Targeted Inhibition of CYP11A1 in Castration-Resistant Prostate Cancer

Targeted Inhibition of CYP11A1 in Prostate CancerIn this single-arm, multicenter, combined phase 1 and phase 2 study, patients with metastatic prostate adenocarcinoma with progression on prior androgen receptor pathway inhibitors and taxane-based chemotherapy were treated with ODM-208. A decrease in prostate-specific antigen levels of 50% or more occurred in 16/42 (38.1%) and 24/45 (53.3%) in phase 1 and 2 respectively. Responses mainly occurred in patients with androgen receptor mutations. Adrenal insufficiency was the dose-limiting toxicity.</p

Niraparib and Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer

PURPOSE: Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with current standard-of-care therapies. Homologous recombination repair (HRR) gene alterations, including BRCA1/2 alterations, can sensitize cancer cells to poly (ADP-ribose) polymerase inhibition, which may improve outcomes in treatment-naïve mCRPC when combined with androgen receptor signaling inhibition. METHODS: MAGNITUDE (ClinicalTrials.gov identifier: NCT03748641) is a phase III, randomized, double-blinded study that evaluates niraparib and abiraterone acetate plus prednisone (niraparib + AAP) in patients with (HRR+, n = 423) or without (HRR-, n = 247) HRR-associated gene alterations, as prospectively determined by tissue/plasma-based assays. Patients were assigned 1:1 to receive niraparib + AAP or placebo + AAP. The primary end point, radiographic progression-free survival (rPFS) assessed by central review, was evaluated first in the BRCA1/2 subgroup and then in the full HRR+ cohort, with secondary end points analyzed for the full HRR+ cohort if rPFS was statistically significant. A futility analysis was preplanned in the HRR- cohort. RESULTS: Median rPFS in the BRCA1/2 subgroup was significantly longer in the niraparib + AAP group compared with the placebo + AAP group (16.6 v 10.9 months; hazard ratio [HR], 0.53; 95% CI, 0.36 to 0.79; P = .001). In the overall HRR+ cohort, rPFS was significantly longer in the niraparib + AAP group compared with the placebo + AAP group (16.5 v 13.7 months; HR, 0.73; 95% CI, 0.56 to 0.96; P = .022). These findings were supported by improvement in the secondary end points of time to symptomatic progression and time to initiation of cytotoxic chemotherapy. In the HRR- cohort, futility was declared per the prespecified criteria. Treatment with niraparib + AAP was tolerable, with anemia and hypertension as the most reported grade ≥ 3 adverse events. CONCLUSION: Combination treatment with niraparib + AAP significantly lengthened rPFS in patients with HRR+ mCRPC compared with standard-of-care AAP

Evaluation des facteurs pronostiques de la survie chez des patients traités par chimiothérapie pour une tumeur urothéliale avancée (la réponse précoce est-elle importante ?)

INTRODUCTION : Nous avons proposé d'établir de manière rétrospective les facteurs pronostiques de survie et particulièrement la réponse objective (RO) précoce, dans une population traitée par une chimiothérapie première pour une tumeur urothéliale avancée (métastatique ou localement évoluée). MATERIEL ET METHODE : Il s'agit d'une étude rétrospective, effectuée sur l'Institut Bergonié incluant les patients traités entre juillet 2003 et octobre 2007. Les données concernant les caractéristiques épidémiologiques, la RO et la toxicité au traitement ont été collectées. Nous avons recueilli les facteurs pronostiques décrits dans la littérature. Puis nous avons testé leur impact pronostique, en analyse univariée, puis multivariée pour ceux qui étaient signifcatifs (p < 0,05). Nous avons secondairement analysé les facteurs prédictifs de RO précoce et décrit les caractéristiques des "longs survivants". RESULTATS : Sur un total de 87 patients, 7 ont été exclus de l'analyse de survie, puis 6 de l'analyse des facteurs pronostiques, puis 4 de l'analyse des facteurs prédictifs. 13 facteurs ont été retrouvés en analyse univariée, 5 en analyse multivariée dont la RO précoce. Deux facteurs prédictifs (âge et métastases osseuses) ont été mis en évidence. Une seule réponse complète était rapportée dans les "longs survivants". DISCUSSION : L'étude est "positive" mais les résultats sont à généraliser avec prudence (critères de sélection plus larges, petit effectif, étude rétrospective) ; néanmoins la RO précoce comme facteur pronostique peut contribuer à l'élaboration de nouveaux algorythmes décisionnels, notamment appliqués aux chimiothérapies séquentielles.BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Staged Radiofrequency Ablation and Surgical Resection for Multiple Lung Metastases of Germ Cell Tumors

Purpose: To evaluate the morbidity and efficacy of percutaneous radiofrequency ablation (RFA) performed before surgical resection for multiple residual lung metastases of germ cell tumors with negative tumor markers. Materials and Methods: This Review Board-approved retrospective study was carried out on five consecutive patients (mean age: 31 years, range: 22–41) treated successively with percutaneous RFA and surgery for multiple lung metastases of germ cell tumors. Mean number of lung metastases before treatment was 9.4. Staged procedures were performed on an average of 7.2 months (range: 1–16) after the primitive tumor resection. Results: The median clinical and imaging follow-up was 26 months (range: 24–36). Percutaneous RFA was technically feasible in one session under general anesthesia and CT guidance in all cases. On average, 2.8 tumors were ablated per patient (range: 1–6), and three of five procedures were bilateral. Three patients developed pneumothorax requiring drainage, but no severe complications were reported. Mean time between RFA and surgical resection of residual tumors was 2.5 months (range: 1–5). No local recurrences were noted, but one patient died due to metastatic evolution. Conclusion: Staged percutaneous RFA and surgical resection could be efficient with low morbidity for the management of multiple lung metastases of germ cell tumors

Early objective response may not be a prognostic factor of survival for patients with metastatic urothelial carcinoma: from a retrospective analysis of a cohort of 113 patients

International audienceBackground: This study aims to better define prognostic factors for patients with metastatic urothelial carcinoma (mUC), and to identify patients who will benefit from first-line cisplatin-based chemotherapy. We test the hypothesis that early objective response (EOR), defined as the occurrence of an objective response following 2 or 3 courses of chemotherapy, could be a prognostic factor for overall survival (OS) and thus be used to guide treatment decisions. Data from 113 patients with evaluable mUC receiving first-line cisplatin-based treatment between January 2004 and December 2006 was collected retrospectively from prospectively-maintained databases across seven French cancer centers. Clinical factors potentially associated with survival and EOR were analyzed in univariate and multivariate analysis. Results: One hundred three patient records were complete and available for inclusion in the multivariate model. Four factors were independently associated with OS: Performance status 1 and 2 (HR 2.3 [95 % CI 1.3–3.9], p = 0.002; HR 3.4 [95 % CI 1.6–7.2], p = 0.001 respectively); presence of visceral metastases (HR 2.2 [95 % CI 1.3–3.9], p = 0.004); abnormal hemoglobin levels (HR 1.7 [95 % CI 1.01–2.8], p = 0.045); disease progression (HR 10.1 [95 % CI 4.2–24.1], p < 0.001)

Diagnostic accuracy and clinical impact of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) in Positron Emission Tomography - Computed Tomography (PET-CT)-positive mediastinal lymphadenopathies in subjects with thoracic or extra-thoracic malignancy

BACKGROUND: The high sensitivity of PET-CT can identify hypermetabolic mediastinal adenopathies during cancer management, but specificity is low and a biopsy is sometimes required to eliminate benign adenopathies. METHODS: This prospective diagnostic accuracy study included patients with hypermetabolic mediastinal lymphadenopathies revealed on PET-CT, during either the initial management of a cancer, treatment evaluation, or monitoring. All patients underwent EUS-FNA. Diagnose of malignancy based on cytological analysis following EUS-FNA were compared with clinical and radiological follow-up informations. Treatment strategy decided before the results of the EUS-FNA pathology reports (Multidisciplinary Team Meeting [MTM-1]) was recorded and compared to the treatment strategy decided once pathological data from EUS-FNA were available (MTM-2). MAIN FINDINGS: Between 2013 and 2018, 75 patients were included with 47 eligible and evaluable patients. The sensitivity, specificity, and positive and negative predictive values of EUS-FNA were 93%, 100%, 100% and 90%, respectively. The concordance value between the therapeutic strategies determined for MTM-1 and MTM-2 was 44.7%. There were no significant differences in the intensity of fixation on PET-CT between malignant and benign lesions. CONCLUSION: The diagnostic accuracy of the minimally invasive EUS-FNA procedure is sufficiently robust to avoid surgical diagnosis. The combination of PET-CT and EUS-FNA may alter the therapeutic strategy that would be considered after PET-CT alone. REGISTRATION: NCT01892501

Safety and efficacy of temsirolimus as second line treatment for patients with recurrent bladder cancer

International audienceBACKGROUND:Bladder cancer is the 7th cause of death from cancer in men and 10th in women. Metastatic patients have a poor prognosis with a median overall survival of 14 months. Until recently, vinflunine was the only second-line chemotherapy available for patients who relapse. Deregulation of the PI3K/AKT/mTOR pathway was observed in more than 40% of bladder tumors and suggested the use of mTOR as a target for the treatment of urothelial cancers.METHODS:This trial assessed the efficacy of temsirolimus in a homogenous cohort of patients with recurrent or metastatic bladder cancer following first-line chemotherapy. Efficacy was measured in terms of non-progression at two months according to the RECIST v1.1 criteria. Based on a two-stage optimal Simon's design, 15 non-progressions out of 51 evaluable patients were required to claim efficacy. Patients were treated at a weekly dose of 25 mg IV until progression, unacceptable toxicities or withdrawal.RESULTS:Among the 54 patients enrolled in the study between November 2009 and July 2014, 45 were assessable for the primary efficacy endpoint. A total of 22 (48.9%) non-progressions were observed at 2 months with 3 partial responses and 19 stable diseases. Remarkably, 4 patients were treated for more than 30 weeks. Fifty patients experienced at least a related grade1/2 (94%) and twenty-eight patients (52.8%) a related grade 3/4 adverse event. Eleven patients had to stop treatment for toxicity. This led to recruitment being halted by an independent data monitoring committee with regard to the risk-benefit balance and the fact that the primary objective was already met.CONCLUSIONS:While the positivity of this trial indicates a potential benefit of temsirolimus for a subset of bladder cancer patients who are refractory to first line platinum-based chemotherapy, the risk of adverse events associated with the use of this mTOR inhibitor would need to be considered when such an option is envisaged in this frail population of patients. It also remains to identify patients who will benefit the most from this targeted therapy.TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT01827943 (trial registration date: October 29, 2012); Retrospectively registered