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Background To determine safety and efficacy of radiofrequency ablation (RFA) for local treatment of lung metastases of renal cell carcinoma (RCC), sequenced or combined with systemic treatments. Methods Retrospectively, we studied 53 patients treated by RFA for a maximum of six lung metastases of RCC. The endpoints were local efficacy, overall (OS), disease-free (DFS), pulmonary progression-free (PPFS) and systemic treatment-free (STFS) survivals, complications graded by the CTCAE classification and factors associated with survivals. Potential factors analysed were: clinical and pathological data, tumoral staging of TNM classification, primary tumor histology, Fuhrman’s grade, age, number and size of lung metastases and extra-pulmonary metastases pre-RFA. Results One hundred metastases were treated by RFA. Median follow-up time was 61 months (interquartile range 90–34). Five-year OS was 62% (95% confidence interval (CI): 44–75). Median DFS was 9.9 months (95% CI: 6–16). PPFS at 1 and 3 years was 58.9% (95%CI: 44.1–70.9) and 35.2% (95%CI: 21.6–49.1), respectively. We observed 3% major complications (grade 3 and 4 of CTCAE classification). Local efficacy was 91%. Median STFS was 28.3 months. Thirteen patients (25%) with lung recurrence could be treated by another RFA. T3/T4 tumors had significantly worse OS, PPFS and STFS. Having two or more lung metastases increased the risk of pulmonary progression more than threefold. Conclusion Integrated to systemic treatment strategy, RFA is safe and effective for the treatment strategy of lung metastasis from RCC with good OS and long systemic treatment-free survival. RFA offers the possibility of repeat procedures, with low morbidity.

BackgroundPapillary renal cell carcinoma (pRCC) is the most common non-clear cell RCC, and associated with poor outcomes in the metastatic setting. In this study, we aimed to comprehensively evaluate the immune tumor microenvironment (TME), largely unknown, of patients with metastatic pRCC and identify potential therapeutic targets.MethodsWe performed quantitative gene expression analysis of TME using Microenvironment Cell Populations-counter (MCP-counter) methodology, on two independent cohorts of localized pRCC (n=271 and n=98). We then characterized the TME, using immunohistochemistry (n=38) and RNA-sequencing (RNA-seq) (n=30) on metastatic pRCC from the prospective AXIPAP trial cohort.ResultsUnsupervised clustering identified two “TME subtypes”, in each of the cohorts: the “immune-enriched” and the “immune-low”. Within AXIPAP trial cohort, the “immune-enriched” cluster was significantly associated with a worse prognosis according to the median overall survival to 8 months (95% CI, 6 to 29) versus 37 months (95% CI, 20 to NA, p=0.001). The two immune signatures, Teff and JAVELIN Renal 101 Immuno signature, predictive of response to immune checkpoint inhibitors (CPI) in clear cell RCC, were significantly higher in the “immune-enriched” group (adjusted p<0.05). Finally, five differentially overexpressed genes were identified, corresponding mainly to B lymphocyte populations.ConclusionFor the first time, using RNA-seq and immunohistochemistry, we have highlighted a specific immune TME subtype of metastatic pRCC, significantly more infiltrated with T and B immune population. This “immune-enriched” group appears to have a worse prognosis and could have a potential predictive value for response to immunotherapy, justifying the confirmation of these results in a cohort of metastatic pRCC treated with CPI and in combination with targeted therapies.Trial registration numberNCT02489695.

Background Healthcare pathways of patients with prostate cancer are heterogeneous and complex to apprehend using traditional descriptive statistics. Clustering and visualization methods can enhance their characterization. Methods Patients with prostate cancer in 2014 were identified in the French National Healthcare database (Système National des Données de Santé—SNDS) and their data were extracted with up to 5 years of history and 4 years of follow‐up. Fifty‐one‐specific encounters constitutive of prostate cancer management were synthesized into four macro‐variables using a clustering approach. Their values over patient follow‐ups constituted healthcare pathways. Optimal matching was applied to calculate distances between pathways. Partitioning around medoids was then used to define consistent groups across four exclusive cohorts of incident prostate cancer patients: Hormone‐sensitive (HSPC), metastatic hormone‐sensitive (mHSPC), castration‐resistant (CRPC), and metastatic castration‐resistant (mCRPC). Index plots were used to represent pathways clusters. Results The repartition of macro‐variables values—surveillance, local treatment, androgenic deprivation, and advanced treatment—appeared to be consistent with prostate cancer status. Two to five clusters of healthcare pathways were observed in each of the different cohorts, corresponding for most of them to relevant clinical patterns, although some heterogeneity remained. For instance, clustering allowed to distinguish patients undergoing active surveillance, or treated according to cancer progression risk in HSPC, and patients receiving treatment for potentially curative or palliative purposes in mHSPC and mCRPC. Conclusion Visualization methods combined with a clustering approach enabled the identification of clinically relevant patterns of prostate cancer management. Characterization of these care pathways is an essential element for the comprehension and the robust assessment of healthcare technology effectiveness. Patients with prostate cancer go through multiple heterogeneous healthcare encounters. Clustering methods were used to summarize correlated encounters in macro‐variables and reconstitute patient healthcare pathways. In the second stage, clinically relevant patterns of prostate cancer management (e.g., watchful waiting and active surveillance) were revealed by applying clustering methods to these healthcare pathways according to the patient cancer stage, highlighting the interest of this approach in real‐world research.

Introduction Primary urethral cancer (PUC) is rare, and limited data exist on optimal treatment and survival, particularly in metastatic cases. The objective of this study was to describe treatment patterns, responses and survival in a contemporary cohort. Patients and Methods Data from patients diagnosed with PUC between January 1, 2000 and December 31, 2018, were retrospectively collected from nine French tertiary centres. To enhance the statistical power of survival analysis in the metastatic stage, patients with synchronous and metachronous metastatic disease were pooled. Results We identified 71 patients (62% males, 38% females). The most common histological types were urothelial (40.0%), squamous cell (34.3%) and adenocarcinomas (14.3%). At diagnosis, 35.2% had localized disease, 49.3% had locally advanced disease and 15.5% had distant metastases. Twenty‐seven patients had a metachronous metastatic cancer. Multimodal therapy was used in 24% of localized and 57.1% of locally advanced disease. Among the 60 patients with non‐metastatic disease, median disease‐free survival (DFS) was 21.2 months. Nodal involvement was associated with worse DFS (HR: 2.03, p = 0.039), while multimodal treatment did not improve DFS (HR: 1.22, p = 0.5419). For metastatic patients, median overall survival was 15.2 months, and progression‐free survival was 6.4 months. Main study limitations were an overrepresentation of locally advanced disease and the small cohort size. Conclusions This retrospective study highlights the significant heterogeneity in terms of histology, stage at diagnosis and treatment of PUC. This study is one of the few to describe treatments and survival in metastatic PUC patients. Efforts must be made to improve survival in these patients.

BackgroundIn the phase 3 METEOR trial, cabozantinib improved progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) versus everolimus in patients with advanced renal cell carcinoma (RCC), after prior antiangiogenic therapy.MethodsOutcomes were evaluated for subgroups defined by prior therapy with sunitinib or pazopanib as the only prior VEGFR inhibitor, or prior anti-PD-1/PD-L1 therapy.ResultsFor the prior sunitinib subgroup (N = 267), median PFS for cabozantinib versus everolimus was 9.1 versus 3.7 months (HR 0.43, 95% CI 0.32–0.59), ORR was 16% versus 3%, and median OS was 21.4 versus 16.5 months (HR 0.66, 95% CI 0.47–0.93). For the prior pazopanib subgroup (N = 171), median PFS for cabozantinib versus everolimus was 7.4 versus 5.1 months (HR 0.67, 95% CI 0.45–0.99), ORR was 19% versus 4%, and median OS was 22.0 versus 17.5 months (HR 0.66, 95% CI 0.42–1.04). For prior anti-PD-1/PD-L1 therapy (N = 32), median PFS was not reached for cabozantinib versus 4.1 months for everolimus (HR 0.22, 95% CI 0.07–0.65), ORR was 22% versus 0%, and median OS was not reached versus 16.3 months (HR 0.56, 95% CI 0.21–1.52).ConclusionsCabozantinib was associated with improved clinical outcomes versus everolimus in patients with advanced RCC, irrespective of prior therapy, including checkpoint inhibitor therapy.

Background High‐dose chemotherapy (HDCT) with TI‐CE regimen is a valid option for the treatment of relapsed advanced germ cell tumors (GCT). We report a phase II trial with therapeutic drug monitoring of carboplatin for optimizing area under the curve (AUC) of this drug. Methods Patients with unfavorable relapsed GCT were treated according to TI‐CE regimen: two cycles combining paclitaxel and ifosfamide followed by three cycles of HD carboplatin plus etoposide administered on 3 days. Carboplatin dose was adapted on day 3 based on carboplatin clearance (CL) at day 1 in order to reach a target AUC of 24 mg.min/mL per cycle. The primary endpoint was the complete response (CR) rate. Results Eighty‐nine patients who received HDCT were included in the modified intent‐to‐treat (mITT) analysis. Measured mean AUC was 24.4 mg.min/mL per cycle (22.4 and 26.8 mg.min/mL for 10th and 90th percentiles). Thirty‐five (44.3%) patients achieved a CR with or without surgery of residual masses and 20 patients achieved a partial response with negative tumor markers. With a median follow‐up of 44 months (m), median PFS was 12.3 m (95% CI: 7.5–25.9) and OS was 46.3 m (95% CI: 18.6–not reached). For high‐ and very high‐risk patients, according to the International Prognostic Score at first relapse or treated after at least one salvage treatment (n = 51), 2‐year PFS rate was 41.1%. Conclusion The rates of complete and favorable responses were clinically relevant in this very poor risk population. Individual monitoring of carboplatin plasma concentration permitted to control more accurately the target AUC and avoided both underexposure and overexposure to the drug. The superiority of HDCT over standard chemotherapy as initial salvage treatment of patients with relapsed or refractory germ cell tumors remains a valid question. In the TI‐CE regimen, TDM was demonstrated to be feasible in routine practice and really allowed to control target AUC more accurately compared to previous reports, avoiding both underexposure and overexposure to carboplatin. In our study, the rate of CR observed in this population with very poor prognosis was 44.3% and increased to 69.6% of favorable responses. Based on our study and if the benefit of HDCT is proven in the TIGER trial, we suggest that the use of carboplatin TDM for dose individualization in current practice should be considered.

Background In patients with renal cell carcinoma (RCC) enrolled in the phase III KEYNOTE-564 trial (NCT03142334), disease-free survival (DFS) following nephrectomy was prolonged with use of adjuvant pembrolizumab therapy versus placebo. Patient-reported outcomes (PROs) provide an important measure of health-related quality of life (HRQoL) and can complement efficacy and safety results. Patients and Methods In KEYNOTE-564, 994 patients were randomly assigned to receive pembrolizumab 200 mg (n = 496) or placebo (n = 498) intravenously every 3 weeks for ≤17 cycles. Patients who received ≥1 dose of treatment and completed ≥1 HRQoL assessment were included in this analysis. HRQoL end points were assessed using the EORTC QLQ-C30, FKSI-DRS, and EQ VAS. Prespecified and exploratory PRO end points were mean change from baseline in EORTC QLQ-C30 GHS/QoL score, EORTC QLQ-C30 physical function subscale score, and FKSI-DRS score. Results No clinically meaningful difference in least squares mean scores for pembrolizumab versus placebo were observed at week 52 for EORTC QLQ-C30 GHS/QoL (–2.5; 95% CI –5.2 to 0.1), EORTC QLQ-C30 physical functioning (–0.87; 95% CI –2.7 to 1.0), and FKSI-DRS (–0.7; 95% CI –1.2 to –0.1). Most PRO scores remained stable or improved for the EORTC QLQ-C30 GHS/QoL (pembrolizumab, 54.3%; placebo, 67.5%), EORTC QLQ-C30 physical functioning (pembrolizumab, 64.7%; placebo, 68.8%), and FKSI-DRS (pembrolizumab, 58.2%; placebo, 66.3%). Conclusions Adjuvant treatment with pembrolizumab did not result in deterioration of HRQoL. These findings together with the safety and efficacy findings support adjuvant pembrolizumab treatment following nephrectomy. Trial Registration Clinicaltrials.gov Identifier: NCT03142334 Patient-reported outcomes provide an important measure of health-related quality of life and can complement efficacy and safety results. This article presents analyses of health-related quality of life in patients enrolled in the KEYNOTE-564 trial.

Over the past decade, major advances have been made in the treatment of advanced and metastatic renal cell carcinomas, specifically clear cell carcinomas. For many years the optimal approach was sequential; thus, monotherapies [principally tyrosine kinase inhibitors (TKIs)] targeting angiogenesis until toxicity or progressive disease developed. The rationale was the common mechanisms of action of the targeting agents and avoidance of the risk of overlapping toxicities. Immune checkpoint inhibitors (ICIs) are effective monotherapies, and combinations thereof with anti-angiogenic agents were thus later considered. Synergistic interactions were reported in vitro. Clinical efficacy was evident in three pivotal phase III trials with axitinib-pembrolizumab, cabozantinib-nivolumab, and lenvatinib-pembrolizumab combinations. Two other combinations showed interesting results but did not improve overall survival. However, the data aided our understanding of the new therapeutic approaches. A combination of the ICIs nivolumab and ipilimumab was the first to evidence better progression-free and overall survival compared to sunitinib in patients with intermediate or unfavourable prognoses as evaluated by the International mRCC Database Consortium (IMDC). Here we focus on the TKI-ICI combinations, emphasising the rationale of their use and the clinical results. To date, no biomarker facilitating the selection of an optimal treatment by disease and patient status has been reported.

Clear cell renal cell carcinoma (RCC) oncogenesis is mainly driven by VHL gene inactivation, leading to overexpression of vascular endothelial growth factor (VEGF). The use of tyrosine-kinase inhibitors (TKIs) directed against VEGF and its receptor (VEGFR) revolutionised the management of metastatic renal cancer in the 2000s. The more recent development of next-generation TKIs such as cabozantinib or lenvatinib has made it possible to bypass some of the mechanisms of resistance to first-generation anti-VEGFR TKIs. During the decade 2010–2020, the development of immune checkpoint blockade (ICB) therapies revolutionised the management of many solid cancers, including RCC, in first- and subsequent-line settings. Dual ICB or ICB plus anti-VEGFR TKI combinations are now the standard of care for patients with advanced clear cell RCC. To optimise these combination therapies while preserving patient quality of life, escalation and de-escalation strategies are being evaluated in prospective randomised trials, based on patient selection according to their prognosis risk. Finally, new therapeutic approaches, such as targeting hypoxia-inducible factor (HIF) and the development of innovative treatments using antibody-drug conjugates (ADCs), CAR-T cells, or radiopharmaceuticals, are all potential candidates to improve further patient survival.

Over the last seven years, seven targeted agents have been approved in the treatment of advanced or metastatic renal cell cancer, changing the therapeutic approach and prognosis of the disease dramatically. The latest agent with demonstrated efficacy is axitinib (Inlyta®). This new generation of tyrosine kinase agent differs from previously existing agents by its greater activity potency of inhibition of vascular endothelial growth factor-receptor (VEGFR1-3). This efficacy has been tested in phase II and III clinical trials. Axitinib is the only targeted agent that benefits from recommended titration, with intra-patient dose escalation. The toxicity profile of the drug is tolerable. This paper reviews the mechanism of action of axitinib, its metabolism, and its pharmacokinetic profile. Clinical data of efficacy and safety is also detailed. The agent has been integrated in the international therapeutic guidelines, as a standard in treatment of renal cell cancer patients, previously treated through antiangiogenic therapy.