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Initially considered as a kind of radiobiological law, the linear no-threshold (LNT) model, which by definition supports the absence of any threshold for cancer risk induction after irradiation, is nowadays more reasonably described as a pragmatic and prudent approach by the International Organizations. However, it remains today a dogma in radiological protection. Actually, this model had been essentially developed for the radiological protection of a general population against low, and sometimes very low, doses of irradiation. Radiation oncologists are dealing with a totally different situation since they deliver, on purpose, high doses of radiations in more or less limited volumes of the body of cancer patients, patients for whom no other alternatives do exist to get rid of their malignant tumors. Simultaneously, the radiation oncologists inevitably give low and even very low doses at distance from the so-called target volumes. In such a specific situation, what is the carcinogenicity of these low doses and the relevance of the LNT model in radiotherapy? Thus, this paper addresses three critical questions: 1) what is the risk acceptability of the radiation doses delivered by radiotherapy of malignant tumors? 2) what is the real carcinogenic risk of (very) low doses delivered at distance from the target volume? 3) are the clinical radiotherapy data, i.e., the number of second primary cancers, accumulated since more than a century, consistent with the LNT model? In conclusion, the LNT model appears to be poorly adapted to the high doses locally delivered to cancer patients and dramatically overestimates, in most cases, the risk of secondary radio-induced cancers. In fine, the real risk of the LNT model in radiotherapy would be to promote radiophobia in cancer patients and to see some of them turning away from a life-saving treatment.

Prostate brachytherapy techniques are described, concerning both permanent seed implant and high dose rate brachytherapy. The following guidelines are presented: brachytherapy indications, implant procedure for permanent low dose rate implants and high dose rate with source projector, as well as dose and dose-constraints objectives, immediate postoperative management, post-treatment evaluation, and long-term follow-up.

The issue of radiation-induced cancers must be taken into consideration during therapeutic irradiations. Risk factors for radiation-induced cancer include: the age of the patients, the volumes irradiated, the presence of risk cofactors and the exposure of critical organs. Those should be part of the therapeutic decision, in terms of indication, as well as choice of the radiotherapy technique (including repositioning systems). We present the update of the recommendations of the French society for radiation oncology on the modalities for preventing radiation-induced cancers.

Forte des travaux pionniers de ses figures historiques emblématiques comme Pierre et Marie Curie, Claudius Regaud ou Antoine Lacassagne, la radiobiologie française se trouve aujourd’hui dans une situation dramatique en matière de ressources humaines et d’expertise, comme la plupart des pays développés. Pourtant, les progrès considérables dans la thérapie des cancers et dans le radiodiagnostic, les enjeux de Défense Nationale et de l’exploration spatiale ainsi qu’une attente sociétale grandissante pour une évaluation objective des risques liés aux radiations ionisantes devrait encourager nos institutions à maintenir et préserver le savoir et le savoir-faire des radiobiologistes. Sans proposer un catalogue des thèmes et des laboratoires, l’objectif de cet article, est de mieux analyser et comprendre l’évolution historique et scientifique de la radiobiologie française pour mieux en dégager les enjeux de demain.

Resume Les irradiations d’affections non cancereuses, essentiellement a visee anti-inflammatoire, ont ete tres largement utilisees jusqu’aux annees 1970–80. A ce moment, la prise de conscience du risque de cancers radio-induits, surtout chez les enfants et les sujets jeunes, et l’arrivee de nouvelles medications anti-inflammatoires (steroidiennes et non steroidiennes), ont quasiment fait disparaitre ces indications, au moins dans notre pays. A l’inverse, nos collegues oncologues radiotherapeutes allemands continuent a traiter pres de 50 000 patients par an pour ce type d’affections (plus ou moins) benignes. Apres un rappel historique, cet article pose la question de savoir si nous sommes alles trop loin dans le rejet de ce type d’irradiation, presque toujours delivrees a faible ou tres faibles doses. L’emergence de nouvelles donnees precliniques, la meilleure comprehension du risque de cancers radio-induits (tres faible, voire nul chez les sujets âges), et l’urgence de certaines situations (comme l’orage de cytokines de la COVID-19), doivent probablement nous pousser a rediscuter ces irradiations a faible, voire tres faibles doses (moins de 1 Gy), pour certaines indications ciblees chez les personnes âgees.

Resume Depuis plus d’une dizaine d’annees, la plupart des centres de radiotherapie ont utilise pour la modulation d’intensite, puis pour l’arctherapie volumetrique modulee, une energie de photons de 6 MV. Ce qui etait devenu une sorte de dogme se basait d’une part sur l’absence d’avantages significatifs a utiliser des hautes energies (15 a 18 MV, voire plus) en termes de distribution des « fortes doses » delivrees au volume cible previsionnel et aux organes a risque adjacents, et d’autre part sur la composante neutronique des que l’energie des photons depassait 10 MV. Des donnees recentes ont amene a moduler quelque peu ce « dogme » de l’utilisation des photons de 6 MV pour ces techniques de radiotherapie. Tout d’abord, nous devons en 2019 prendre imperativement en compte les doses en dehors du volume traite, et donc evaluer au mieux la « dose integrale ». De fait, cette dose integrale est systematiquement plus elevee avec les photons de 6 MV qu’avec les plus hautes energies. Par ailleurs, plusieurs etudes recentes vont dans le sens d’une surestimation, par le passe, de la composante neutronique liee aux hautes energies. La dose neutron parait de fait inferieure, et parfois tres inferieure, a la dose que nous acceptons pour l’imagerie. Enfin, quelques etudes de cohortes ne montrent pas d’augmentation du risque de cancers secondaires avec les photons de hautes energies. Dans ce contexte, le travail d’un « task group » de l’American Association of Physicists in Medicine (AAPM; TG 158), publie fin 2017, a reconnu clairement qu’un compromis devait etre trouve entre les hautes energies generatrices de neutrons, et les basses energies responsables d’une dose integrale plus elevee. Pour l’AAPM, l’energie optimale pourrait etre une valeur intermediaire telle que 10 MV.

The French society of oncological radiotherapy (Société française de radiothérapie oncologique, SFRO) was created in 1990. On the occasion of its thirtieth annual congress, in October 2019, a session was devoted to it, with the objective of exposing its functioning, its actions and its productions during these three decades during which radiotherapy and oncology have undergone unprecedented transformations. We propose in this article to outline the content of this session.

The irradiation of non-malignant diseases, essentially for anti-inflammatory purpose, have been largely proposed and performed worldwide until the 1970-80s. At that time, the better assessment of the radio-induced malignancies, essentially in children and young patients, as well as the efficacy of the new anti-inflammatory drugs (steroids and non-steroids), led to the almost disappearance of those techniques, at least in France. In contrast, our German colleagues are still going on treating about 50,000 patients per year for non-malignant (more or less severe) diseases. After a short historical overview, the present article suggests that we were possibly going too far in the rejection of those low-dose irradiations for benign lesions. The recent emergence of new preclinical data, the better understanding of the risk of radio-induced secondary tumours (almost nil in the elderly), and the severity of some situations, such as the cytokine storm of the COVID-19, should probably lead us to reconsider those low - and sometimes very low (less than 1Gy) - irradiations for well-selected indications in the elderly.

Resume Objectif Etablir un etat des lieux des modalites d’evaluation et des resultats actuels des traitements ablatifs in situ dans le cancer de la prostate localise. Materiels et methodes Une recherche bibliographique a partir de Medline ( http://www.ncbi.nlm.nih.gov ) et Embase ( http://www.embase.com ) a ete realisee et les articles ont ete selectionnes sur leur methodologie, leur langue de publication (anglais/francais) et leur pertinence. Apres selection, 102 articles ont ete analyses. Resultats L’interpretation des resultats des traitements ablatifs est souvent difficile au regard de l’heterogeneite des indications, des techniques et des modalites d’evaluation. Cependant, les series les plus recentes et les plus homogenes rapportent des resultats encourageants, tant sur le plan carcinologique que fonctionnel. Sur le plan carcinologique, les biopsies post-therapie ablative, qui representent le critere essentiel, sont indemnes de cellules tumorales en zone traitee dans 75 a 95 % des cas. Parallelement, le statut fonctionnel urinaire et sexuel preoperatoire est preserve (ou retrouve precocement) en postoperatoire dans plus de 90 % des cas. Les differentes etudes mettent en evidence des resultats qui dependent egalement du type d’energie selon le volume prostatique et la localisation de l’« index lesion » ciblee. Conclusion L’evaluation histologique post-traitement par des biopsies de controle guidees par IRM (voire, dans le futur, par des techniques d’echographie innovantes) represente la cle de l’evaluation carcinologique des therapies ablatives dans le cancer de prostate localise. Les essais en cours permettront d’harmoniser les methodes d’evaluation et de preciser les indications et les modalites techniques pour optimiser les resultats pour un patient donne.

Resume Objectif Etablir un etat des lieux des indications et des limites actuelles des traitements ablatifs in situ dans le cancer de la prostate localise. Materiels et methodes Une recherche bibliographique a partir de Medline ( http://www.ncbi.nlm.nih.gov ) et Embase ( http://www.embase.com ) a ete realisee et les articles ont ete selectionnes sur leur methodologie, leur langue de publication (anglais/francais) et leur pertinence. Apres selection, 107 articles ont ete analyses. Resultats L’objectif de concilier la reduction des effets secondaires et le maintien d’une efficacite carcinologique a conduit au developpement recent de traitements ablatifs, divers dans leurs principes et dans leurs indications. Malgre cette heterogeneite, un certain nombre d’indications preferentielles apparaissent : cancer de prostate unilateral de risque faible (mais avec volume tumoral significatif recusant donc l’indication de surveillance active) ou surtout de risque intermediaire (actuellement sans grade 4 majoritaire, point toujours objet de discussion) ; traitement de la lesion principale (« index lesion »), en quadrant ou en hemi-ablation, s’appuyant sur les resultats des biopsies et de l’IRM multiparametrique. A ces elements s’ajoutent les limites liees aux specificites des energies employees, notamment en ce qui concerne le volume de la glande prostatique ou la localisation tumorale. Conclusion Les therapies ablatives, appuyees sur l’imagerie (IRM ou techniques innovantes), les biopsies et le developpement de nouvelles energies, sont amenees a prendre une place importante dans la prise en charge du cancer de prostate localise. Les multiples etudes internationales en cours permettront aux panels d’experts de preciser et d’optimiser le consensus sur les indications de ces traitements.

For prostate cancer, hypofractionation has been based since 1999 on radiobiological data, which calculated a very low alpha/beta ratio (1.2 to 1.5Gy). This suggested that a better local control could be obtained, without any toxicity increase. Consequently, two types of hypofractionated schemes were proposed: "moderate" hypofractionation, with fractions of 2.5 to 4Gy, and "extreme" hypofractionation, utilizing stereotactic techniques, with fractions of 7 to 10Gy. For moderate hypofractionation, the linear-quadratic (LQ) model has been used to calculate the equivalent doses of the new protocols. The available trials have often shown a "non-inferiority", but no advantage, while the equivalent doses calculated for the hypofractionated arms were sometimes very superior to the doses of the conventional arms. This finding could suggest either an alpha/beta ratio lower than previously calculated, or a negative impact of other radiobiological parameters, which had not been taken into account. For "extreme" hypofractionation, the use of the LQ model is discussed for high dose fractions. Moreover, a number of radiobiological questions are still pending. The reduced overall irradiation time could be either a positive point (better local control) or a negative one (reduced reoxygenation). The prolonged duration of the fractions could lead to a decrease of efficacy (because allowing for reparation of sublethal lesions). Finally, the impact of the large fractions on the microenvironment and/or immunity remains discussed. The reported series appear to show encouraging short to mid-term results, but the results of randomized trials are still awaited. Today, it seems reasonable to only propose those extreme hypofractionated schemes to well-selected patients, treating small volumes with high-level stereotactic techniques.

In 1999, Brenner and Hall reported for prostate cancer a very low alpha/beta ratio (1.5Gy). In the following years, this value has been confirmed by a large series of papers, so that this very low alpha/beta ratio became a "dogma", on which a large number of hypofractionated schemes were being built. This was logical, since this very low value strongly suggested a beneficial advantage of hypofractionation for prostate cancer. However, more recently, several questions arose; first, a number of authors reported, from the analysis of their own data, values of alpha/beta ratio which were higher than the "dogma". Secondly, the three modern "superiority trials", aiming at demonstrating the advantages of hypofractionated schemes, actually failed to show such a superiority, in spite of high equivalent doses (calculated with an alpha/beta of 1.5Gy), reaching up to 84 - 90Gy. In 2018, three review papers/metanalyses shed a new light on what could be the value of the alpha/beta ratio for prostate cancer. In particular, those studies took into account a "time factor" (for repopulation), a parameter which had been either forgotten or underestimated before. In those three studies, the alpha/beta ratio was ranging from 2.7Gy to 4.9Gy. Those data do confirm the sensitivity to the fraction dose variation of prostate cancer, but this sensitivity could be lower than suggested by an alpha/beta ratio of 1.5Gy.

For more than a decade, the majority of radiation oncology centres have been delivering intensity-modulated radiotherapy (then volumetric-modulated arctherapy) with 6 MV photons as their standard of care. This « dogma » had been supported by the usual absence of dosimetric advantages with high-energy photons (15 to 18 MV or more), at least for the planning target volume and the dose received by the adjacent organs at risk, and by the neutron component as soon as the photon energy exceeds 10 MV. Recent data could question such a dogma. First, in 2019, one cannot avoid taking into account the integral dose, delivered outside the treated volume. Actually, most available data show that integral dose is higher with low energy photons (as 6 MV) than with higher energies. Moreover, recent studies have shown that the neutron component at high energies may have been overestimated in the past; in fact, the neutron dose appears to be lower, and sometimes much lower, than the dose we accept for imaging. Finally, a few cohort studies did not show any increase in second cancers incidence after high-energy photon radiotherapy. In such a context, the American Association of Physicists in Medicine (AAPM) TG 158 document, released a few months ago, clearly states that there is a trade-off between high- and low-energy treatments. High-energy therapy is associated with neutron production, while low-energy therapy results in higher stray photon dose. According to the AAPM, « the optimal energy is likely an intermediate such as 10 MV ».

To perform a state of the art about indications and limits of ablative therapies for localized prostate cancer.A review of the scientific literature was performed in Medline database (http://www.ncbi.nlm.nih.gov) and Embase (http://www.embase.com) using different associations of keywords. Publications obtained were selected based on methodology, language and relevance. After selection, 107 articles were analysed.The objective to combine reduction of side effects and oncological control has induced recent development of several ablative therapies. Beyond this heterogeneity, some preferential indications appear: unilateral cancer of low risk (but with significant volume, excluding active surveillance) or intermediate risk (excluding majority of grade 4); treatment targeted the index lesion, by quarter or hemi-ablation, based on biopsy and mpMRI. In addition, indications must considered specific limits of each energy, such as gland volume and tumor localization.Based on new imaging and biopsy, ablative therapies will probably increased its role in the future in management of localize prostate cancer. The multiple ongoing trials will certainly be helpful to better define their indications and limits.

To perform a state of the art about methods of evaluation and present results in ablative therapies for localized prostate cancer.A review of the scientific literature was performed in Medline database (http://www.ncbi.nlm.nih.gov) and Embase (http://www.embase.com) using different associations of keywords. Publications obtained were selected based on methodology, language and relevance. After selection, 102 articles were analysed.Analyse the results of ablative therapies is presently difficult considering the heterogeneity of indications, techniques and follow-up. However, results from the most recent and homogeneous studies are encouraging. Oncologically, postoperative biopsies (the most important criteria) are negative (without any tumor cells in the treated area) in 75 to 95%. Functionally, urinary and sexual pre-operative status is spared (or recovered early) in more than 90% of the patients treated. More and more studies underline also the correlation between the results and the technique used considering the volume of the gland and, moreover, the "index lesion" localization.The post-treatment pathological evaluation by biopsies (targeted with MRI or, perhaps in a near future, with innovative ultrasonography) is the corner stone of oncological evaluation of ablative therapies. Ongoing trials will allow to standardize the follow-up and determine the best indication and the best techniques in order to optimize oncological and functional results for each patient treated.

The question whether a reirradiation is possible, with either curative of palliative intent, is a frequent issue and a true therapeutic challenge, in particular for a critical organ sensitive to cumulative dose, such as the spinal cord. Preclinical experimental data, based on debatable models that are hardly transferable to patients, suggest that there is a possibility of reirradiation, beyond the classical threshold for dose constraints, taking into account the "time-dose factor". Although the underlying biological mechanisms are however uncertain, scarce clinical data seem to confirm that the tolerance of spinal cord to reirradiation does exist, provided that a particular attention to total dose is given. In the context where modern stereotactic irradiation facilities expand therapeutic perspectives, we review the literature on possibilities of reirradiation, through the example of spinal cord reirradiation.

For prostate cancer, hypofractionation has been based since 1999 on radiobiological data, which calculated a very low alpha/beta ratio (1.2 to 1.5Gy). This suggested that a better local control could be obtained, without any toxicity increase. Consequently, two types of hypofractionated schemes were proposed: "moderate" hypofractionation, with fractions of 2.5 to 4Gy, and "extreme" hypofractionation, utilizing stereotactic techniques, with fractions of 7 to 10Gy. For moderate hypofractionation, the linear-quadratic (LQ) model has been used to calculate the equivalent doses of the new protocols. The available trials have often shown a "non-inferiority", but no advantage, while the equivalent doses calculated for the hypofractionated arms were sometimes very superior to the doses of the conventional arms. This finding could suggest either an alpha/beta ratio lower than previously calculated, or a negative impact of other radiobiological parameters, which had not been taken into account. For "extreme" hypofractionation, the use of the LQ model is discussed for high dose fractions. Moreover, a number of radiobiological questions are still pending. The reduced overall irradiation time could be either a positive point (better local control) or a negative one (reduced reoxygenation). The prolonged duration of the fractions could lead to a decrease of efficacy (because allowing for reparation of sublethal lesions). Finally, the impact of the large fractions on the microenvironment and/or immunity remains discussed. The reported series appear to show encouraging short to mid-term results, but the results of randomized trials are still awaited. Today, it seems reasonable to only propose those extreme hypofractionated schemes to well-selected patients, treating small volumes with high-level stereotactic techniques.

Salvage brachytherapy after a first prostate radiation therapy is an emerging technique, which has to be considered in the therapeutic armamentarium in the clinically challenging context of patients with isolated local failure from prostate cancer who may still be considered for cure. These occult failures are more and more frequently diagnosed at an early stage, thanks to targeted biopsies and advances in imaging modalities, such as multiparametric MRI and PET-CT. Salvage brachytherapy benefits from the implantation accuracy of brachytherapy procedures using 3D dosimetry and has resulted in more than 50% tumour control rates with long-term. Incontinence rates are always below those of other salvage treatments such as radical prostatectomy, HIFU or cryotherapy. Today, a consensus has been reached to better define good candidates for salvage brachytherapy with respect to disease characteristics at baseline and at failure. No consensus has been clearly defined yet regarding the choice of the technique (low or high dose rate), the total dose to be delivered, or the volume to be implanted (whole gland or focal). While we await robust data from recently completed phase II studies and given the heterogeneous results in the literature, this technique (although already included in the last 2016 NCCN guidelines) remains to be precisely evaluated, optimally within the frame of controlled trials.

The article deals with the prevention of cancers only directly related to therapeutic radiation which are distinguished from "secondary cancer". The consideration of the risk of radiation-induced cancers after radiation therapy, although it is fortunately rare events, has become indispensable today. With a review of the literature, are detailed the various involved parameters. The age of the irradiated patient is one of the main parameters. The impact of the dose is also discussed based on the model used, and based on clinical data. Other parameters defining a radiation treatment are discussed one after the other: field with the example of Hodgkin's disease, the type of radiation and the participation of secondary neutrons, spreading and splitting. All these parameters are discussed according to each organ whose sensitivity is different. The article concludes with a list of recommendations to reduce the risk of radio-induced cancers. Even with the advent of conformal radiotherapy, intensity modulation, the modulated volume arctherapy, and the development of specific machinery for the extra-cranial stereotactic, the radiation therapist must consider this risk and use of reasonable and justified control imaging. Although they constitute a small percentage of cancers that occur secondarily after a first malignant tumor, radiation-induced cancers, can not and must not be concealed or ignored and justify regular monitoring over the long term, precisely adapted on the described parameters.

Radiotherapy is 120 years old. A few months only after the discoveries of Roentgen, Becquerel and Marie and Pierre Curie, a few scientists tried to use the newly discovered rays to treat patients. The question of the name of the first "radiation therapist" remains debated. Although often proposed, Emil Grubbé from Chicago seems to have been disqualified. Leopold Freund from Vienna treated a benign cutaneous lesion. Finally, Victor Despeignes from Lyon appears to be the most serious candidate, having treated in 1896 a gastric cancer, and obtaining a very significant tumour regression. The pioneers of radiotherapy paid a heavy tribute to the development of the specialty; a number of them appears on the - most probably incomplete - list of 352 names engraved on the monument dedicated to the "radiation martyrs" in Hamburg. We must keep in mind that it is only within a few years that a handful of brilliant pioneers built the foundations on which radiotherapy could emerge.

The goal of external-beam radiotherapy is to provide precise dose localisation in the treatment volume of the target with minimal damage to the surrounding normal tissue. Ion beams, such as protons and carbon ions, provide excellent dose distributions due primarily to their finite range, allowing a significant reduction of undesired exposure of normal tissue. Careful treatment planning is required for the given type and localisation of the tumour to be treated in order to maximise treatment efficiency and minimise the dose to normal tissue. Radiation exposure in out-of-field volumes arises from secondary neutrons and photons, particle fragments, and photons from activated materials. These unavoidable doses should be considered from the standpoint of radiological protection of the patient. Radiological protection of medical staff at ion beam radiotherapy facilities requires special attention. Appropriate management and control are required for the therapeutic equipment and the air in the treatment room that can be activated by the particle beam and its secondaries. Radiological protection and safety management should always conform with regulatory requirements. The current regulations for occupational exposures in photon radiotherapy are applicable to ion beam radiotherapy with protons or carbon ions. However, ion beam radiotherapy requires a more complex treatment system than conventional radiotherapy, and appropriate training of staff and suitable quality assurance programmes are recommended to avoid possible accidental exposure of patients, to minimise unnecessary doses to normal tissue, and to minimise radiation exposure of staff.

With an experience of more than 25 years for the pioneers (and more than 14 years in France), permanent implant brachytherapy using iodine 125 seeds (essentially) is now recognized as a valuable alternative therapy for localized low-risk prostate cancer patients. The possible extension of the indications of exclusive brachytherapy towards selected patients in the intermediate-risk group has now been confirmed by several studies. Moreover, for the other patients in the intermediate-risk group and for the patients in the high-risk group, brachytherapy, as an addition to external radiotherapy, could represent one of the best ways to escalate the dose. Different permanent implant brachytherapy techniques have been proposed; preplanning or real-time procedure, loose or stranded seeds (or both), manual or automatic injection of the seeds. The main point here is the ability to perfectly master the procedure and to comply with the dosimetric constraints, which have been recently redefined by the international societies, such as the GEC-ESTRO group. Mid- and long-term results, which are now available in the literature, indicate relapse-free survival rates of about 90% at 5-10 years, the best results being obtained with satisfactory dosimetric data. Comparative data have shown that the incontinence and impotence rates after brachytherapy seemed to be significantly inferior to what is currently observed after surgery. However, a risk of about 3 to 5% of urinary retention is usually reported after brachytherapy, as well as an irritative urinary syndrome, which may significantly alter the quality of life of the patients, and last several months. In spite of those drawbacks, with excellent long-term results, low rates of incontinence and impotence, and emerging new indications (focal brachytherapy, salvage brachytherapy after localized failure of an external irradiation), permanent implant prostate brachytherapy can be expected to be proposed to an increasing number of patients in the next future.

Ionizing radiations have been reported as an in vitro apoptosis initiating stimulus in human lymphocytes. As the cytotoxicity of ionizing radiations and chemotherapeutic agents appears to be dependent on the efficacy of cell death induction, the manipulation of apoptosis initiation might be used as a means to supress some pathological process. In the present study the in vivo induction of gamma-ray mediated programmed cell death in humans is reported. The in vivo induction of apoptosis in peripheral blood lymphocytes (PBL) by ionizing radiations was investigated in 33 patients after each of two sessions (2 Gy and 4 Gy) of fractionated total body irradiation (FTBI) as part of their conditioning regimen before bone marrow transplantation. PBL committed to apoptosis were scored before irradiation (S1), 4 h (S2) and 24 h after 2 Gy (S3, 14-17 h after the second 2 Gy fraction). Nuclear morphology and chromatin-DNA were analysed by fluorescence microscopy immediately after blood sample withdrawal (I) and after 24 h in cell culture medium (II). When scored immediately after withdrawal, no circulating PBL with the apoptotic nuclear morphology were observed in S1 and S2 blood samples whereas S3 disclosed 21.9 +/- 11.7% of circulating lymphocytes with an apoptotic nuclear morphology. After 24 h in culture, S1 samples (before irradiation) generally contained less than 20% of apoptotic lymphocytes. A higher percentage of apoptotic cells was noted in some cases in relation with recent chemotherapy and possibly with pathology. After 24 h in culture, S2 and S3 samples contained 51.7 +/- 17.9% and 60.4 +/- 16.4% of apoptotic lymphocytes, respectively. These results confirm that ionizing radiations induce apoptosis in vivo in human lymphocytes and that the commitment to apoptosis can be determined after low doses (2 Gy) of therapeutic whole body irradiation. The results suggest that susceptibility to apoptosis induction by ionizing radiations could be related to previous therapy by cytotoxic drugs and possibly to the type of haematological malignancy.

Since the discovery of X-rays, the goal of radiotherapy has been to deliver an optimal dose in the target volume and the lowest possible dose in the normal tissues. The history of radiotherapy can be divided in three periods. The Kilovoltage era (1900-1939) where only superficial and radiosensitive tumours could be controlled, the Megavoltage era (1950-1995) where Telecobalt and linear accelerators could deliver high doses in all parts of the body. Radiotherapy has since been playing an important curative and conservative role for most cancers. The Computer-Assisted Radiotherapy era (1995-2010) now provides the capacity to optimise the dose distribution in three dimensions. Dose is better conformed to the target volume and organ at risk are better preserved. intensity modulated radio-therapy (IMRT) allows to "shape" concave isodoses and to spare the parotids when irradiating oropharyngeal tumours. Moving targets (lung, liver etc.) are efficiently irradiated using "on-line tracking" and "image-guided radiotherapy". Stereotactic irradiation, first initiated for brain lesions, is now performed for extra-cranial tumours and due to its millimetric precision opens the way back to hypo-fractionated treatments. The next period, already ongoing, is Hadrontherapy with protons and soon helium or carbon ions techniques. In a multidisciplinary strategy, progress in radiotherapy is based on a global approach of the patient and tailored/personalized well targeted treatment of the tumour.

Disseminating the knowledge and lessons learned from accidental exposures is crucial in preventing re-occurrence. This is particularly important in radiation therapy; the only application of radiation in which very high radiation doses are deliberately given to patients to achieve cure or palliation of disease. Lessons from accidental exposures are, therefore, an invaluable resource for revealing vulnerable aspects of the practice of radiotherapy, and for providing guidance for the prevention of future occurrences. These lessons have successfully been applied to avoid catastrophic events with conventional technologies and techniques. Recommendations, for example, include the independent verification of beam calibration and independent calculation of the treatment times and monitor units for external beam radiotherapy, and the monitoring of patients and their clothes immediately after brachytherapy. New technologies are meant to bring substantial improvement to radiation therapy. However, this is often achieved with a considerable increase in complexity, which in turn brings opportunities for new types of human error and problems with equipment. Dissemination of information on these errors or mistakes as soon as it becomes available is crucial in radiation therapy with new technologies. In addition, information on circumstances that almost resulted in serious consequences (near-misses) is also important, as the same type of events may occur elsewhere. Sharing information about near-misses is thus a complementary important aspect of prevention. Lessons from retrospective information are provided in Sections 2 and 4 of this report. Disseminating lessons learned for serious incidents is necessary but not sufficient when dealing with new technologies. It is of utmost importance to be proactive and continually strive to answer questions such as 'What else can go wrong', 'How likely is it?' and 'What kind of cost-effective choices do I have for prevention?'. These questions are addressed in Sections 3 and 5 of this report. Section 6 contains the conclusions and recommendations. This report is expected to be a valuable resource for radiation oncologists, hospital administrators, medical physicists, technologists, dosimetrists, maintenance engineers, radiation safety specialists, and regulators. While the report applies specifically to new external beam therapies, the general principles for prevention are applicable to the broad range of radiotherapy practices where mistakes could result in serious consequences for the patient and practitioner.

Ionizing radiations induce cell death, causing deterministic or stochastic side-effects. This paper briefly summarizes the biological mechanisms of early and late side-effects of ionizing radiations on healthy tissue.

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.

With an experience of more than 20 years for the pionneers (and more than 10 years in France), permanent implant brachytherapy using Iodin 125 seeds is now recognized as a valuable alternative therapy for localized low-risk prostate cancer patients. An extension of the indications of exclusive brachytherapy towards selected patients in the intermediate-risk group is presently under study. Moreover, for patients in the high-risk group, brachytherapy, as an addition to external radiotherapy, could represent one of the best way to escalate the dose for some patients. Various permanent implant brachytherapy techniques have been proposed; preplanning or real-time techniques, loose seeds or stranded seeds, manual or automatic injection of the seeds. The main point here is the ability to perfectly master the procedure and to comply with the dosimetric constraints which have been recently redefined by the Groupe européen de curiethérapie--European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) group. Mid- and long-term results which are now available in the literature indicate relapse-free survival of about 90% at 5-10 years, the best results being obtained with satisfactory dosimetric data. Some comparative data have shown that the incontinence and impotence rates after brachytherapy seemed to be significantly inferior to what is currently observed after surgery. However, a risk of about 3-5% of urinary retention is usually reported after brachytherapy, as well as an irritative urinary syndrome which may be significant and last several months. In spite of those drawbacks, with excellent long-term results and low rates of incontinence and impotence, brachytherapy can be expected to be proposed to an increasing number of patients in France in the next future.

Whereas it has been proposed almost one century ago, brachytherapy for prostate cancer has only recently emerged, especially thanks to endorectal echography, allowing to visualize seed implantation, to the development of seeds for permanent delivery and of micro-sources for high-dose rate delivery, and also to the development of three-dimension dosimetry programs allowing real-time implantations. For selected patients with localized prostate cancer (PSA10, Gleason7, no extracapsular extension, volume50-60 g), prostate brachytherapy with permanent implants (iodine 125 or, less frequently, palladium 103) gives results which appear at 10-15 years comparable to those of surgery. Incontinence and impotence rates appear lower than those of classical surgery. However, the first post-implant months are usually accompanied by urinary toxicity that should not be minimized. High-dose rate brachytherapy (HDR) could find its indications, in combination with conformal radiotherapy, in the treatment of more advanced forms, presenting an intermediate risk. It could also be an alternative to brachytherapy with permanent implants for the low-risk forms mentioned above, especially in developing countries where the cost of radioactive seeds slows down the use of this technique. Brachytherapy for prostate cancer should, therefore, find more and more indications, because of the increased incidence of prostate cancer, due to population ageing, of the increased proportion of localized forms, due to better detection, of the patient's request for less toxicity, and of the expecting lowering of the costs, which are now equivalent to those of surgery and should further lower.

To assess the frequency of the PSA "bouncing" phenomenon after a significant follow-up in a series of patients treated by permanent implant brachytherapy for a prostate cancer. To look for the clinical and dosimetric parameters possibly linked to this transitory secondary PSA increase. To evaluate in which percentage of cases this bouncing could have mimicked a biochemical relapse according to the ASTRO consensus criteria.From January 1999, to December 2001, 295 patients were treated by a permanent prostate implantation (real-time technique, with free (125)I seeds- Isoseed Bebig-) by the Institut Curie-Hôpital Cochin-Hôpital Necker Paris group. The mean follow-up is 40.3 months (9-66 months). The PSA level was regularly checked, at least every 6 months. We defined as a "bouncing" all increase in PSA, starting at 0.1 ng/ml, subsequently followed by a spontaneous (without any treatment) decrease, with return to the previous level or lower. We particularly focused on the patients fulfilling the criteria for a biochemical relapse according to the ASTRO consensus (Three successive increases in PSA). A multivariate analysis tried to identify independent factors among the usual clinical and dosimetric parameters.In our series, 161 patients (55%) showed a transitory PSA increase (bouncing) of at least 0.1 ng/ml; 145 patients (49%) a bouncing of 0.2 ng/ml, 93 patients (32%) a bouncing of 0.4 ng/ml and 43 patients (15%) a bouncing of at least 1 ng/ml. Mean PSA bounce was 0.8 ng/ml (0.1-4.1), and mean time to bounce was 19 months. Thirty-two patients (11% of the total number) presented three successive PSA increases with a significant (3 months) interval between the dosages, and therefore were to be considered as being in biochemical relapse according to the ASTRO consensus criteria. Actually, among those 32 patients, 18 (56%) subsequently showed a complete normalization of their PSA, without any treatment. Ten patients went on increasing their PSA, and were considered to be really in biochemical relapse. For the last 4 patients, the situation still remains ambiguous. In multivariate analysis, age70 years (P0.00001) and D90200 Gy (P0.003) were identified as independent factors for a PSA bouncing of at least 0.4 ng/ml.The observed rate of 32% of patients showing a PSA bouncing of at least 0.4 ng/ml in our series is in good agreement with what has been previously reported in the literature. Age70 years and D90200 Gy were found to be independent factors predicting for such a secondary transitory increase in PSA. Interestingly, among 32 patients fulfilling the classical criteria of the ASTRO for a biochemical relapse, 18 (56%) subsequently showed a spontaneous PSA decrease, demonstrating that the ASTRO consensus is not well adapted to the biochemical follow-up of our patients undergoing permanent implant prostate Brachytherapy.

Low-dose brachytherapy for prostate cancer was actually proposed in the first years of the XXth century. Its modern version (iodin 125 or palladium 103 permanent implants) now benefits from some 15 years of experience in a few pioneer centers, with very satisfactory results in term of efficacy/toxicity ratio. More recently, a high-dose rate (HDR) prostate brachytherapy technique has been introduced. Initially utilized essentially as a "boost" irradiation combined with external radiotherapy, it is now being proposed by some authors as a monotherapy for selected localized prostate cancers. Although sophisticated radiobiological models have been proposed to compare those two dose-rates, they are not considered to be valid and reliable enough to compare such different irradiation schemes (A low-dose rate irradiation lasting several months vs a few high-dose fractions given in a few days). When it comes to the implantation techniques, it seems that most of the technical problems which arose for both schemes have been solved, and that the experience of a given team is now much more important than the technique itself. Clinical results cannot be reliably compared so far, the follow-up of the patients treated by HDR brachytherapy being usually shorter, and the patients treated with HDR usually presenting with more advanced lesions. Radioprotection features are very different, with no accident reported for low-dose rate implants. For HDR no irradiation is given at all to the staff and family during a normal application, but one has to face the threat of manipulating high activity sources, with a few accidents or incidents reported in the literature. Financial studies show that for more than 20-30 patients treated in a year, HDR is more economical, although a decrease in the cost of the seeds could change the picture. In conclusion, for low-risk localized prostate cancer, it does not appear reasonable to give up using a low-dose rate technique, which proved to be both efficient and poorly toxic. This actually corresponds to the recent GEC-ESTRO recommendations. For the other patients, a dose escalation is appealing: this could be performed using brachytherapy (LDR or HDR), with or without hormonotherapy. Several trials are ongoing or will be activated very soon to try and answer.

ICRP (International Commission for Radiological Protection) Committee 3 ("Radioprotection in medicine") is currently finalizing two recommendations about Brachytherapy. The first text, from Task Group (TG) 53, is focussing on the prevention of high-dose-rate brachytherapy accidents. It reminds the reader of the 500 accidents/incidents which have been reported so far in the literature, and reports in details on some representative accidents. Building on those data, the text gives general and specific recommendations, aiming at reducing both the frequency and the severity of those accidents. The second text, from Task Group 57, considers the radiation safety aspects of brachytherapy for prostate cancer using permanently implanted sources. For this topic, no severe accident has never been reported so far. However, some radioprotection problems arose, due to the dose received from the patients, to migrating seeds and to cremation. The text presents recommendations specifically addressing those issues.

Lung cancer is one of the most difficult challenges for radiotherapy. Problems include ballistic targeting compromised by respiratory movements, poor tolerance of neighboring healthy tissues and difficult dosimetry due to the heterogeneous nature of the thoracic tIssues. New perspectives are offered by recent developments allowing a more comprehensive approach to thoracic radiotherapy integrating new advances in imaging techniques, contention, dosimetry, and treatment devices. Two techniques are particularly promising: conformal radiotherapy and respiration-gated radiotherapy. Conformal radiotherapy, a three-dimensional conformal mode of irradiation with or without intensity modulation, is designed to achieve high-precision dose delivery by integrating advanced imaging techniques into the irradiation protocol. These tools are used to optimize irradiation of target Volumes and avoid recurrence while sparing as much as possible healthy tissues. If healthy tissue can be correctly protected, increased doses can be delivered to the target tumor. Respiration-gated techniques offer promising prospects for the treatment of tumors which are displaced by respiratory movements. These techniques allow better adaptation of the irradiation fields to the target tumor and better protection of healthy tissues (lung, heart...). These new approaches are now routine practices in many centers. Early results have been very promising. We describe here the currently available techniques for thoracic radiotherapy.

Intensity modulated radiation therapy (IMRT) is based on a methodology called inverse planning. Starting from dosimetric objectives, constraints of optimization are fixed and given to the inverse planning system, which in turn calculates the modulated intensity to apply to each beam. Since the algorithms allow the constraints to be violated, the results of optimization may differ from the initial dosimetric objectives. Consequently, the user is compelled to adapt the choice of the constraints according to the type of modulation and until satisfactory results are found. The purpose of this work is to present our experience in the choice of these constraints for prostate cancer treatments, as we moved from conformal radiotherapy to IMRT. Treatments were performed with a Varian 23EX linac and calculations were realized with the Varian CadPlan-Helios planning system.The approach used for the first 12 patients treated at institut Curie with IMRT from June 2002 was analysed. The treatment always consisted of a combination of conformal radiotherapy with and without intensity modulation.Results showed that, a larger fraction of the treatment performed with IMRT induced a better sparing of the organs at risk for the same homogeneous dose distribution to the target volume. Apart from the dose-volume constraint for the rectum, a fixed set of constraints, slightly more restrictive than the dosimetric objectives, could be used for all patients. Compared with conformal radiotherapy, the conformation factor for IMRT increased up to 16%. A specific study was undertaken in view of treatments completely performed with IMRT. The optimal technique consisted in performing separated IMRT plans for the two target volumes, the prostate volume and the prostate plus seminal vesicles volume respectively. Another satisfactory possibility was to define new constraints on two separated planning target volumes, prostate and seminal vesicles. This last approach is now routinely implemented for our IMRT patients.

To evaluate the use of external ionizing radiation for the prevention of intimal hyperplasia in anastomosis between PTFE and artery.Bypass using a 6 mm PTFE was performed on a swine subrenal aorta with a distal conventional anastomosis (N = 35) associated (test group; N = 17) or not (control group; N = 18) with post-operative external radiation (20 Gy) on this anastomosis. At 45 days, histological studies and morphometric studies were performed on the aorta receiving the anastomosis. Two protocols were performed, the first protocol with standard analysis and the animals were randomly assigned to either group (test group; N = 11 and control group; N = 13) and the second protocol with test of extraction comparing the biomechanical resistance between the irradiated group (N = 6) and the control group (N = 5).Twenty-one animals survived the procedure in the first protocol, 11 in the second. The endothelium was restored in either group. Histological recasting was observed in the media after radiation with fibrosis and areas of necrosis. Intimal thickness was significantly lower after irradiation in the heel (P0.01), the head (P0.01) and the suture line (P0.001) of the artery in the first protocol. The intimal thickness was also significantly lower in the second protocol after radiation in the heel (P0.05) and the head of the artery (P0.05). There was no difference between the two groups comparing the resistance.After external irradiation, the thickness parameter of the intima decreased significantly in comparison with the control group with similar resistance. Media fibrosis and necrosis need to be confirmed by further investigation.

To study the number of migrating seeds, the anatomical site of migration and possible predictive parameters of migration, after prostate cancer brachytherapy using a loose-seed (I125) implantation technique.The charts of the 170 patients consecutively treated by the Institut Curie/Hospital Cochin/Hospital Necker Group between September 1, 2001 and August 31, 2002, were analysed. All seeds having migrated to the lungs and seen on the chest X-ray systematically performed at 2 months, have been recorded, as well as the seeds lost by the urines (after sieving) or in the sperm (condom).Among 12,179 implanted seeds, 44 were found to have migrated (0.36%). Most of the migrating seeds (32/44; 73%), were found in the lungs. Overall, one or several seed migrations were observed in 35 patients (21% of the total number of patients in this series). In the majority of cases (77%), only one seed migrated. A significant relationship (P = 0.04) was found between the number of migrating seeds and the number of implanted ones (or with the prostate volume, but those two parameters were closely linked in our series). More specifically, a significant relationship (P = 0.02) could be demonstrated between the number of seeds implanted at the periphery of the prostate and the number of seeds migrating to the lungs.The percentage of migrating seeds observed in this series is low, actually one of the lowest found in the literature when using the loose-seed technique. There was no clinical consequences and the loss of-usually-only one seed is very unlikely to alter the quality of the dose distribution. However, the predominance of pulmonary migrations in our series led us to slightly modify our implantation technique. We now try to avoid too "peripheral" seed implantations, due to the risk of migration towards the periprostatic veins, and subsequently to the lungs.

Restenosis after vascular surgery using bypasses or endovascular techniques for dilatation or recanalisation remains the major Achilles' heel for these techniques. The progressive decrease of vessel lumen in an anastomose leading to graft failure or after arterial transluminal angioplasty is due to a complex process: intimal hyperplasia. This process can be compared to an hypertrophic healing into the intimal layer, reducing the lumen of the vessel. This process appears shortly after surgery or dilatation, between the 3rd and the 18th month. Mechanisms leading to this process are particularly complex, involving several cells and many regulatory processes still unclear. Smooth muscle cells are the main actor by their ability to proliferate and to secrete matrix into the media layer but stimulation and control of this process appear nevertheless complicated. The present review focuses on the pathophysiology of intimal hyperplasia, on different cells acting and on their regulation. Also, we reviewed the experimental and clinical trials evaluating approaches to the prevention of intimal hyperplasia in arteries.

To evaluate the ionizing radiation for intimal hyperplasia prevention and to assess the production of growth factors.An oversized injury using an embolectomy catheter was performed on a rabbit distal aorta (N=23), associated (test group; N=12) or not (control group; N=11) with a post-operative external radiation (25 Gy). At t=45 days, histological studies and morphometric studies were performed on the aorta. Smooth muscular cells and endothelial cells were stained using immuno-histologic revelation. Immuno-histological analysis was performed on arteries for growth factors PDGFbb, bFGF and TGFb1.Twenty-one animals survived the procedure, 11 were in the test group and 10 in the control group. Intimal thickness and ratio intima/media were significantly lower after radiation (respectively p=0.008, p=0.008). There was no difference for the medial thickness (p=0.155). Immuno-histochemical positive staining for PDGF and TGFb1 was lower after radiation (respectively 18.44 +/- 2.963% versus 47.64 +/- 6.86%, p0.001 and 10.11 +/- 3.18% versus 29.45 +/- 4.156%, p0.001). There was no difference for the expression of bFGF growth factor. After radiation, the media was found to be reduced and replaced by interstitial fibrosis.After external radiation the thickness parameter of the intima and the ratio intima/media decreased significantly in comparison with the control group. PDGF and TGFb1 were also less expressed in the artery irradiated. Fibrosis recasting needs to be confirmed by further investigation.

To study different methods of CT and MR images fusion in patient treated by brachytherapy for localized prostate cancer. To compare the results of the dosimetric study realized on CT slices and images fusion.Fourteen cases of patients treated by I125 were retrospectively studied. The CT examinations were realized with contiguous section of 5mm thickness, and MR images were obtained with a surface coil with contiguous section of 3 mm thickness. For the images fusion process, only the T2 weighted MR sequence was used. Two processes of images fusion were realized for each patient, using as reference marks the bones of the pelvis and the implanted seeds. A quantitative and qualitative appreciation was made by the operators, for each patient and both methods of images fusion. The dosimetric study obtained by a dedicated software was realized on CT images and all types of images fusion. The usual dosimetric indexes (D90, V100 and V150) were compared for each type of image.The quantitative results given by the software of images fusion showed a superior accuracy to the one obtained by the pelvic bony reference marks. Conversely, qualitative and quantitative results obtained by the operators showed a better accuracy of the images fusion based on iodine seeds. For two patients out of three presenting a D90 inferior to 145 Gy on CT examination, the D90 was superior to this norm when the dosimetry was based on images fusion, whatever the method used.The images fusion method based on implanted seed matching seems to be more precise than the one using bony reference marks. The dosimetric study realized on images fusion could allow to rectify possible errors, mainly due to difficulties in surrounding prostate contour delimitation on CT images.

The conformal radiotherapy approach, three-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy (IMRT), is based on modern imaging modalities, efficient 3D treatment planning systems, sophisticated immobilization systems and rigorous quality assurance and treatment verification. The central objective of conformal radiotherapy is to ensure a high dose distribution tailored to the limits of the target volume while reducing exposure of normal tissues. These techniques would then allow further tumor dose escalation. Head-and-neck tumors are some of the most attractive localizations to test conformal radiotherapy. They combine ballistic difficulties due to particularly complex shapes (nasopharynx, ethmoid) and problems due to the number and low tolerance of neighbouring organs like parotids, eyes, brainstem and spinal cord. The therapeutic irradiation of head-and-neck tumors thus remains a challenge for the radiation oncologist. Conformal radiotherapy does have a significant potential for improving local control and reducing toxicity when compared to standard radiotherapy. However, in the absence of prospective randomized trials, it is somewhat difficult at present to evaluate the real benefits drawn from 3DCRT and IMRT. The published clinical reports on the use of conformal radiotherapy are essentially dealing with dosimetric comparisons on relatively small numbers of patients. Recently, a few publications have emphasized the clinical experience of several precursor teams with a suitable follow-up. This paper describes the current state-of-the-art of 3DCRT and IMRT in order to evaluate the impact of these techniques on head-and-neck cancers irradiation.

The conformal radiotherapy approach, three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT), is based on modern imaging modalities, efficient 3D treatment planning systems, sophisticated immobilization devices and demanding quality assurance and treatment verification. The main goal of conformal radiotherapy is to ensure a high dose distribution tailored to the limits of the target volume while reducing exposure of healthy tissues. These techniques would then allow a further dose escalation increasing local control and survival. Non-small cell lung cancer (NSCLC) is one of the most difficult malignant tumors to be treated. It combines geometrical difficulties due to respiratory motion, and number of low tolerance neighboring organs, and dosimetric difficulties because of the presence of huge inhomogeneities. This localization is an attractive and ambitious example for the evaluation of new techniques. However, the published clinical reports in the last years described very heterogeneous techniques and, in the absence of prospective randomized trials, it is somewhat difficult at present to evaluate the real benefits drawn from those conformal radiotherapy techniques. After reviewing the rationale for 3DCRT for NSCLC, this paper will describe the main studies of 3DCRT, in order to evaluate its impact on lung cancer treatment. Then, the current state-of-the-art of IMRT and the last technical and therapeutic innovations in NSCLC will be discussed.