Évaluation prospective de la toxicité, de la qualité de vie et de la réponse tumorale durant la première année après une curiethérapie interstitielle à l'iode 125 pour soixante quatorze patients traités pour un cancer localisé de la prostate

POITIERS-BU Médecine pharmacie (861942103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Mesure de l'évolution de la toxicité et de la qualité de vie chez des patients porteurs d'un cancer localisé de la prostate traités par radiothérapie conformationnelle (résultats préliminaires après un an de suivi prospectif)

POITIERS-BU Médecine pharmacie (861942103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Delineation of the Prostate Bed: The “Invisible Target” Is Still an Issue?

For pathological high-risk prostate cancer, adjuvant irradiation has shown a survival benefit. Phase III studies have highlighted that half men would face biochemical relapse and would be candidate for radiotherapy at adjuvant or salvage times. Despite at least four published international contouring guidelines from different collaborative groups, discrepancies remain for volumes, delineation, and margins to be considered in order to optimize radiotherapy planning. This article from “Groupe d’Etude des Tumeurs UroGénitales (GETUG)” members will focus on controversies to help clinicians to create best volume delineation for adjuvant or salvage post prostatectomy radiotherapy

Definition of lymph node areas for radiotherapy of prostate cancer: A critical literature review by the French Genito-Urinary Group and the French Association of Urology (GETUG-AFU)

International audiencePurpose Recommendations for pelvic lymph node (LN) contouring rely on relatively dated studies that defined the Clinical Target Volume (CTV) of interest proposed for radiotherapy. The aim of this article was to review these recommendations with a critical analysis of published data on prostate cancer drainage. Methods We performed a review of data on LN drainage in prostate cancer, based on anatomy texts and studies on lymphography, pelvic LN dissections, sentinel LN techniques, magnetic resonance imaging, computed tomography and functional imaging. We also present the GETUG experts’ opinion, based on a survey on nodal CTV definition. Results For lymphatic drainage of prostate cancers, pelvic LN areas classically considered are: distal common iliac, external iliac, internal iliac and obturator regions. Recently published data allow a mapping of sites at risk of pathological LN invasion. In 10–70% of cases, these sites are not included in the pelvic LN CTVs defined in consensuses. In accordance with other cooperative groups, the GETUG experts’ survey showed that proximal common iliac, para-aortic, para-rectal and pre-sacral regions could include sites at risk of invasion in extended LN CTV, but were not considered in CTV contouring common practice. New recommendations are needed for nodal CTV in radiotherapy of prostate cancer. Conclusions The assessment of the efficacy and safety of LN radiotherapy is still the subject of several randomised studies. Whether or not meaningful results are obtained depends directly on the quality and homogeneity of the data analysed. A new consensus for delineation of LN regions appears necessar

Reoxygenation during radiotherapy in intermediate-risk prostate cancer

International audienceHypoxia is a major risk factor of prostate cancer radioresistance. We evaluated hypoxia non-invasively, using 18 F-Misonidazole PET/CT prior to radiotherapy and after a dose of 20 Gy in intermediate-risk pros-tate cancer patients. Decreased hypoxic volumes were observed in all patients, suggesting that radiother-apy induces early prostate tumor reoxygenation. Hypoxia is a major factor of resistance to radiotherapy because it selects radioresistant mutant cells and reduced levels of oxygen decrease the amount of reactive oxygen species induced by irradiation [1]. In prostate cancer, hypoxic markers based on direct inva-sive measurement of oxygen levels [2,3] or hypoxia-related protein or gene expression [4,5] were shown to predict tumor aggressiveness and recurrence following irradiation. Because sampling some prostate areas using biopsies may not reflect the whole extent of hypoxia within the prostate, functional imaging of hypoxic regions may better reflect the intraprostatic heterogeneity of hypoxic regions. In two recent series of prostate cancer patients, FMISO detected a hypoxic signal in 33% to 63 % of patients [6,7], confirming results of previous smaller series [8,9]. We showed that FMISO-positive volumes were partly located both in cancerous areas and in the normal gland [6]. FMISO may therefore represent a potent non-invasive tool to map hypoxia within the whole prostate. Evaluating hypoxia using only one single image may be insufficient since hypoxia is a dynamic process and is influenced by treatment. Preclinical prostate cancer models [10] and clinical data in other tumors [11] suggest that reoxygenation frequently occurs during fractionated radiotherapy. To increase the dose to hypoxic areas in the context of a dose-painting strategy, chronic and stable hypoxia may imply the use of a simultaneous-integrated boost strategy, while intermittent or decreasing hypoxia may imply boosting hypoxic regions prior to fractionated radiotherapy [9,12]. It is therefore important to evaluate hypoxia before and during the course of radiotherapy. We hypothesized that FMISO could be used to evaluate radiotherapy-induced reoxygenation during the course of radio-therapy in intermediate-risk prostate cancer patients. Patients and methods Patient selection and treatment The study was approved by the local Ethics Committee and registered in the NCI database (NCT01898065). Inclusion criteria were NCCN-defined intermediate-risk prostate cancer patients in whom high-dose radiotherapy to the prostate without hormone therapy was indicated. Our goal was to evaluate the influence of radiother-apy on prostate cancer hypoxia. Since prostate hypoxia is affected by hormone therapy (HT), we excluded high-risk prostate cancer patients who are routinely treated with RT + HT [13]. We also excluded low-risk tumors because the need for improved radio-therapy is not striking since most patients are now on active surveillance instead of radical treatment and the tumor is often not visible on prostate MRI. Intermediate-risk prostate cancer is the most frequent and also the more heterogeneous group wit

Evaluation of tumor hypoxia prior to radiotherapy in intermediate-risk prostate cancer using [18]F-fluoromisonidazole PET/CT: a pilot study

International audiencePurpose: Hypoxia is a major factor in prostate cancer aggressiveness and radioresistance. Predicting which patients might be bad candidates for radiotherapy may help better personalize treatment decisions in intermediate-risk prostate cancer patients. We assessed spatial distribution of [18]F-Misonidazole (FMISO) PET/CT uptake in the prostate prior to radiotherapy treatment.Materials and Methods: Intermediate-risk prostate cancer patients about to receive high-dose (>74 Gy) radiotherapy to the prostate without hormonal treatment were prospectively recruited between 9/2012 and 10/2014. Prior to radiotherapy, all patients underwent a FMISO PET/CT as well as a MRI and [18]F-choline-PET. [18]F-choline and FMISO-positive volumes were semi-automatically determined using the fuzzy locally adaptive Bayesian (FLAB) method. In FMISO-positive patients, a dynamic analysis of early tumor uptake was performed. Group differences were assessed using the Wilcoxon signed rank test. Parameters were correlated using Spearman rank correlation.Results: Of 27 patients (median age 76) recruited to the study, 7 and 9 patients were considered positive at 2.5h and 3.5h FMISO PET/CT respectively. Median SUV[max] and SUV[max] tumor to muscle (T/M) ratio were respectively 3.4 and 3.6 at 2.5h, and 3.2 and 4.4 at 3.5h. The median FMISO-positive volume was 1.1 ml.Conclusions: This is the first study regarding hypoxia imaging using FMISO in prostate cancer showing that a small FMISO-positive volume was detected in one third of intermediate-risk prostate cancer patients

Short-term androgen deprivation therapy combined with radiotherapy as salvage treatment after radical prostatectomy for prostate cancer (GETUG-AFU 16): a 112-month follow-up of a phase 3, randomised trial

International audienc

At the crossroads of fertility and metabolism: the importance of AMPK-dependent signaling in female infertility associated with hyperandrogenism

International audienceStudy question: What biological processes are linked to the signaling of the energy sensor 5'-AMP-activated protein kinase (AMPK) in mouse and human granulosa cells (GCs)?Summary answer: The lack of α1AMPK in GCs impacted cell cycle, adhesion, lipid metabolism and induced a hyperandrogenic response.What is known already: AMPK is expressed in the ovarian follicle, and its activation by pharmacological medications, such as metformin, inhibits the production of steroids. Polycystic ovary syndrome (PCOS) is responsible for infertility in approximately 5-20% of women of childbearing age and possible treatments include reducing body weight, improving lifestyle and the administration of a combination of drugs to improve insulin resistance, such as metformin.Study design, size, duration: AMPK signaling was evaluated by analyzing differential gene expression in immortalized human granulosa cells (KGNs) with and without silencing α1AMPK using CRISPR/Cas9. In vivo studies included the use of a α1AMPK knock-out mouse model to evaluate the role of α1AMPK in folliculogenesis and fertility. Expression of α1AMPK was evaluated in primary human granulosa-luteal cells retrieved from women undergoing IVF with and without a lean PCOS phenotype (i.e. BMI: 18-25 kg/m2).Participants/materials, setting, methods: α1AMPK was disrupted in KGN cells and a transgenic mouse model. Cell viability, proliferation and metabolism were evaluated. Androgen production was evaluated by analyzing protein levels of relevant enzymes in the steroid pathway by western blots, and steroid levels obtained from in vitro and in vivo models by mass spectrometry. Differential gene expression in human GC was obtained by RNA sequencing. Analysis of in vivo murine folliculogenesis was performed by histology and immunochemistry, including evaluation of the anti-Müllerian hormone (AMH) marker. The α1AMPK gene expression was evaluated by quantitative RT-PCR in primary GCs obtained from women with the lean PCOS phenotype (n = 8) and without PCOS (n = 9).Main results and the role of chance: Silencing of α1AMPK in KGN increased cell proliferation (P < 0.05 versus control, n = 4), promoted the use of fatty acids over glucose, and induced a hyperandrogenic response resulting from upregulation of two of the enzymes involved in steroid production, namely 3β-hydroxysteroid dehydrogenase (3βHSD) and P450 side-chain cleavage enzyme (P450scc) (P < 0.05, n = 3). Female mice deficient in α1AMPK had a 30% decrease in their ovulation rate (P < 0.05, n = 7) and litter size, a hyperandrogenic response (P < 0.05, n = 7) with higher levels of 3βHSD and p450scc levels in the ovaries, and an increase in the population of antral follicles (P < 0.01, n = 10) compared to controls. Primary GCs from lean women with PCOS had lower α1AMPK mRNA expression levels than the control group (P < 0.05, n = 8-9).Large scale data: The FastQ files and metadata were submitted to the European Nucleotide Archive (ENA) at EMBL-EBI under accession number PRJEB46048.Limitations, reasons for caution: The human KGN is a not fully differentiated, transformed cell line. As such, to confirm the role of AMPK in GC and the PCOS phenotype, this model was compared to two others: an α1AMPK transgenic mouse model and primary differentiated granulosa-lutein cells from non-obese women undergoing IVF (with and without PCOS). A clear limitation is the small number of patients with PCOS utilized in this study and that the collection of human GCs was performed after hormonal stimulation.Wider implications of the findings: Our results reveal that AMPK is directly involved in steroid production in human GCs. In addition, AMPK signaling was associated with other processes frequently reported as dysfunctional in PCOS models, such as cell adhesion, lipid metabolism and inflammation. Silencing of α1AMPK in KGN promoted folliculogenesis, with increases in AMH. Evaluating the expression of the α1AMPK subunit could be considered as a marker of interest in infertility cases related to hormonal imbalances and metabolic disorders, including PCOS.Study funding/competing interest(s): This study was financially supported by the Institut National de la Recherche Agronomique (INRA) and the national programme « FERTiNERGY » funded by the French National Research Agency (ANR). The authors report no intellectual or financial conflicts of interest related to this work. R.K. is identified as personnel of the International Agency for Research on Cancer/World Health Organization. R.K. alone is responsible for the views expressed in this article and she does not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization.Trial registration number: N/A

Nomograms to predict late urinary toxicity after prostate cancer radiotherapy.

International audienceOBJECTIVE: To analyze late urinary toxicity after prostate cancer radiotherapy (RT): symptom description and identification of patient characteristics or treatment parameters allowing for the generation of nomograms. METHODS: Nine hundred and sixty-five patients underwent RT in seventeen French centers for localized prostate cancer. Median total dose was 70 Gy (range, 65-80 Gy), using different fractionations (2 or 2.5 Gy/day) and techniques. Late urinary toxicity and the corresponding symptoms (urinary frequency, incontinence, dysuria/decreased stream, and hematuria) were prospectively assessed in half of the patients using the LENT-SOMA classification. Univariate and multivariate Cox regression models addressed patient or treatment-related predictors of late urinary toxicity (≥grade 2). Nomograms were built up, and their performance was assessed. RESULTS: The median follow-up was 61 months. The 5-year (≥grade 2) global urinary toxicity, urinary frequency, hematuria, dysuria, and urinary incontinence rates were 15, 10, 5, 3 and 1 %, respectively. The 5-year (≥grade 3) urinary toxicity rate was 3 %. The following parameters significantly increased the 5-year risk of global urinary toxicity (≥grade 2): anticoagulant treatment (RR = 2.35), total dose (RR = 1.09), and age (RR = 1.06). Urinary frequency was increased by the total dose (RR = 1.07) and diabetes (RR = 4). Hematuria was increased by anticoagulant treatment (RR = 2.9). Dysuria was increased by the total dose (RR = 1.1). Corresponding nomograms and their calibration plots were generated. Nomogram performance should be validated with external data. CONCLUSIONS: The first nomograms to predict late urinary toxicity but also specific urinary symptoms after prostate RT were generated, contributing to prostate cancer treatment decision