-six patients had chordomas (CH), 3 had low-grade chondrosarcomas (CS), and 1 had an aggressive chondroma (AC). The mean age was 12.8 years. At the time of radiation, all but 1 patient had a gross residue. The anatomic sites affected were skull base (n = 16), cervical canal (n = 1), or both (n = 13). Mean total dose was 68.4 cobalt Gray equivalents, conventionally fractionated., Results: With a mean follow-up of 26.5 months, 5 of 30 children failed locally: 5 of 5 lesions were CH, 5 of 5 patients had experienced pain at presentation (p = 0.03), and 4 of 5 had cervical extension (p = 0.07). The 5-year overall survival/progression-free survival rates for CS and CH were 100%/100% and 81%/77%, respectively. Side effects were scored according to the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. Acute toxicity ranged between 0 and 2. Late toxicity of radiotherapy was severe in 1 patient (Grade 3 auditory) and minor or mild in the rest of the population (7 patients with Grade 2 pituitary dysfunction)., Conclusions: High-dose combined fractionated photon-proton therapy is well tolerated in children and allows excellent local control with minimal long-term toxicity.

Purpose: To compare treatment planning between combined photon-proton planning (CP) and proton planning (PP) for skull base tumors, so as to assess the potential limitations of CP for these tumors., Methods and Materials: Plans for 10 patients were computed for both CP and PP. Prescribed dose was 67 cobalt Gray equivalent (CGE) for PP; 45 Gy (photons) and 22 CGE (protons) for CP. Dose-volume histograms (DVHs) were calculated for gross target volume (GTV), clinical target volume (CTV), normal tissues (NT), and organs at risk (OARs) for each plan. Results were analyzed using DVH parameters, inhomogeneity coefficient (IC), and conformity index (CI)., Results: Mean doses delivered to the GTVs and CTVs with CP (65.0 and 61.7 CGE) and PP (65.3 and 62.2 Gy CGE) were not significantly different (p > 0.1 and p = 0.72). However, the dose inhomogeneity was drastically increased with CP, with a mean significant incremental IC value of 10.5% and CP of 6.8%, for both the GTV (p = 0.01) and CTV (p = 0.04), respectively. The CI(80%) values for the GTV and CTV were significantly higher with PP compared with CP. Compared with CP, the use of protons only led to a significant reduction of NT and OAR irradiation, in the intermediate-to-low dose (< or =80% isodose line) range., Conclusions: These results suggest that the use of CP results in levels of target dose conformation similar to those with PP. Use of PP significantly reduced the tumor dose inhomogeneity and the delivered intermediate-to-low dose to NT and OARs, leading us to conclude that this treatment is mainly appropriate for tumors in children.

Purpose: To evaluate efficacy and tolerance of external fractionated combination of photon and proton radiation therapy (RT) for intracranial benign meningiomas., Methods and Materials: Between 1994 and 2002, 51 patients with intracranial meningiomas of the base of the skull were treated with a combination of photon and proton RT. Median total dose was 60.6 cobalt Gy equivalent (54-64). One hundred eight eye-related symptoms were collected; 80 other symptoms were noted and followed up., Results: Mean follow-up was 25.4 months. Acute tolerance was excellent. Out of the 108 eye-related symptoms, 106 (96%) were evaluated. Improvements were reported for 73 (68.8%) of them. Out of the 88 other miscellaneous symptoms, 81 (92%) were evaluated. Improvements were reported in 54 cases (67%). Median time to improvement ranged from 1 to 24 months after completion of the radiotherapy, depending on the symptom. We did not observe any worsening of primary clinical signs. Radiologically, 1 patient relapsed 4 months after the end of irradiation. Pathology revealed a malignant (Grade 3) transformation of the initial Grade 1 meningioma. Four-year local control and overall survival rates were, respectively, 98% and 100%. Stabilization of the tumor was observed in 38 cases (72%), volume reduction in 10 cases (20%), and intratumor necrosis in 3 cases. Two patients complained of Grade 3 side effects: 1 unilateral hearing loss requiring aid and 1 case of complete pituitary deficiency., Conclusion: These results stressed the clinical efficacy of fractionated-associated photon-proton RT in the treatment of meningiomas, especially on cranial nerve palsies, without severe toxicity in almost all patients.

Aims: To evaluate the efficacy and the tolerance of an escalated dose of external conformal fractionated radiation therapy combining photons and protons in the treatment of intracranial meningiomas., Patients and Methods: Between December 1995 and December 1999, 17 patients received a treatment by 201-MeV proton beam at the Centre de Protonthérapie d'Orsay (CPO) for a meningioma. Five patients presented a histologically atypical or malignant meningioma, twelve patients a benign one that was recurrent or rapidly progressive. In two cases radiotherapy was administered in the initial course of the disease and in 15 cases at the time of relapse. A highly conformal approach was used combining high-energy photons and protons for approximately 2/3 and 1/3 of the total dose. The median total dose delivered within gross tumor volume was 61 Cobalt Gray Equivalent CGE (25-69)., Results: Median follow-up was 37 months (17-60). The 4-year local control and overall survival rates were 87.5 +/- 12% and 88.9 +/- 11%, respectively. One patient failed locally within the clinical tumor volume. One patient died of intercurrent disease. A complete or partial clinical improvement was seen in most of patients. Radiologically, there were eleven stable diseases and five partial responses. In 12/15 recurrent cases, the free interval after radiotherapy is longer than that achieved by the initial surgery. This radiotherapy was well tolerated., Conclusions: In both benign and more aggressive meningiomas, the combination of conformal photons and protons with a dose escalated by 10-15% offers clinical improvements in most patients as well as radiological long-term stabilization.

Purpose: Prospective analysis of local tumor control, survival, and treatment complications in 44 consecutive patients treated with fractionated photon and proton radiation for a chordoma or chondrosarcoma of the skull base., Methods and Materials: Between December 1995 and December 1998, 45 patients with a median age of 55 years (14-85) were treated using a 201-MeV proton beam at the Centre de Protonthérapie d'Orsay, 34 for a chordoma and 11 for a chondrosarcoma. Irradiation combined high-energy photons and protons. Photons represented two-thirds of the total dose and protons one-third. The median total dose delivered within the gross tumor volume was 67 cobalt Gray equivalent (CGE) (range: 60-70)., Results: With a mean follow-up of 30.5 months (range: 2-56), the 3-year local control rates for chordomas and chondrosarcomas were 83.1% and 90%, respectively, and 3-year overall survival rates were 91% and 90%, respectively. Eight patients (18%) failed locally (7 within the clinical tumor volume and 1 unknown). Four patients died of tumor and 2 others of intercurrent disease. In univariate analysis, young age at time of radiotherapy influenced local control positively (p < 0.03), but not in multivariate analysis. Only 2 patients presented Grade 3 or 4 complications., Conclusion: In skull-base chordomas and chondrosarcomas, the combination of photons with a proton boost of one-third the total dose offers an excellent chance of cure at the price of an acceptable toxicity. These results should be confirmed with a longer follow-up.