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Proton therapy allows to avoid excess radiation dose on normal tissues. However, there are some limitations. Indeed, passive delivery of proton beams results in an increase in the lateral dose upstream of the tumor and active scanning leads to strong differences in dose delivery. This study aims to assess possible differences in the transcriptomic response of skin in C57BL/6 mice after TBI irradiation by active or passive proton beams at the dose of 6 Gy compared to unirradiated mice. In that purpose, total RNA was extracted from skin samples 3 months after irradiation and RNA-Seq was performed. Results showed that active and passive delivery lead to completely different transcription profiles. Indeed, 140 and 167 genes were differentially expressed after active and passive scanning compared to unirradiated, respectively, with only one common gene corresponding to RIKEN cDNA 9930021J03. Moreover, protein-protein interactions performed by STRING analysis showed that 31 and 25 genes are functionally related after active and passive delivery, respectively, with no common gene between both types of proton delivery. Analysis showed that active scanning led to the regulation of genes involved in skin development which was not the case with passive delivery. Moreover, 14 ncRNA were differentially regulated after active scanning against none for passive delivery. Active scanning led to 49 potential mRNA-ncRNA pairs with one ncRNA mainly involved, Gm44383 which is a miRNA. The 43 genes potentially regulated by the miRNA Gm44393 confirmed an important role of active scanning on skin keratin pathway. Our results demonstrated that there are differences in skin gene expression still 3 months after proton irradiation versus unirradiated mouse skin. And strong differences do exist in late skin gene expression between scattered or scanned proton beams. Further investigations are strongly needed to understand this discrepancy and to improve treatments by proton therapy.

Background: The purpose of the study was to evaluate clinical results and complications of a combination of proton and photon irradiation administered to 17 children with selected central nervous system (CNS) tumors., Procedure: Between July 1994 and September 2000, 17 children, aged from 5 to 17 years (median: 12 years) with intracranial benign (6 cases) or malignant (11 cases) tumors, were treated with photons (median dose: 40 Gy; 24-54) and protons (median dose: 20 CGE; 9-31) at the Centre de Protonthérapie d'Orsay (CPO)., Results: Mean follow-up was 27 months (3-81). Two patients recurred locally (one marginal and one in situ). Fifteen patients are alive and doing well. Overall, 12, 24, and 36-month local control rate was 92 +/- 8% and, 12, 24, and 36-month overall survival rates were 93 +/- 6%, 83 +/- 11%, and 83 +/- 11%, respectively. Clinical initial symptoms remained stable or subsided in all patients. Early toxicities were in the expected range., Conclusions: With a mean 27 months follow-up, protontherapy was well tolerated for doses upto 69 CGE and with an excellent local control rate., (Copyright 2003 Wiley-Liss, Inc.)

A 52-year-old-male patient was treated for a posterior choroid melanoma of the right eye. When it was diagnosed, it measured 6mm in thickness and 11.9mm for the largest diameter and had a typical mushroom shape. General investigations found no metastatic disease. It was treated with proton-beam irradiation. Seven years later, the patient experienced increased intraocular pressure associated with cataract and pain. The patient finally accepted enucleation, as the vision of this eye was completely lost and the eye had become painful. Histologic analysis of the eye showed changes affecting both the anterior and the posterior segments of the eye, mostly related to the tumor and the consequences of treatment. Neovascular glaucoma is a major complication that very often leads to enucleation.

Purpose: Retrospective analysis of the treatment of choroidal melanoma with protontherapy at the Centre de protonthérapie d'Orsay, France., Patients and Methods: Between September 1991 and September 1995, 612 patients presenting with choroidal melanoma were treated by protontherapy in Orsay. Following initial management of the first 464 patients, results were analyzed, as were results after a 1-year follow-up for 305 patients, a 2-year follow-up for 169 patients, and a 3-year follow-up for 59 patients., Results: Univariate analysis showed that the actuarial local recurrence rate was 5%, the 3-year survival rate 88%, and the overall metastasic rate 5%. The initial tumor volume was the most significant predictive factor for visual results and metastases. Multivariate analysis revealed that visual results were significantly related to the initial tumor volume, initial retinal detachment, and total dose delivered to the optic nerve and macula., Conclusion: Protontherapy of choroidal melanoma allows in most cases conservation of the eye without modification of survival. Visual results mainly depend on the site and size of the tumor.

Proton therapy began at the 'Centre de Protonthérapie d'Orsay' (CPO) in September 1991. Our treatment protocol and the preliminary results have been presented on the first 146 irradiated patients with one-year minimal follow-up. The subsequent developments have also been mentioned.

The degree of accuracy and reliability required in proton therapy can only be guaranteed if a comprehensive quality assurance (QA) programme is established. Such a programme obviously has common features with general QA in radiotherapy, but some aspects are specific to the use of protons and particularly to the characteristics of each facility. A study is in progress at Orsay to convert a series of quality controls into a systematic quality assurance programme. It includes some basic steps on organisation, setting up a QA committee and QA task groups, organising meetings, policies, procedures, records, qualifications, and determining some examples of tolerance in controls. Among some critical and specific points identified in this process are the combined treatment with photons at different institutions, the specificity of a non-hospital-based and complex facility, the high degree of precision required for the patient setup, and the need to develop in-house basic tools such as the treatment planning system. The inclusion of all the patients in prospective well-defined clinical trials, the comparison with alternative techniques and the radiobiological studies are considered as fundamentals for the QA programme. Present dosimetric and radiobiological intercomparisons between protontherapy centres are considered as partial audits. A study is in progress to establish common dosimetric and clinical protocols, radiobiological models and dose and volume specifications. In spite of the differences between the existing facilities, it should also be possible to obtain international consensus on general guidelines for a QA programme in proton therapy.

Proton therapy offers considerable potential advantages in the management of poorly resectable, radio-resistent tumors close to critical anatomical structures. So far over 15,000 patients have been treated worldwide with two major indications: conservative management of ocular melanomas in which local control exceeds 95% at 5 years and curative irradiation of sarcomas at the base of the skull and cervical canal, with a survival rate between 84 and 94% at 5 years. The different protocols tested currently worldwide are discussed.

Proton therapy offers potentially considerable advantages in the management of slow-growing, poorly resectable or non-resectable tumors resistant to x-rays and located close to critical radiosensitive anatomical structures, such as the brain stem of the spinal cord. Among over 13,000 irradiated patients in the USA, Europe, and Japan, two major clinical indications have been documented: 1. The conservative management of choroidal melanomas, in which 98% 5-year local control can be expected at the price of low toxicity and visual preservation in approximately half of them. 2. The curative management of low-grade chondrosarcomas and chordomas of the base of the skull and cervical spine, leading to, in combination with maximal tumor resection, 84%-94% long-term survival. Other ongoing studies concern prostate, head and neck carcinomas as well as various intracranial tumors. Radiosurgical programs are being conducted generally with single fractions and under stereotactic conditions.

The success of proton therapy depends on its cost. Hospital based equipment in fabrication for the Massachusetts General Hospital in Boston costs in the excess of 17 millions dollars, the accelerator being only a fraction of the cost. We think that price can be significantly decreased. We review the different new ways of accelerating protons currently under study in France in order to build a smaller, less expensive but reliable treatment device.

Using proton beams for treatment of malignant tumors of the eye allows high dose irradiation of the tumor volume with negligible irradiation of the surrounding critical structures. Actually, the clinical results reported from the Boston or Villigen groups which have experience of such a technique, are impressive. In France, it is planned to use soon 200 MeV proton beams from the Orsay synchrocyclotron 20 km from Paris. Therefore, a feasibility study has been conducted during year 1988, consisting of a dosimetric analysis of the characteristics of the Orsay proton beams. It was concluded that only simple modifications were necessary to make the beam clinically available for protontherapy and more specifically for treatment of uveal melanomas.

Heavy particles have been used in transcutaneous radiotherapy for almost 50 years. If these particles and pi mesons remain the domain of highly specialized centers, neutron therapy and, to a lesser degree, proton therapy can be considered common clinical protocols; their limits, complications, efficacities and costs are sufficiently well known to encourage several centers to acquire the necessary equipment. Their practical advantages involve a limited number of patients however, for the patients implicated, the prognoses are appreciably improved by the application of these therapies. Hyperthermia-associated radiotherapy is limited by the poor technical capabilities of the currently available hyperthermia machines. If biological experimentation was highly promising, clinical results to date have been unfulfilling. Nonetheless, hyperthermia-associated interstitial radiotherapy represents an interesting clinical possibility. Radiosensitizers are being extensively developed. The results of randomized therapeutic trials are still contradictory and the toxicity of these products renders their use difficult. New products are being tested; their lower toxicity and potent radiosensitization capacity are encouraging for the future use of this class of compounds.