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Stereotactic body radiation therapy (SBRT) has become a new therapeutic option for primary renal cell carcinoma. However, treatment doses lack consistency in the literature. The primary objective of this study was to determine the maximum tolerated dose for renal cancer SBRT.This phase 1 multicentric dose-escalation study assessed 4 dose levels: 8 Gy × 4, 8 Gy × 5, 10 Gy × 4, and 12 Gy × 4. The primary objective of this study was to determine the maximal tolerated dose, defined by the occurrence of dose-limiting toxicity was defined as any acute side effect of grade ≥4 based on the Common Terminology Criteria for Averse Events, version 4.0.From October 2010 to September 2017, 13 patients were enrolled. The median follow-up was 23 months. There was no dose-limiting toxicity in our study, and the highest dose was reached successfully. No acute or late toxic effects above grade 2 were seen. There was no significant alteration of renal function after treatment. At 24 months, 2 patients had partial response and the others had stable disease.After 24 months of follow-up, no dose-limiting toxicity was seen at any of the prescribed dose levels in our study. The findings suggest that our last dose level of 48 Gy in 4 12-Gy fractions can be considered safe and can be used in further studies.

Objective: The most commonly used dose for prostate cancer stereotactic body radiotherapy (SBRT) is 5 × 7.25 Gy. The aim of this study was to evaluate the dosimetric feasibility of a 5 × 9 Gy SBRT regimen while still limiting the dose to the urethra to 5 × 7.25 Gy. This dosimetric study is part of the groundwork for a future Phase III randomized trial. Methods: The prostate, the urethra and the tumors were delineated on 20 dosimetric CT-scans with MRI-registration. The planning target volume (PTVp) was defined as a 5 mm expansion (3 mm posteriorly) of the prostate. The planning at risk volume (PRVu) was defined as a 2 mm expansion of the urethra. The tumors were delineated on the MRI (GTVt) and a 3 mm-margin was added to create a tumoral planning target volume (PTVt). IMRT plans were optimized to deliver 5 × 9 Gy to the PTVp, limiting the dose to the PRVu to 5 × 7.25 Gy. Results are presented using average (range) values. Results: PTVp doses were D98% = 36.2 Gy (35.6–36.8), D2% = 46.9 Gy (46.5–47.5) and mean dose = 44.1 Gy (43.8–44.5). The dose to the PRVu was within tolerance limits for all 20 patients: V34.4Gy = 99.8% (99.2–100) and D5% = 38.7 Gy (38.6–38.8). Dose coverage of PTV-PRVu was D95% = 40.6 Gy (40.5–40.9), D5% = 46.6 Gy (46.2–47.2) and mean dose = 44.6 Gy (44.3–44.9). Dose to the PTVt reached 44.6 Gy (41.2–45.9). Doses to the OAR were respected, except V36Gy ≤1 cc for the rectum. Conclusion: A SBRT dose-escalation to 5 × 9 Gy on the prostate while sparing the urethra + 2 mm at 36.25 Gy is feasible without compromising dose coverage to the tumor. This radiation regimen will be used for a Phase-III trial. Advances in knowledge: In prostate SBRT, dose optimization on the urethra is feasible and could decrease urinary toxicities.

Stereotactic body radiotherapy (SBRT) has become treatment option for localized prostate cancer but the evidence base remains incomplete. Several clinical studies, both prospective and retrospective, have been published. However, treatment techniques, target volumes and dose constraints lack consistency between studies. Based on the current available literature, the French Genito-Urinary Group (GETUG) suggests that.

Personalized treatment and precision medicine have become the new standard of care in oncology and radiotherapy. Because treatment outcomes have considerably improved over the last few years, permanent side-effects are becoming an increasingly significant issue for cancer survivors. Five to ten percent of patients will develop severe late toxicity after radiotherapy. Identifying these patients before treatment start would allow for treatment adaptation to minimize definitive side effects that could impair their long-term quality of life. Over the last decades, several tests and biomarkers have been developed to identify these patients. However, out of these, only the Radiation-Induced Lymphocyte Apoptosis (RILA) assay has been prospectively validated in multi-center cohorts. This test, based on a simple blood draught, has been shown to be correlated with late radiation-induced toxicity in breast, prostate, cervical and head and neck cancer. It could therefore greatly improve decision making in precision radiation oncology. This literature review summarizes the development and bases of this assay, as well as its clinical results and compares its results to the other available assays.

International audience; Radiotherapy is one of the main treatments for solid tumors. The total dose that can be delivered to the tumor is limited by the radiation amount received by the surrounding normal tissues, which are at risk of developing acute and late radiation-induced effects. Areas covered: Severe late radiation-induced toxicity occurs in 5% to 10% of patients following radiotherapy. However, the current radiotherapy and radiation protection protocols do not take into account the variations in radiosensitivity among individuals. This review will focus on late radiotherapy-induced side effects and on the different cellular assays (γ-H2AX/53BP1 focus formation, G2 metaphase, G0 micronucleus formation and radio-induced apoptosis in CD8+ T-lymphocytes: level I evidence) that have been developed to predict their occurrence in patients. Expert commentary: The routine prediction of late radiation-induced toxicity in normal tissues in the clinic will allow personalized radiotherapy with better outcome and less side effects. Patients at low risk of late toxicity could receive a higher total dose to the tumor. Conversely, patients at high risk of late toxicity should receive lower radiation doses per fraction, using state-of-the-art treatment techniques, or alternative therapies to avoid radiation-induced side effects.

Sexual preservation is an important issue in the treatment of localized prostate cancer. A technique of irradiation was developed to better preserve this function and has been evaluated.Eleven patients, with no erectile dysfunction (ED), were treated with daily IMRT-IGRT (total dose: 76-78 Gy). The pudendal arteries, penile bulb and cavernous body were delineated on the planning CT scan. The doses to these structures (with a 5 mm margin) were optimized to be as low as possible. The erectile function was documented using IIEF-5 scores at baseline, 6 months, 1 and 2 years. No ED was defined by an IIEF5 ≥ 20/25, a mild ED by an IIEF5 score of 17-19 and an important ED by a score17.The mean age was 68.4 years. At the median follow-up of 36 months, there was no biochemical relapse. Before RT, the mean IIEF5 score in all 11 patients was 23.4 (range, 20-25). At 6, 12, 18 and 24 months after RT, the mean IIEF scores were 21.2 (14-25), 21.3 (14-25), 21.8 (16-25) and 21.8 (16-25), respectively. At 2 years, 8 patients (72.7%) had no ED and 2 patients (18.2%) experienced a mild ED. The only patient with an important ED had a medical treatment and recovered a satisfactory IIEF score from 16 to 24.The results of this technique of optimisation for sexual preservation are encouraging. Despite a mean age close to 70 years at the time of treatment, 90.9% of the patients had no to mild ED at 2 years. This rate increases at 100% with medical treatment. Advances in knowledge: Dose optimization on sexual organs is possible and could decrease the ED rates.

e17502Background: Neuroendocrine cervical carcinoma (NECC) is a very aggressive and rare disease. To date, only 2 prospective studies with scarce patient numbers have been reported in the literatur...

International audience; Head and neck squamous cell carcinomas (HNSCC) represent a multifactorial disease of poor prognosis. They have lagged behind other cancers in terms of personalized therapy. With expansion and high throughput sequencing methods, recent landmark exonic studies and Cancer Genome Atlas data have identified genes relevant to carcinogenesis and cancer progression. Mutational profiles and rates vary widely depending on exposure to carcinogens, anatomic subsites and human papilloma virus (HPV) infection. Tumors may exhibit specific, tissue-specific, not exclusively HPV-related, gene alterations, such those observed in oral cavity cancers in Asia or Occident. Except for the PI3K pathway, the rate of mutations in HPV+ cancers is much lower than in tobacco/alcohol-related cancers. Somatic driver mutation analyses show that relatively few driver genes are druggable in HNSCC and that tumor suppressor gene alterations prevail. More mature for therapeutic applications is the oncogenic PI3K pathway, with preclinical human xenograft models suggesting that PI3KCA pathway mutations may be used as predictive biomarkers and clinical data showing efficacy of mTOR/Akt inhibitors. Therapeutic guidance, to date, relies on classical histoprognostic factors, anatomic subsite and HPV status, with integration of hierarchized supervised mutational profiling to provide additional therapeutic options in advanced HNSCC in a near future. Unsupervised controlled genomic analyses remain necessary to unravel potentially relevant genes.

Radiation therapy plays a central role in patients with locally advanced NSCLC who are not eligible for surgery. In fit patients, radiation is administered with concurrent chemotherapy leading to improved survival compared to either modality alone or the sequence of both. Different strategies to improve local control have been explored. Multiple dose escalation protocols produced higher local control rates and promising 2-year survival rates at radiation doses above 70 or even 80 Gy. However, higher doses are currently not recommended following the results of the recent phase III RTOG 0617 trial comparing standard dose radiotherapy with highdose (74 Gy) conformal radiotherapy which demonstrated a significant increase in the risk of death in the high dose arm. Altered fractionation regimens using concomitant boost or hyperfractionated and/or accelerated radiation therapy have reported to be successful, but logistics limited its use in routine practice. Technical advances in radiation therapy include PET CT planning, visualization of tumour hypoxia by dynamic PET-CT, stereotactic boost on hypoxic areas, proton beam therapy, IMRT and image-guided radiation therapy. The best systemic regimen to be used concurrently with radiation has yet to be defined; as has the role of induction and consolidation therapy in addition to concurrent chemoradiotherapy. Monoclonal antibodies such as bevacizumab and cetuximab have not been able to improve outcomes and the results of the phase III study of the novel anti-folate pemetrexed in combination with cisplatin compared to standard etoposide/cisplatin are awaited. The role of targeted agents in molecularly selected subgroups and the optimal treatment approach in unfit and elderly patients has yet to be defined and are the subject of ongoing clinical trials.

e634 Background: Salvage radiation therapy (RT) after radical prostatectomy (RP) for prostate cancer using 66 Gy may not be enough to treat macroscopic disease. The presence of a macroscopic nodule on the MRI could justify a focal dose escalation. This study evaluates the tolerance and efficacy of a new technique of irradiation including a focal boost to the nodule. Methods: Between 2011 and 2015, 14 patients, with a macroscopic relapse diagnosed on the MRI, underwent targeted MRI-guided biopsies. Three gold markers were implanted into the prostatic bed for a more accurate MRI/CT fusion and image guided IMRT. A dose of 60 Gy was delivered to the prostatic bed followed by a dose escalation to 72Gy on the macroscopic nodule. Acute and late genitourinary (GU) and gastrointestinal (GI) toxicities were evaluated using the CTCAE v4. PSA level and late toxicities were assessed at 1 month and then every 6 months for 3 years. Results: The mean follow-up was 26.2 [18 – 36] months. Two patients had a biochemical failure after salvage RT (one bone metastasis and one lymph node recurrence). The local control rate was 100% and the biochemical control rate was 85.7%. Results for acute and late toxicities are summarized in the table. One patient presented with grade 2 urinary toxicity during the prostatic bed irradiation which lowered to grade 1 when the dose was focalized to the nodule. No grade 2 acute GI toxicity was seen. All late GI and GU toxicities were grade 1. Conclusions: Dose escalation to the macroscopic nodule visible on MRI is feasible using an IMRT-IGRT approach with gold makers. This technique allows a perfect initial local control at 3 years with a good tolerance. [Table: see text]

105 Background: Sexual preservation is an important issue in the treatment of localized prostate cancer. In this study, we evaluate the long-term incidence of erectile dysfunction (ED) after prostate brachytherapy (PBT), in men without ED. Methods: Between 2006 and 2012, prospective data of patients treated with brachytherapy for a low or intermediate-risk prostate cancer (d’Amico classification), were collected. Erectile function (EF) was assessed with IIEF5 score (5-Item Version of the International Index of Erectile Dysfunction) at six weeks and then every year during the follow-up. No ED was defined by an IIEF5 score ≥ 22/25 and a mild ED by a score between 17 and 21. Results: Up to this point, 70 patients, with an initial IIEF5 ≥22, were analyzed with a mean follow-up of 46.5 months. At 6 weeks and 1, 2, 3 and 4 years after brachytherapy, mean IIEF5 scores in all 70 patients were 24.6, 21.3, 19.7, 19.1 and 17.3, respectively. In ≤ 65 years old group, the scores were 24.7, 20.9, 21.3, 21.1, 19.7 and 20, respectively. In > 65 years old group, the scores were 24.6, 21.8, 21.3, 18.1, 18.2 and 14.9, respectively. The evaluation of ED according to age groups is represented in the table. Conclusions: At 4 years of follow-up after brachytherapy, patients 65 years old and younger have an EF preservation rate >80% with 50% of them having no ED. For patients older than 65 years, the rate of EF preservation decreased at 50% after 4 years of follow up with only few of them having no ED. This difference between the 2 groups of age is probably more related to an age effect than a brachytherapy toxicity. At the time of the meeting, more data and results will be available. [Table: see text]

SummaryAdult humans have about 25 trillion red blood cells (RBCs), and each second we recycle about 5 million RBCs by erythrophagocytosis (EP) in macrophages of the reticuloendothelial system. Despite the central role for EP in mammalian iron metabolism, the molecules and pathways responsible for heme trafficking during EP remain unknown. Here, we show that the mammalian homolog of HRG1, a transmembrane heme permease in C. elegans, is essential for macrophage iron homeostasis and transports heme from the phagolysosome to the cytoplasm during EP. HRG1 is strongly expressed in macrophages of the reticuloendothelial system and specifically localizes to the phagolysosomal membranes during EP. Depletion of Hrg1 in mouse macrophages causes attenuation of heme transport from the phagolysosomal compartment. Importantly, missense polymorphisms in human HRG1 are defective in heme transport. Our results reveal HRG1 as the long-sought heme transporter for heme-iron recycling in macrophages and suggest that genetic variations in HRG1 could be modifiers of human iron metabolism.