Association of Radiochemotherapy to Immunotherapy in unresectable locally advanced Oesophageal carciNoma-randomized phase 2 trial ARION UCGI 33/PRODIGE 67: the study protocol.

BACKGROUND: In case of locally advanced and/or non-metastatic unresectable esophageal cancer, definitive chemoradiotherapy (CRT) delivering 50 Gy in 25 daily fractions in combination with platinum-based regimen remains the standard of care resulting in a 2-year disease-free survival of 25% which deserves to be associated with new systemic strategies. In recent years, several immune checkpoint inhibitors (anti-PD1/anti-PD-L1, anti-Program-Death 1/anti-Program-Death ligand 1) have been approved for the treatment of various solid malignancies including metastatic esophageal cancer. As such, we hypothesized that the addition of an anti-PD-L1 to CRT would provide clinical benefit for patients with locally advanced oesophageal cancer. To assess the efficacy of the anti-PD-L1 durvalumab in combination with CRT and then as maintenance therapy we designed the randomized phase II ARION (Association of Radiochemotherapy with Immunotherapy in unresectable Oesophageal carciNoma- UCGI 33/PRODIGE 67). METHODS: ARION is a multicenter, open-label, randomized, comparative phase II trial. Patients are randomly assigned in a 1:1 ratio in each arm with a stratification according to tumor stage, histology and centre. Experimental arm relies on CRT with 50 Gy in 25 daily fractions in combination with FOLFOX regimen administrated during and after radiotherapy every two weeks for a total of 6 cycles and durvalumab starting with CRT for a total of 12 infusions. Standard arm is CRT alone. Use of Intensity Modulated radiotherapy is mandatory. The primary endpoint is to increase progression-free survival at 12 months from 50 to 68% (HR = 0.55) (power 90%; one-sided alpha-risk, 10%). Progression will be defined with central external review of imaging. ANCILLARY STUDIES ARE PLANNED: PD-L1 Combined Positivity Score on carcinoma cells and stromal immune cells of diagnostic biopsy specimen will be correlated to disease free survival. The study of gut microbiota will aim to determine if baseline intestinal bacteria correlates with tumor response. Proteomic analysis on blood samples will compare long-term responder after CRT with durvalumab to non-responder to identify biomarkers. CONCLUSION: Results of the present study will be of great importance to evaluate the impact of immunotherapy in combination with CRT and decipher immune response in this unmet need clinical situation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT: 03777813.Trial registration date: 5th December 2018.

Randomized phase II trial in prostate cancer with hormone-sensitive OligometaSTatic relapse: Combining stereotactic ablative radiotherapy and durvalumab (POSTCARD GETUG P13): Study protocol.

Background: As in other solid tumors, increasing evidence indicates that patients diagnosed with a limited number of prostate cancer metastases, so-called oligometastases, have a better prognosis than patients with extensive metastatic disease. Stereotactic body radiotherapy (SBRT) is now considered an option in this population.Programmed death-1 (PD-1) and its ligands (PD-L1) are targeted by immune checkpoint inhibitors. Preclinical studies have shown that the tumor immune microenvironment changes when combining radiotherapy with immunotherapy, especially with hypofractionated radiotherapy.The oligometastatic setting appears to be the most relevant clinical situation for evaluating the immune response generated by radiotherapy and immune checkpoint inhibitors in patients with an intact immune system.We hypothesize that durvalumab will enhance the immune response following SBRT targeting oligometastatic lesions. Our purpose is to demonstrate, via a randomized 2:1 phase II trial, that SBRT (3 fractions) with durvalumab in oligometastatic hormone-sensitive prostate cancer patients would improve progression-free survival in patients with prostate cancer with up to 5 metastases compared to patients who exclusively received SBRT. Methods: This is a multicentric randomized phase II study in French academic hospitals. Patients with prostate cancer and up to 5 metastases (lymph node and/or bone) were randomized into a 2:1 ratio between Arm A (experimental group), corresponding to durvalumab and SBRT to the metastases, and Arm B (control group), corresponding to SBRT alone to the metastases. The study aims to accrue a total of 96 patients within 3 years. The primary endpoint is two-year progression-free survival and secondary endpoints include androgen deprivation therapy-free survival, quality of life, toxicity, prostate cancer specific survival, overall survival, and immune response. Discussion: The expected benefit for the patients in the experimental arm is longer life expectancy with acceptable toxicity. We also expect our study to provide data for better understanding the synergy between immunotherapy and radiotherapy in oligometastatic prostate cancer.

In vitro modeling of the neurobiological effects of glucocorticoids: A review.

Hypothalamic-pituitary adrenal (HPA)axis dysregulation has long been implicated in stress-related disorders such as major depression and post-traumatic stress disorder. Glucocorticoids (GCs) are released from the adrenal glands as a result of HPA-axis activation. The release of GCs is implicated with several neurobiological changes that are associated with negative consequences of chronic stress and the onset and course of psychiatric disorders. Investigating the underlying neurobiological effects of GCs may help to better understand the pathophysiology of stress-related psychiatric disorders. GCs impact a plethora of neuronal processes at the genetic, epigenetic, cellular, and molecular levels. Given the scarcity and difficulty in accessing human brain samples, 2D and 3D in vitro neuronal cultures are becoming increasingly useful in studying GC effects. In this review, we provide an overview of in vitro studies investigating the effects of GCs on key neuronal processes such as proliferation and survival of progenitor cells, neurogenesis, synaptic plasticity, neuronal activity, inflammation, genetic vulnerability, and epigenetic alterations. Finally, we discuss the challenges in the field and offer suggestions for improving the use of in vitro models to investigate GC effects.

Regulation of PPARα by APP in Alzheimer disease affects the pharmacological modulation of synaptic activity.

Among genetic susceptibility loci associated with late-onset Alzheimer disease (LOAD), genetic polymorphisms identified in genes encoding lipid carriers led to the hypothesis that a disruption of lipid metabolism could promote disease progression. We previously reported that amyloid precursor protein (APP) involved in Alzheimer disease (AD) physiopathology impairs lipid synthesis needed for cortical networks' activity and that activation of peroxisome proliferator-activated receptor α (PPARα), a metabolic regulator involved in lipid metabolism, improves synaptic plasticity in an AD mouse model. These observations led us to investigate a possible correlation between PPARα function and full-length APP expression. Here, we report that PPARα expression and activation were inversely related to APP expression both in LOAD brains and in early-onset AD cases with a duplication of the APP gene, but not in control human brains. Moreover, human APP expression decreased PPARA expression and its related target genes in transgenic mice and in cultured cortical cells, while opposite results were observed in APP-silenced cortical networks. In cultured neurons, APP-mediated decrease or increase in synaptic activity was corrected by a PPARα-specific agonist and antagonist, respectively. APP-mediated control of synaptic activity was abolished following PPARα deficiency, indicating a key function of PPARα in this process.

Automated contour propagation of the prostate from pCT to CBCT images via deep unsupervised learning.

PURPOSE: To develop and evaluate a deep unsupervised learning (DUL) framework based on a regional deformable model for automated prostate contour propagation from planning computed tomography (pCT) to cone-beam CT (CBCT). METHODS: We introduce a DUL model to map the prostate contour from pCT to on-treatment CBCT. The DUL framework used a regional deformable model via narrow-band mapping to augment the conventional strategy. Two hundred and fifty-one anonymized CBCT images from prostate cancer patients were retrospectively selected and divided into three sets: 180 were used for training, 12 for validation, and 59 for testing. The testing dataset was divided into two groups. Group 1 contained 50 CBCT volumes, with one physician-generated prostate contour on CBCT image. Group 2 contained nine CBCT images, each including prostate contours delineated by four independent physicians and a consensus contour generated using the STAPLE method. Results were compared between the proposed DUL and physician-generated contours through the Dice similarity coefficients (DSCs), the Hausdorff distances, and the distances of the center-of-mass. RESULTS: The average DSCs between DUL-based prostate contours and reference contours for test data in group 1 and group 2 consensus were 0.83 ± 0.04, and 0.85 ± 0.04, respectively. Correspondingly, the mean center-of-mass distances were 3.52 mm ± 1.15 mm, and 2.98 mm ± 1.42 mm, respectively. CONCLUSIONS: This novel DUL technique can automatically propagate the contour of the prostate from pCT to CBCT. The proposed method shows that highly accurate contour propagation for CBCT-guided adaptive radiotherapy is achievable via the deep learning technique.

Evaluation of the Theoretical Teaching of Postgraduate Radiation Oncology Medical Residents in France: a Cross-Sectional Study.

This study's purpose was to have residents evaluate Radiation Oncology (RO) theoretical teaching practices in France. An anonymous electronically cross-functional survey on theoretical teaching practices in the RO residents was conducted by (i) collecting data from residents in the medical faculties in France, (ii) comparing the data across practices when possible and (iii) suggesting means of improvement. A total of 103 out of 140 RO residents responded to the survey (73.5% response rate). National, inter-university, university and internships courses do not exist in 0% (0), 16.5% (17), 53.4% (55) and 40.8% (42) of residents, respectively. Residents need additional training due to the shortage of specialised postgraduate degree training (49.5% (51)), CV enhancement to obtain a post-internship position (49.5% (51)) or as part of a career plan (47.6% (49)). The topics covered in teaching to be improved were the following: basic concept 61.2% (63), advanced concept 61.2 (63) and discussion of frequent clinical cases 50.5% (52). The topics not covered in teaching to be improved were the following: the development of career (66.0% (68)), medical English (56.3% (58)), the organisation of RO speciality (49.5% (51)) and the hospital management of RO department (38.8% (40)). This is the first national assessment of theoretical teaching of RO residents in France.

Salvage robotic SBRT for local prostate cancer recurrence after radiotherapy: preliminary results of the Oscar Lambret Center.

BACKGROUND: Currently, there is no standard option for local salvage treatment for local prostate cancer recurrence after radiotherapy. Our objective was to investigate the feasibility and efficiency of Robotic Stereotactic Body Radiation Therapy (SBRT) in this clinical setting. METHODS/MATERIALS: We retrospectively reviewed patients who were treated at our institution with SBRT for local prostate cancer recurrence after External Beam Radiation Therapy (EBRT) or brachytherapy. Multidisciplinary staff approved the treatment, and recurrence was biopsy-proven when feasible. A dose of 36 Gy was prescribed in six fractions. Treatment was delivered every other day. RESULTS: Between August 2011 and February 2014, 23 patients were treated with SBRT for intra-prostate cancer recurrence with a median follow up of 22 months (6 to 40). Twenty patients had biopsy-proven recurrence. For 19 patients, EBRT was the initial treatment and in four patients, brachytherapy was the initial treatment; the median relapse-time from initial treatment was 65 months (28 to 150). At relapse, 10 patients had an extra-capsular extension. Fourteen patients were treated with androgen deprivation that could be stopped after a median of 1 month after SBRT (range 0-24). A PSA decrease occurred in 82.6% of the patients after SBRT. The 2-year disease-free survival and overall survival rates were 54 and 100%, respectively. Disease progression was observed for nine patients (39.1%) (five local, three metastatic and one nodal progression) after a median of 20 months (7-40 months). The median nadir PSA was 0.35 ng/ml and was achieved after a median of 8 months (1 to 30) after treatment. We observed no grade 4 or 5 toxicity. Two patients presented with grade 3 toxicities (two Cystitis and one neuralgia). Other toxicities included urinary toxicities (five grade 2 and nine grade 1) and rectal toxicities (two grade 2 and two grade 1). CONCLUSION: SBRT for local prostate cancer recurrence seems feasible and well tolerated with a short follow up. Prospective evaluation is needed.

Low-dose-rate interstitial brachytherapy boost for the treatment of anal canal cancers.

PURPOSE: Evaluate the efficacy and tolerance of interstitial brachytherapy (IBT) after external beam radiotherapy (EBRT) or radio chemotherapy (RCT) for the treatment of anal canal cancers (ACC). METHODS AND MATERIALS: From 01, 1990 to 01, 2013, 103 patients (p) with ACC were treated with IBT after EBRT or RCT at our institution. Tumor node metastasis stage included Tis (1 p), T1 (18 p), T2 (46 p), T3 (33 p), and T4 (5 p). There was a lymph node involvement in 19 p. Ninety-nine patients presented with squamous cell carcinoma (95.5%) and seven with adenocarcinoma (4.5%). The median EBRT dose was 45 Gy (18-65 Gy). Thirty-nine patients (37.86%) received concomitant RCT. IBT was performed 0.9 months (0-4.38) after RCT or EBRT. The median IBT dose was 17.2 Gy (10-30 Gy). RESULTS: Within 4.8 years of followup, 15 p (14.6%) had an abdominoperineal amputation with definitive colostomy (11 p had locoregional failure, and 4 p had anal incontinence). Late toxicity was presented in 40 p (38.8%). Overall survival rates of 99% at 1 year, 89.4% at 3 years, and 85.7% at 5 years, and 1-year, 3-year, and 5-year local control rates of 97.9%, 95.4%, and 89.1%, respectively. The 1-year, 3-year, and 5-year colostomy-free rates were 98.9%, 94.0%, and 86.4%, respectively. No factors in the multivariate analysis were associated with the overall survival or any failure type. CONCLUSIONS: IBT boost provides excellent local control with low colostomy rates and a late toxicity profile in ACC treatment.

Neutrophilia in locally advanced cervical cancer: A novel biomarker for image-guided adaptive brachytherapy?

OBJECTIVE: To study the prognostic value of leucocyte disorders in a prospective cohort of cervical cancer patients receiving definitive chemoradiation plus image-guided adaptive brachytherapy (IGABT). RESULTS: 113 patients were identified. All patients received a pelvic irradiation concomitant with chemotherapy, extended to the para-aortic area in 13 patients with IVB disease. Neutrophilia and leukocytosis were significant univariate prognostic factors for poorer local failure-free survival (p = 0.000 and p = 0.002, respectively), associated with tumor size, high-risk clinical target volume (HR-CTV) and anemia. No effect was shown for distant metastases but leukocytosis and neutrophila were both poor prognostic factors for in-field relapses (p = 0.003 and p < 0.001). In multivariate analysis, HR-CTV volume (p = 0.026) and neutrophils count > 7,500/µl (p = 0.018) were independent factors for poorer survival without local failure, with hazard ratio (HR) of 3.1. MATERIALS AND METHODS: We examined patients treated in our Institution between April 2009 and July 2015 by concurrent chemoradiation (45 Gy in 25 fractions +/- lymph node boosts) followed by a magnetic resonance imaging (MRI)-guided adaptive pulse-dose rate brachytherapy (15 Gy to the intermediate-risk clinical target volume). The prognostic value of pretreatment leucocyte disorders was examined. Leukocytosis and neutrophilia were defined as a leukocyte count or a neutrophils count exceeding 10,000 and 7,500/µl, respectively. CONCLUSIONS: Neutrophilia is a significant prognostic factor for local relapse in locally advanced cervical cancer treated with MRI-based IGABT. This biomarker could help identifying patients with higher risk of local relapse and requiring dose escalation.

Mobile technology and social media in the clinical practice of young radiation oncologists: results of a comprehensive nationwide cross-sectional study.

PURPOSE: Social media and mobile technology are transforming the way in which young physicians are learning and practicing medicine. The true impact of such technologies has yet to be evaluated. METHODS AND MATERIALS: We performed a nationwide cross-sectional survey to better assess how young radiation oncologists used these technologies. An online survey was sent out between April 24, 2013, and June 1, 2013. All residents attending the 2013 radiation oncology French summer course were invited to complete the survey. Logistic regressions were performed to assess predictors of use of these tools in the hospital on various clinical endpoints. RESULTS: In all, 131 of 140 (93.6%) French young radiation oncologists answered the survey. Of these individuals, 93% owned a smartphone and 32.8% owned a tablet. The majority (78.6%) of the residents owning a smartphone used it to work in their department. A total of 33.5% had more than 5 medical applications installed. Only 60.3% of the residents verified the validity of the apps that they used. In all, 82.9% of the residents had a social network account. CONCLUSIONS: Most of the residents in radiation oncology use their smartphone to work in their department for a wide variety of tasks. However, the residents do not consistently check the validity of the apps that they use. Residents also use social networks, with only a limited impact on their relationship with their patients. Overall, this study highlights the irruption and the risks of new technologies in the clinical practice and raises the question of a possible regulation of their use in the hospital.

[Radiotherapy promises: focus on lung cancer]. / Les promesses de la radiothérapie. Focus sur les tumeurs pulmonaires.

Radiotherapy is a key cancer treatment, which greatly modified its practice in recent years thanks to medical imaging and technical improvements. The systematic use of computed tomography (CT) for treatment planning, the imaging fusion/co-registration between CT/magnetic resonance imaging (MRI) or CT/positron emission tomography (PET) improve target identification/selection and delineation. New irradiation techniques such as image-guided radiotherapy (IGRT), stereotactic radiotherapy or hadron therapy offer a more diverse therapeutic armamentarium to patients together with lower toxicity. Radiotherapy, as well as medical oncology, tends to offer a personalized treatment to patients thanks to the IGRT, which takes into account the inter- or intra-fraction anatomic variations. IGRT leads to adaptive radiotherapy (ART) with a new planification in the treatment course in order to decrease toxicity and improve tumor control. The use of systemic therapies with radiations needs to be studied in order to improve efficiency without increasing toxicities from these multimodal approaches. Finally, radiotherapy advances were impacted by radiotherapy accidents like Epinal. They led to an increased quality control with the intensification of identity control, the emergence of in vivo dosimetry or the experience feedback committee in radiotherapy. We will illustrate through the example of lung cancer.

Extracranial stereotactic body radiotherapy. Review of main SBRT features and indications in primary tumors.

AIM: Review of main SBRT features and indications in primary tumors. BACKGROUND: Stereotactic body radiotherapy has been developed in the last few years. SBRT allows the hypofractionated treatment of extra cranial tumors, using either a single or limited number of dose fractions, and resulting in the delivery of a high biological effective dose with low toxicity. MATERIAL AND METHODS: SBRT REQUIRES A HIGH LEVEL OF ACCURACY FOR ALL PHASES OF THE TREATMENT PROCESS: effective patient immobilization, precise target localization, highly conformed dosimetry and image guided systems for treatment verification. The implementation of SBRT in routine requires a careful considering of organ motion. Gating and tracking are effective ways to do so, and less invasive technologies "fiducials free" have been developed. Due to the hypofractionated scheme, the physician must pay attention to new dosimetric constraints in organ at risk and new radiobiological models are needed to assess the optimal fractionation and dose schemes. RESULTS: Currently, SBRT is safe and effective to treat primary tumors, which are otherwise untreatable with conventional radiotherapy or surgery. SBRT has quickly developed because of its excellent results in terms of tolerance and its high locoregional control rates. SBRT indications in primary tumors, such as lung primary tumors, have become a standard of care for inoperable patients. SBRT seems to be effective in many others indications in curative or palliative intent such as liver primary tumors, and novel indications and strategies are currently emerging in prostate cancer, head and neck tumor recurrences or pelvis reirradiations. CONCLUSION: Currently, SBRT is mainly used when there is no other therapeutic alternative for the patient. This is due to the lack of randomized trials in these settings. However, the results shown in retrospective studies let us hope to impose SBRT as a new standard of care for many patients in the next few years.

The French Society of Young Radiation Oncologists: History, goals and perspective.

The SFjRO was created ten years ago to promote radiation oncology teaching in France. Our society has now more than 120 members from all around the country. Each year, two national courses are organized where all members are invited.