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The world has now been facing the coronavirus disease 2019 (COVID-19) pandemic due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) since over a year. If most of clinical presentations are benign, fragile patients are at greater risk of developing severe or fatal lung disease. Many therapies have been explored with very low impact on mortality. In this context, Kirkby et Mackenzie have published in April 2020 a report reminding the anti-inflammatory properties of low-dose radiotherapy (delivering less than 1Gy) and its use in the treatment of viral and bacterial pneumopathies before antibiotics era. Large in vivo and in vitro data have demonstrated the biological rationale and anti-inflammatory activity of low-dose radiotherapy in many pathologies. Over the past year, three phase I/II clinical trials have been published, as well as one randomized controlled trial, reporting the feasibility and the clinical and biological improvement of a 0.5 to 1Gy treatment dose to the entire lung. 13 other studies, including a randomized phase III trial, are currently ongoing worldwide. These studies may provide data in the effect of low-dose radiotherapy in the treatment of SARS-CoV-2 pneumonia. This article explains biological rationale of low-dose radiotherapy, and reports already published or ongoing studies on low-dose radiotherapy for SARS-CoV-2 pneumonia.

Purpose Iodine-125 (125I) brachytherapy (BT) alone for intermediate-risk (IR) prostate adenocarcinoma (PCA) is controversial. The purpose of the study was to investigate potential predictive factors in selected IR-PCA patients treated with BT. Material and methods Among 547 patients treated with 125I BT between 2003 and 2013, 149 IR-PCA cases were selected according to NCCN classification after an additional exclusion of patients with prostate specific antigen (PSA) > 15 ng/ml and ISUP group 3. A relapse was defined as a biochemical failure, using ASTRO Phoenix definition, or a relapse identified on imaging. Survival curves were estimated with Kaplan-Meier method. Potential prognostic variables including EAU/ESTRO/SIOG guidelines eligibility criteria were analyzed using univariate and Cox's proportional hazards regression analysis. Results Of the 149 IR patients, 112 were classified as favorable, with 69 cases eligible to BT according to EAU/ESTRO/SIOG guidelines, and 37 patients were identified as unfavorable as per NCCN. Androgen deprivation therapy (ADT) was applied in 6 patients only. Percentage of positive biopsy cores were ≤ 33% and ≥ 50% for 119 and 11 patients, respectively. With a median follow-up of 8.5 years, 30 patients experienced a relapse. 10-year overall survival, progression-free survival (PFS), and relapse-free survival (RFS) were 84% (95% CI: 75-90%), 66% (95% CI: 56-75%), and 77% (95% CI: 67-84%), respectively. Failure to meet EAU/ESTRO/SIOG criteria was significantly associated with a lower RFS (p = 0.0267, HR = 2.37 [95% CI: 1.10-5.08%]). Conclusions Brachytherapy is an effective treatment for selected IR-PCA cases. Patients who were not eligible according to EAU/ESTRO/SIOG guidelines demonstrated a lower RFS.

Radiation plexitis, also known as radiation-induced brachial neuropathy is a rare toxicity following axillary, breast, cervical or thoracic radiotherapy, first described in 1966 by Stoll and Andrew. Although improvements in radiotherapy techniques have greatly reduced its risk over the past seventy years, its severe form remains a dreaded complication that is difficult to manage in patients with increased life expectancy. This article summarizes the epidemiological elements, risk factors, diagnostic methods, doses and constraints to be respected in radiotherapy and the treatment strategies of radiation plexitis.

Summary Background In 2013, the interim analysis of the Protocol for Herceptin as Adjuvant therapy with Reduced Exposure (PHARE) trial could not show that 6 months of adjuvant trastuzumab was non-inferior to 12 months. Here, we report the planned final analysis based on the prespecified number of occurring events. Methods PHARE is an open-label, phase 3, non-inferiority randomised trial of patients with HER2-positive early breast cancer comparing 6 months versus 12 months of trastuzumab treatment concomitant with or following standard neoadjuvant or adjuvant chemotherapy. The study was undertaken in 156 centres in France. Eligible patients were women aged 18 years or older with non-metastatic, operable, histologically confirmed adenocarcinoma of the breast and either positive axillary nodes or negative axillary nodes but a tumour of at least 10 mm. Participants must have received at least four cycles of a chemotherapy for this breast cancer and have started receiving adjuvant trastuzumab-treatment. Eligible patients were randomly assigned to either 6 months or 12 months of trastuzumab therapy duration between the third and sixth months of adjuvant trastuzumab. The randomisation was stratified by concomitant or sequential treatment with chemotherapy, oestrogen receptor status, and centre. The primary objective was non-inferiority in the intention-to-treat population in the 6-month group in terms of disease-free survival with a prespecified hazard margin of 1·15. This trial is registered with ClinicalTrials.gov, number NCT00381901. Findings 3384 patients were enrolled and randomly assigned to either 12 months (n=1691) or 6 months (n=1693) of adjuvant trastuzumab. One patient in the 12-month group and three patients in the 6-month group were excluded, so 1690 patients in each group were included in the intention-to-treat analysis. At a median follow-up of 7·5 years (IQR 5·3–8·8), 704 events relevant to disease-free survival were observed (345 [20·4%] in the 12-month group and 359 [21·2%] in the 6-month group). The adjusted hazard ratio for disease-free survival in the 12-month group versus the 6-month group was 1·08 (95% CI 0·93–1·25; p=0·39). The non-inferiority margin was included in the 95% CI. No differences in effects pertaining to trastuzumab duration were found in any of the subgroups. After the completion of trastuzumab treatment, rare adverse events occurred over time and the safety analysis remained similar to the previously published report. In particular, we found no change in the cardiac safety comparison, and only three additional cases in which the left ventricular ejection fraction decreased to less than 50% have been reported in the 12-month group. Interpretation The PHARE study did not show the non-inferiority of 6 months versus 12 months of adjuvant trastuzumab. Hence, adjuvant trastuzumab standard duration should remain 12 months. Funding The French National Cancer Institute.

// Celine Bourgier 1 , Florence Castan 1 , Olivier Riou 1 , Tan-Dat Nguyen 2 , Karine Peignaux 3 , Claire Lemanski 1 , Jean-Leon Lagrange 4 , Youlia Kirova 5 , Eric Lartigau 6 , Yazid Belkacemi 4 , Sofia Rivera 7 , Georges Noel 8 , Sebastien Clippe 9 , Francoise Mornex 10 , Christophe Hennequin 11 , Sophie Gourgou 1 , Muriel Brengues 1 , Pascal Fenoglietto 1 , Esat Mahmut Ozsahin 12 and David Azria 1 1 Institute de Recherche en Cancerologie de Montpellier, Inserm U1194, Universite de Montpellier, Institut Regional du Cancer de Montpellier, Montpellier, France 2 Institute Jean Godinot, Reims, France 3 Centre GF Leclerc, Dijon, France 4 AP-HP Henri Mondor, Creteil, France 5 Institute Curie, Paris, France 6 Centre Oscar Lambret, Lille, France 7 Gustave Roussy, Villejuif, France 8 Centre Paul Strauss, Strasbourg, France 9 Centre Marie Curie, Valence, France 10 Centre Hospitalier Lyon Sud, Pierre Benite, France 11 AP-HP Saint-Louis, Paris, France 12 Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland Correspondence to: David Azria, email: david.azria@icm.unicancer.fr Keywords: radiotherapy; breast cancer; hormonotherapy; individual radiosensitivity; late effects Received: November 30, 2017 Accepted: February 25, 2018 Epub: March 02, 2018 Published: March 20, 2018 ABSTRACT Background: To evaluate risk of severe breast fibrosis occurrence in patients treated by breast-conserving surgery, adjuvant radiotherapy and hormonotherapy (HT) according to individual radiosensitivity (RILA assay). Results: HT – and RILA high were the two independent factors associated with improved breast-fibrosis free survival (BFFS). BFFS rate at 36 months was lower in patients with RILA low and HT + than in patients with RILA high and HT – (75.8% and 100%, respectively; p = 0.004, hazard ratio 5.84 [95% confidence interval (CI) 1.8–19.1]). Conversely, BFFS at 36 months was comparable in patients with RILA high and HT + and in patients with RILA low and HT – (89.8% and 93.5%, respectively; p = 0.39, hazard ratio 1.7 [95% CI 0.51–5.65]), showing that these two parameters influenced independently the occurrence of severe breast fibrosis. BFFS rate was not affected by the HT type (tamoxifen or aromatase inhibitor) and timing (concomitant or sequential with radiotherapy). Conclusions: HT and RILA score independently influenced BFFS rate at 36 months. Patients with RILA high and HT – presented an excellent BFFS at 36 months (100%). Materials and methods: Breast Fibrosis-Free Survival (BFFS) rate was assessed relative to RILA categories and to adjuvant HT use (HT + and HT – , respectively) in a prospective multicentre study (NCT00893035) which enrolled 502 breast cancer patients (456 evaluable patients). Breast fibrosis was recorded according to CTCAE v3.0 grading scale; RILA score was defined according to two categories (

Purpose. - This work evaluated the interobserver variability in cone beam computed tomography (CBCT) registration for prostate cancers treated with intensity-modulated radiotherapy. Material and methods. - Twelve technologists realized 286 CBCT/CT registrations (bone registration followed by prostate to prostate registration). The registration results were compared to those obtained by two radiation oncologists (reference). Each technologist reported the shifts calculated by the software in all three axes. A statistical analysis allowed us to calculate the minimum threshold under which 95% of the observers found similar values. A variance analysis followed by the post hoc test were used to find differences in interobserver registration variability and determine whether any individual users performed registrations which differed significantly from those of the other users. Results. - The registration differences compared to the reference in the three directions in terms of 95th percentile are: 2.1 mm left-right, 3.5 mm target-gun, 7.3 mm anterior-posterior. In the posterior direction, 4% of the observers have found differences superior to 8 mm, margin used in routine without the use of a daily CBCT. The variance test revealed a P-value

Objectifs Des cohortes monocentriques ont suggere que le taux d’apoptose lymphocytaire radio-induit CD8 (RILA) peut predire les toxicites pelviennes (pt + ) tardives apres radiotherapie (RT) prostatique en intention curative. Nous avons evalue le role du RILA comme predicteur de pt + apres radiotherapie prostatique dans un essai prospectif multicentrique francais. Methodes Au total, 383 patients (pts) ont ete inclus dans 8 centres francais et traites par RT pour un cancer de prostate. Le RILA a ete realise en cytometrie de flux avant la RT. La RT a ete delivree en IMRT selon des volumes correspondant aux risques pronostiques (prostate + vesicules seminales 80 Gy ; prostate + pelvis 74 Gy ; loge prostatique 66 Gy). L’impact du RILA sur les toxicites pelviennes (objectif principal) ou sur les recidives a ete evalue en utilisant la methode des risques competitifs. Les analyses de type receiver-operator characteristic (ROC) ont ete realisees en intention de traiter. Cette etude a ete enregistree sur ClinicalTrials.gov ( NCT00893035 ). Resultats Au total, 352 ont recu la radiotherapie avec un tube de sang analysable. Au total, 222 (63 %), 83 (23,6 %) et 47 (13,4 %) pts ont recu respectivement une RT sur la prostate, la loge (prostatectomie) et le pelvis-prostate. Une hormonotherapie concomitante a ete administree chez 54 %. Avec un suivi median de 38 mois, les taux de toxicites tardives (grade 1–3) urinaires et digestives etaient respectivement de 22,7 % et de 11,7 %. L’incidence des pt + de grade ≥ 2 diminuait lorsque les pourcentages de RILA augmentaient (p = 0,03). Le risque de pt+ de grade ≥ 2 diminuait de moitie lorsque le RILA etait superieur a 24 %. Les symptomes urinaires initiaux pre-RT et une dose delivree a 50 % du rectum > 31 Gy augmentaient independamment le pt+. Le risque etait diminuee avec le RILA > 15 %. Conclusion Le RILA predit significativement le risque de pt+ associe a la presence de symptomes urinaires pre-therapeutiques et d’une dose rectale elevee. Cette etude valide l’utilisation du RILA dans un nomogramme multiparametrique en pratique clinique et permet de guider les praticiens et les patients dans la pertinence du choix entre prostatectomie et radiotherapie externe.

Rationale: Issues have been reported with aromatase inhibitors (AI) compliance in adjuvant breast cancer. The present study was performed in order to better assess patient (pt) compliance, and to test whether educational material (EM) can improve compliance rate. Methods: This 2-year observational study (NCT00681122) was conducted on 2,758 patients in 18 countries, and completed in March 2009. Pts were allocated to Standard Therapy AI (anastrozole or letrozole), Group A, or to Standard Therapy + EM (Group B) following a 1:1 randomisation. EM consisted of a range of information on breast cancer-related topics. Primary endpoint was compliance rate for AI: patient is defined as being compliant if she took more than 80% of her tablets during the last year. Secondary endpoints were: persistence rate at 1 and 2 years (patient is classified as a persistent user of adjuvant AI medication when the data supports the persistent intake of adjuvant AI medication during the one-year period), and reasons for and time to AI discontinuation. Specialised questionnaires were used to evaluate pt compliance and behaviour (EORTC-INPATSAT-32, OPTIMA-X, GHQ-12, FACT-ES, compliance questionnaire and EM feedback in Group B).Results: 711 pts were randomised in France, 348 in Groupe A and 363 in Groupe B. Pt characteristics were well balanced across randomised arms. Mean age was 65 years, mean BMI was 26, 20% of pts had received hormone replacement therapy, and 68% had associated co-morbidities, including musculoskeletal disorders in 12%. Preliminary analysis showed that compliance rate at 1 year was only 74%, with no difference between the 2 groups (73% in Group A vs. 74% in Group B). Persistence rates were also similar (77% vs.78%). AI discontinuations were mainly attributed to AI related side effects. Prognostic factor analysis showed no baseline characteristics associated with compliance behaviours.Conclusion: At 1 year, Cariatide preliminary analysis showed that compliance rate of adjuvant AI in France does not exceed 74%, and is not improved by EM. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-11-06.

Background Monocentric cohorts suggested that radiation-induced CD8 T-lymphocyte apoptosis (RILA) can predict late toxicity after curative intent radiotherapy (RT). We assessed the role of RILA as a predictor of breast fibrosis (bf +) after adjuvant breast RT in a prospective multicenter trial. Methods A total of 502 breast-cancer patients (pts) treated by conservative surgery and adjuvant RT were recruited at ten centers. RILA was assessed before RT by flow cytometry. Impact of RILA on bf + (primary endpoint) or relapse was assessed using a competing risk method. Receiver–operator characteristic (ROC) curve analyses were also performed in intention to treat. This study is registered with ClinicalTrials.gov, number NCT00893035 and final analyses are presented here. Findings Four hundred and fifty-six pts (90.8%) were included in the final analysis. One hundred and eight pts (23.7%) received whole breast and node irradiation. A boost dose of 10–16 Gy was delivered in 449 pts (98.5%). Adjuvant hormonotherapy was administered to 349 pts (76.5%). With a median follow-up of 38.6 months, grade ≥ 2 bf + was observed in 64 pts (14%). A decreased incidence of grade ≥ 2 bf + was observed for increasing values of RILA (p = 0.012). No grade 3 bf + was observed for patients with RILA ≥ 12%. The area under the ROC curve was 0.62. For cut-off values of RILA ≥ 20% and, Highlights • High value of radiation-induced lymphocyte apoptosis (RILA) was clearly associated with no risk of severe toxicities. • RILA is done rapidly (72 h) and from a single blood sample without any tissue biopsy. • RILA will change the practice and has to be integrated in multivariate models to optimize the evaluation of the risk. Of original research, some reports from our group focused on the development of the radiation-induced lymphocyte apoptosis assay. High values of this test were shown to be correlated with the absence of late effect after curative intent radiotherapy. For breast cancer, surgery and immediate reconstruction could be offered instead of conserving-surgery and radiotherapy. Reduced volume as in partial breast radiotherapy could also be proposed in the case of low-risk tumors to protect healthy tissues without carcinologic risk. In addition, low values of this test will be arguments against breast reconstruction. If no alternatives are available new radiotherapy techniques have to be considered.

http://www.creatis.insa-lyon.fr/rio/Publications?action=AttachFile&do=get&target=sarrut-ijrobp2005.pdf article; International audience; PurposeTo study the interfraction reproducibility of breath-holding using active breath control (ABC), and to develop computerized tools to evaluate three-dimensional (3D) intrathoracic motion in each patient.Methods and materialsSince June 2002, 11 patients with non–small-cell lung cancer enrolled in a Phase II trial have undergone four CT scans: one during free-breathing (reference) and three using ABC. Patients left the room between breath-hold scans. The patient's breath was held at the same predefined phase of the breathing cycle (about 70% of the vital capacity) using the ABC device, then patients received 3D-conformal radiotherapy. Automated computerized tools for breath-hold CT scans were developed to analyze lung and tumor interfraction residual motions with 3D nonrigid registration.ResultsAll patients but one were safely treated with ABC for 7 weeks. For 6 patients, the lung volume differences were 300 cm3 and displacements >10 mm, probably owing to atelectasia and emphysema. One patient was excluded, and two others had incomplete data sets.ConclusionBreath-holding with ABC was effective in 6 patients, and discrepancies were clinically accountable in 2. The proposed 3D nonrigid registration method allows for personalized evaluation of breath-holding reproducibility with ABC. It will be used to adapt the patient-specific internal margins.

Introduction Computerized Tomography (CT) scan provides Hounsfield Unit information (HU) and so Electronic Density (ED) which is necessary for planned dose treatment calculation in radiotherapy (RT). For prostate cancer and for delineation issues, MRI provides excellent soft tissue contrast compared to CT images and it is increasingly used for target delineation. Our project was first to develop our own algorithm conversion and image transformation between MRI signal intensity into HU and then to evaluate the algorithm on prostate clinical case as previous studies have obtained encouraging results [1] . Methods First, we set up MRI parameters (GE Signa 1.5 T, Lava Flex sequence) so that signal information matches CT-scan ones (Philips Big Bore). We selected 4 pelvic patients that were installed on a flat table to have a close installation to that of CT-scan. Using Matlab R2016a, we developed our own algorithm of conversion and image transformation between MRI signal intensity and HU using 3DSlicer 4.5 for specific density segmentation. MRI intensity signals for muscles and soft tissue were similar: we needed two conversion functions (soft tissues and bones). Images produced thanks to conversion functions were compared to real CT-scan images used for RT. We compared the depth dose profile of a 6MV field over 5 × 5 cm2 targeting the prostate and a 6 MV Volumetric Modulated Arc (VMAT). VMAT dose distributions were compared in terms of Gamma Index criteria. Results Preliminary results gave distinct intervals function definition for different structures, which was similar to the Finish-Helsinki university hospital study [1] , [2] . We identified spongy bone and cortical bone (bone function), fat, muscle, urine and prostate (soft tissue). Those distinct intervals testified the accuracy of our image conversion to produce the pseudo-CT. Dose differences were less than 5% outside the build-up region between depth dose profiles of a 6MV beam. For the VMAT treatment plan, 99% of points passed the gamma criterion of 3% dose and 3 mm distance to agreement. Finally, the pseudo-CT produced using our model showed a small effect on dose differences compared to real CT images. Conclusions This study revealed promising results to the possibility of using specific sequences of MRI for dose calculation in RT. Taking into account the potential limitation of our work, further investigation could be necessary. It could be particularly interesting to increase the number of patients, to improve the acquisition conditions and to integrate the different uncertainties of the MRI in the model. Finally, we plan to study the potential and feasibility of this model for other localization such as lung and head&neck.

Background: Radical prostatectomy and external beam radiation therapy (EBRT) are the mainstays of treatment of prostate cancer with curative intent. The possible development of radiation proctitis and rectal bleeding are major concerns when using EBRT. Recently, conformal radiotherapy has been introduced in an attempt to improve the results of EBRT. This paper presents an overview of the Lyon experience using standard EBRT with doses of 68 Gy, and reports the preliminary results of a study of conformal radiotherapy with dose escalation. Methods: From 1981 to 1995, EBRT was used to treat 231 patients with localized adenocarcinomas of the prostate. The dose of EBRT was 68 Gy/34 fractions/7 weeks using a four-field box technique with 18-MeV photons. A feasibility study of conformal radiotherapy was commenced in 1996. To date, 145 patients have been treated with doses escalating from 68 to 80 Gy. Results: In the EBRT group of 231 patients, the 5-year overall survival was 80.3%. Anorectal function was scored as excellent in 90% of patients. Rectal bleeding was seen in 14.3% of patients and required local treatment in only seven. In the group treated with conformal radiotherapy, the preliminary results indicate good early tolerance. Conclusion: The curative treatment of patients with prostate cancer using EBRT gives good long-term survival with low rectal toxicity. Conformal radiotherapy appears to be an interesting approach to improve local control and perhaps survival.

Purpose To evaluate predictive factors for PSA bounce after 125I permanent seed prostate brachytherapy and identify criteria that distinguish between benign bounces and biochemical relapses. Materials and methods Men treated with exclusive permanent 125I seed brachytherapy from November 1999, with at least a 36 months follow-up were included. Bounce was defined as an increase ≥ 0.2 ng/ml above the nadir, followed by a spontaneous return to the nadir. Biochemical failure (BF) was defined using the criteria of the Phoenix conference: nadir +2 ng/ml. Results 198 men were included. After a median follow-up of 63.9 months, 21 patients experienced a BF, and 35.9% had at least one bounce which occurred after a median period of 17 months after implantation (4-50). Bounce amplitude was 0.6 ng/ml (0.2-5.1), and duration was 13.6 months (4.0-44.9). In 12.5%, bounce magnitude exceeded the threshold defining BF. Age at the time of treatment and high PSA level assessed at 6 weeks were significantly correlated with bounce but not with BF. Bounce patients had a higher BF free survival than the others (100% versus 92%, p = 0,007). In case of PSA increase, PSA doubling time and velocity were not significantly different between bounce and BF patients. Bounces occurred significantly earlier than relapses and than nadir + 0.2 ng/ml in BF patients (17 vs 27.8 months, p < 0.0001). Conclusion High PSA value assessed 6 weeks after brachytherapy and young age were significantly associated to a higher risk of bounces but not to BF. Long delays between brachytherapy and PSA increase are more indicative of BF.

Purpose: To evaluate the role of interstitial brachytherapy as an exclusive radiotherapy modality for primary T1-T2 squamous cell carcinomas (SCC) of the velotonsillar area. Methods and Materials: Between 1992 and 2000, 44 patients with T1-T2 SCC of the tonsil (n = 36) and soft palate (n = 8) were treated to the primary with brachytherapy alone (37 patients) or after a limited resection (7 patients). Eight patients had prior external beam radiation therapy (EBRT) for previous head-and-neck carcinoma. Nineteen patients had initial neck dissection. The mean brachytherapy dose was 58.7 Gy, and the mean reference dose rate and Ir-192 linear activity were 58.2 cGy/h and 1.51 mCi/cm respectively. Results: With a 75-month median follow-up, 1 patient recurred locally. Isolated nodal relapses occurred in 4 patients, none of whom had initial neck dissection, and salvage therapy was successful in 2. Five-year overall and progression-free survival rates were 76% and 68%, respectively. Full-course radiation therapy was possible in 7 of 12 patients who developed a second primary head-and-neck carcinoma. Late toxicity was limited to 6 mild soft-tissue necroses, and was significantly associated with previous surgery to the primary and high linear activity. Conclusions: Exclusive brachytherapy for T1-T2 velotonsillar carcinomas is safe and effective, and permits definitive reirradiation for a second head-and-neck cancer. Initial neck dissection should be performed for optimal selection for exclusive brachytherapy.

Germ-cell tumors of the testis are rare tumors of the young adult. Half of them are seminoma. The majority of patients have disease limited to the testis. Radiotherapy still remains the standard treatment of these patients. Almost all patients are cured by orchidectomy and radiotherapy on the lomboaortic area extended to homolateral iliac area. The dose is 24 to 30 Gy in a standard fractionation. Different studies are ongoing to reduce the irradiation field (omission of the pelvic irradiation), to decrease irradiation dose (to 20 Gy). Other treatment options are strict surveillance and adjuvant carboplatin based chemotherapy. None of these options are standard treatments. A strict attention must be directed on controlateral germ-cell tumors and second cancers.

Purpose:To evaluate survival and functional results of the treatment of carcinomas of the vallecula using surgery, irradiation, and interstitial brachytherapy. Methods and Materials: Between 1990 and 1998, 36 patients with squamous cell carcinoma of the vallecula were treated with horizontal supraglottic functional laryngectomy, external beam radiotherapy (median dose 54 Gy), and additional interstitial brachytherapy (median dose 16 Gy). Results were compared with a previous series of 22 patients treated without brachytherapy. Results: The median follow-up was 44 months. The 5-year actuarial overall survival rate was 61.3%. The 5-year specific survival rate was 86%, with 2 local failures (local control rate 94.4%) and 4 isolated distant metastases. Ten patients developed a second primary. The overall survival was 34% for 22 patients previously treated without brachytherapy. Severe toxicities occurred in 9 patients: death (related to larynx edema or inhalation, n = 1), soft tissue necrosis ( n = 1), aspiration pneumonia ( n = 1), mandibular necrosis ( n = 2), pharyngocutaneous fistula ( n = 2), and laryngeal edema ( n = 2). All the patients fed orally with no definitive gastrostomy or tracheotomy. Conclusion: Additional brachytherapy for vallecula carcinoma seems to improve locoregional control and overall survival dramatically. Functional results were also excellent. To our knowledge, this original therapeutic schedule has never been previously described.

Purpose: By using as an experimental model the male mouse gonad, which contains both radiosensitive (germ) and radioresistant (somatic) cells, we have studied the growth factor (and/or receptor) expression of transforming growth factor-β receptor (TGFβ RI), stem cell factor (SCF), c-kit, Fas-L, Fas, tumor necrosis factor receptor (TNF R55), and leukemia inhibiting factor receptor (LIF-R) after local irradiation. Methods and Materials: Adult male mice were locally irradiated on the testes. Induction of apoptosis in the different testicular cell types following X-ray radiation was identified by the TdT-mediated dUTP Nick End Labeling (TUNEL) approach. Growth factor expression was evidenced by semiquantitative RT-PCR and Western blot analyses. Results: Apoptosis, identified through the TUNEL approach, occurred in radiosensitive testicular (premeotic) germ cells with the following kinetics: the number of apoptotic cells increased after 24 h (p < 0.001) and was maximal 48 h after a 2-Gy ionizing radiation (p < 0.001). Apoptotic cells were no longer observed 72 h after a 2-Gy irradiation. The number of apoptotic cells increased with the dose of irradiation (1–4 Gy). In the seminiferous tubules, the growth factor expression in premeiotic radiosensitive germ cells was modulated by irradiation. Indeed Fas, c-kit, and LIF-R expression, which occurs in (radiosensitive) germ cells, decreased 24 h after a 2-Gy irradiation, and the maximal decrease was observed with a 4-Gy irradiation. The decrease in Stra8 expression occurred earlier, at 4 h after a 2-Gy irradiation. In addition, a significant (p < 0.03) decrease in Stra8 mRNA levels was observed at the lowest dose used (0.5 Gy, 48 h). Moreover, concerning a growth factor receptor, such as TGFβ RI, which is expressed both in radiosensitive and radioresistant cells, we observed a differential expression depending on the cell radiosensitivity after irradiation. Indeed, TGFβ RI expression was increased after irradiation in interstitial radioresistant testicular cells in a dose- and time-dependent manner, while it decreased in seminiferous radiosensitive (germ cells) testicular cells. Such a differential expression between radioresistant and radiosensitive cells in TGFβ RI levels was observed in terms of both mRNA and protein. In contrast, the growth factors specifically expressed in the somatic radioresistant (Sertoli) cells in the seminiferous tubules (SCF, Fas-L, TNF R55) were not affected by ionizing radiation (up to 4 Gy, 72 h). Conclusion: Growth factor expression decreased in the radiosensitive testicular cells after irradiation. Such a decrease occurred before the detection of apoptosis using the TUNEL approach. TGFβ RI mRNA levels decreased in the radiosensitive cells, whereas it increased in the radioresistant cells, suggesting that TGFβ RI may represent a biomarker of the intrinsic radiosensitivity of cells.

International audience; Background: In 2013, the interim analysis of the Protocol for Herceptin as Adjuvant therapy with Reduced Exposure (PHARE) trial could not show that 6 months of adjuvant trastuzumab was non-inferior to 12 months. Here, we report the planned final analysis based on the prespecified number of occurring events.Methods: PHARE is an open-label, phase 3, non-inferiority randomised trial of patients with HER2-positive early breast cancer comparing 6 months versus 12 months of trastuzumab treatment concomitant with or following standard neoadjuvant or adjuvant chemotherapy. The study was undertaken in 156 centres in France. Eligible patients were women aged 18 years or older with non-metastatic, operable, histologically confirmed adenocarcinoma of the breast and either positive axillary nodes or negative axillary nodes but a tumour of at least 10 mm. Participants must have received at least four cycles of a chemotherapy for this breast cancer and have started receiving adjuvant trastuzumab-treatment. Eligible patients were randomly assigned to either 6 months or 12 months of trastuzumab therapy duration between the third and sixth months of adjuvant trastuzumab. The randomisation was stratified by concomitant or sequential treatment with chemotherapy, oestrogen receptor status, and centre. The primary objective was non-inferiority in the intention-to-treat population in the 6-month group in terms of disease-free survival with a prespecified hazard margin of 1·15. This trial is registered with ClinicalTrials.gov, number NCT00381901.Findings: 3384 patients were enrolled and randomly assigned to either 12 months (n=1691) or 6 months (n=1693) of adjuvant trastuzumab. One patient in the 12-month group and three patients in the 6-month group were excluded, so 1690 patients in each group were included in the intention-to-treat analysis. At a median follow-up of 7·5 years (IQR 5·3-8·8), 704 events relevant to disease-free survival were observed (345 [20·4%] in the 12-month group and 359 [21·2%] in the 6-month group). The adjusted hazard ratio for disease-free survival in the 12-month group versus the 6-month group was 1·08 (95% CI 0·93-1·25; p=0·39). The non-inferiority margin was included in the 95% CI. No differences in effects pertaining to trastuzumab duration were found in any of the subgroups. After the completion of trastuzumab treatment, rare adverse events occurred over time and the safety analysis remained similar to the previously published report. In particular, we found no change in the cardiac safety comparison, and only three additional cases in which the left ventricular ejection fraction decreased to less than 50% have been reported in the 12-month group.Interpretation: The PHARE study did not show the non-inferiority of 6 months versus 12 months of adjuvant trastuzumab. Hence, adjuvant trastuzumab standard duration should remain 12 months.