This review examines the development and efficacy of novel treatment options for advanced prostate cancer and discusses novel therapies that are on the horizon. Since the introduction of docetaxel as ...the standard treatment for patients with metastatic castration-resistant prostate cancer (CRPC), a number of different agents have been tested but failed to demonstrate improvement in overall survival (OS). Recently, three novel compounds have demonstrated OS benefit and one other showed reduction in skeletal-related events (SREs). Sipuleucel-T, a novel vaccine, was approved by the US regulatory authorities in April 2010 for patients with early advanced prostate cancer. A new taxane, cabazitaxel, and abiraterone acetate, an androgen biosynthesis inhibitor, have shown an OS benefit in advanced CRPC after docetaxel, leading to drug approval. A new bone-targeting agent, denosumab, a receptor activator of nuclear factor κB ligand (RANKL) antagonist, showed a modest reduction in SREs in comparison to zoledronic acid in patients with bone metastases. Other promising novel agents are currently being tested in the clinical setting of advanced CRPC. These include, androgen receptor inhibitors (MDV3100), androgen biosynthesis inhibitors, angiogenesis inhibitors (thalidomide, lenalidomine, aflibercept, tasquinimod), a novel form of radiotherapy (radium-223), and immune-modulating compounds (PROSTVAC-VF). Improvements in progression-free survival and OS rates, observed with novel agents, in metastatic prostate cancer have led to a shift in treatment paradigm. The challenge will be to position the current established and expected novel treatments in the new landscape of metastatic prostate cancer and to determine at what point and time in the disease course they can best be administered.
Abstract
Background. There are no validated markers that predict outcome in metastatic renal cell cancer (mRCC) patients treated with sunitinib. Recently, single nucleotide polymorphism (SNP) ...rs9582036 in VEGFR1 has been proposed as a predictor of progression-free survival (PFS) and overall survival (OS) to bevacizumab in patients with pancreatic cancer and rs7993418 in VEGFR1 as predictor for PFS in mRCC-patients treated with bevacizumab. Here, we aim to study the impact of these SNPs in mRCC patients treated with sunitinib. Methods. We included patients with mRCC treated in 15 institutions in France and Belgium. Patients received sunitinib as first-line targeted therapy. We assessed response, time-to-tumor progression (TTP), OS, and clinical and biochemical parameters associated with outcome. We genotyped rs9582036 and rs7993418 as well as three other surrounding SNPs in VEGFR1: rs9554320, rs9554316 and rs9513070. Association between SNPs and treatment outcome were studied by univariate analysis and by multivariate Cox regression using relevant clinical factors associated with TTP and OS as covariates. Findings. Ninety-one patients were included. We found that mRCC patients with the CC-variant in rs9582036 in VEGFR1 have a poorer response rate (RR) (0% vs. 46%, p = 0.028), a poorer PFS (10 vs. 18 months, p = 0.033 on univariate and 0.06 on multivariate analysis) and a poorer OS (14 vs. 31 months, p = 0.019 on univariate and 0.008 on multivariate analysis) compared to patients with the AC- and AA-genotypes. mRCC patients with the AA-variant in rs9554320 in VEGFR1 have a poorer PFS (12 vs. 21 months, p = 0.0066 on univariate and 0.005 on multivariate analysis) and a poorer OS (22 vs. 34 months, p = 0.019 on univariate and 0.067 on multivariate analysis) compared to patients with the AC- and CC-genotypes. Interpretation. mRCC patients with the CC-genotype in VEGFR1 SNP rs9582036 have a poorer response rate, PFS and OS when treated with sunitinib. These findings are in agreement with the association of rs9582036 and outcome observed in bevacizumab treated pancreatic cancer patients. Prospective validation of this SNP is warranted.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Survival in patients with urothelial cancer (UC) recurrence after initial treatment with curative intent is limited and treatment options are sparse. Metastasectomy could be considered a treatment ...option in selected cases. Identifying prognostic factors for survival can be used to counsel patients and aid multidisciplinary teams in making treatment decisions.
We collected a retrospective case series of patients undergoing metastasectomy for oligometastatic UC between 1999 and 2018 at University Hospitals Leuven. Oligometastatic UC was defined as recurrence of UC in a single organ with ≤3 metastases. Survival outcomes of interest were: overall survival (OS), cancer-specific survival (CSS), and secondary recurrence-free survival (RFS2). Complications were reported using the Clavien-Dindo classification (CDC). Survival analysis are descriptive and were performed using Kaplan-Meier plots to visualize survival data and log-rank was used to compare survival between groups.
From 1999 to 2018, a total of 22 patients underwent metastasectomy of oligometastatic UC. Metastasectomy sites were: pulmonary (59.1%), loco-regional (13.6%), hepatic (9.1%), adrenal (4.5%), testicular (4.5%), nodal above aortic bifurcation (4.5%), and renal transplant (4.5%). The 5-year OS, CSS and RFS2 after metastasectomy were 51.4%, 57.0%, and 49.9%, respectively. Patients with primary upper tract urothelial cancer (UTUC) involvement and patients treated with hepatic metastasectomy had a significantly worse OS, CSS, and RFS2. Patients with a lesion size >8 mm and patients with >1 pulmonary lesion had a significantly worse CSS. Two CDC grade 3B occurred during follow-up and were both non-procedure related.
Metastasectomy of oligometastatic UC is feasible and can achieve durable cancer control in a highly selected subgroup of patients. Our results suggest that patients with hepatic metastases or primary UTUC involvement could be considered poor candidates for metastasectomy, while patients with a small (<8 mm) or solitary pulmonary lesion might benefit most. These findings should be validated in multi-institutional collaborations or prospective clinical studies.
Abstract Background The occurrence of positive surgical margins (PSMs) after partial nephrectomy (PN) is rare, and little is known about their natural history. Objective To identify predictive ...factors of cancer recurrence and related death in patients having a PSM following PN. Design, setting, and participants Some 111 patients with a PSM were identified from a multicentre retrospective survey and were compared with 664 negative surgical margin (NSM) patients. A second cohort of NSM patients was created by matching NSM to PSM for indication, tumour size, and tumour grade. Measurements PSM and NSM patients were compared using student t tests and chi-square tests on independent samples. A Cox proportional hazards regression model was used to test the independent effects of clinical and pathologic variables on survival. Results and limitations Mean age at diagnosis was 61 ± 12.5 yr. Mean tumour size was 3.5 ± 2 cm. Imperative indications accounted for 39% (43 of 111) of the cases. Some 18 patients (16%) underwent a second surgery (partial or total nephrectomy). With a mean follow-up of 37 mo, 11 patients (10%) had recurrences and 12 patients (11%) died, including 6 patients (5.4%) who died of cancer progression. Some 91% (10 of 11) of the patients who had recurrences and 83% of the patients (10 of 12) who died belonged to the group with imperative surgical indications. Rates of recurrence-free survival, of cancer-specific survival, and of overall survival were the same among NSM patients and PSM patients. The multivariable Cox model showed that the two variables that could predict recurrence were the indication ( p = 0.017) and tumour location ( p = 0.02). No other variable, including PSM status, had any effect on recurrence. None of the studied parameters had any effect on the rate of cancer-specific survival. Conclusions PSM status occurs more frequently in cases in which surgery is imperative and is associated with an increased risk of recurrence, but PSM status does not appear to influence cancer-specific survival. Additional follow-up is needed.
The benefit of surgical metastasectomy (SM) for patients with metastatic renal cell carcinoma (mRCC) remains controversial because of the lack of high-level evidence on the role of SM in terms of ...survival benefit in the era of systemic therapy.
To perform a systematic review of the literature on the role of SM in the treatment of mRCC and discuss key issues in the SM decision-making process.
A systematic search of the Embase and Medline databases was carried out and a systematic review of the role of SM in mRCC was performed. A total of 56 studies were finally included in the evidence synthesis.
All the studies included were retrospective and mostly noncomparative. Median overall survival (OS) ranged from 36 to 142mo for those undergoing SM, compared to 8–27mo for no SM. SM was associated with a lower risk of all-cause mortality compared to no SM (pooled adjusted hazard ratio 2.37, 95% confidence interval 2.03–2.87; p<0.001). Morbidity and mortality were similar for SM and primary tumor surgery. The most important prognostic factor for OS was complete resection of metastases. Other prognostic factors included disease free-survival from nephrectomy, primary tumor features (T stage ≥3, high grade, sarcomatoid features, and pathological nodal status), the number of metastases, and performance status. Lung metastasectomy seemed to show the best survival benefit.
Although no randomized clinical data are available, published studies support the role of SM in selected patients in the modern era. Complete SM allows sustained survival free of systemic treatment. Integration of SM and systemic therapy in a multimodal approach remains a valid option for some patients.
Surgical resection of metastases originating from renal cell carcinoma may play a role in prolonging survival and avoiding systemic therapy when complete resection is achievable. This strategy is an option for selected patients with a limited number of metastases who still have good general health status.
Surgical metastasectomy in renal cell carcinoma has potential benefits. It offers prolonged survival in a subgroup of patients with slowly growing disease and allows survival free from medical treatment, thus avoiding treatment-related toxicities. Complete resection is the primary goal in all patients. However, relief of metastases-related symptoms is also an indication for the procedure. Features identifying the best candidates for metastasectomy include achievable complete resection, good performance status, a long disease-free interval (from nephrectomy), and limited metastatic sites, ideally in the lungs. In all cases, the decision should be individualized and closely discussed within dedicated multidisciplinary cancer centers.
Background and objective
While decision support tools such as decision aids can contribute to shared decision making, implementing these tools in daily practice is challenging. To identify and ...address issues around the use of decision support tools in routine care, this study explores the views of men and general practitioners on using a DA for early detection of prostate cancer.
Methods, setting and participants
Group discussions and semi‐structured interviews were carried out with 43 men and 16 general practitioners familiar with a previously developed decision aid. Data were analysed using qualitative description.
Results
Views on using the decision support tool could be classified into four categories: no need for decision making, need for support, perceived benefit and practical barriers. For each category, several underlying themes could be identified that reflect the absence or presence of prerequisites to successful decision support delivery.
Discussion and conclusion
While men and general practitioners generally have positive attitudes to shared decision making, for both parties attitudes such as not agreeing that there is a decision to be made and doubts on the beneficence of using DAs were identified as factors that may hinder the use of a DA in clinical practice. Participants formulated strategies to support the use of DAs, mainly supplementing DAs with short tools and investing in both training programmes and large‐scale awareness raising of the general public.
Purpose We identified microRNA driven mechanisms in clear cell renal cell carcinoma associated with the tumor response to the multitargeted receptor tyrosine kinase inhibitor sunitinib. Materials and ...Methods We performed screening genome-wide microRNA real-time quantitative polymerase chain reaction on 20 freshly frozen clear cell renal cell carcinoma tissue samples of patients who received sunitinib as first line targeted therapy. Nine patients with progressive disease within 6 months after initiating therapy were considered poor responders and 11 with at least 1-year progression-free survival were considered good responders. We studied microRNA-141 function in vitro by stable up-regulation of microRNA-141, quantification of target gene expression and cell viability in normoxic and hypoxic conditions. Relative expression in clinical and cell line samples was determined by real-time quantitative polymerase chain reaction. Localization of microRNA-141 and its targets was assessed by microRNA in situ hybridization and immunohistochemistry. Hypoxia induced cytotoxicity was assessed by a luminescence adenosine triphosphate detection assay. Results Compared to good responders, microRNA-141 was significantly down-regulated in tumors of poor responders to sunitinib. This seemed spatially linked to epithelial-to-mesenchymal transition in vivo. Reintroduction of microRNA-141 in vitro reversed epithelial-to-mesenchymal transition and decreased cell viability in hypoxic conditions. Conclusions In our study microRNA-141 down-regulation driven epithelial-to-mesenchymal transition in clear cell renal cell carcinoma was linked to an unfavorable response to sunitinib therapy. Reintroduction of microRNA-141 in vitro led to epithelial-to-mesenchymal transition reversal and increased sensibility to a hypoxic environment. Future experiments should be done in vivo to see whether microRNA-141 driven reversal of epithelial-to-mesenchymal transition could affect the efficacy of sunitinib treatment.
Luteinizing hormone‐releasing hormone (LHRH) agonists and antagonists are commonly used androgen deprivation therapies prescribed for patients with advanced prostate cancer (PCa). Both types of agent ...target the receptor for LHRH but differ in their mode of action: agonists, via pituitary LRHR receptors (LHRH‐Rs), cause an initial surge in luteinizing hormone (LH), follicle‐stimulating hormone (FSH) and, subsequently, testosterone. Continued overstimulation of LHRH‐R down‐regulates the production of LH and leads to castrate levels of testosterone. LHRH antagonists, however, block LHRH‐R signalling causing a rapid and sustained inhibition of testosterone, LH and FSH. The discovery and validation of the presence of functional LHRH‐R in the prostate has led to much work investigating the role of LHRH signalling in the normal prostate as well as in the treatment of PCa with LHRH agonists and antagonists. In this review we discuss the expression and function of LHRH‐R, as well as LH/human chorionic gonadotropin receptors and FSH receptors and relate this to the differential clinical responses to agonists and antagonists used in the hormonal manipulation of PCa.
Abstract Background and purpose In men with adverse pathology at the time of radical prostatectomy (RP), the most appropriate timing to administer radiotherapy (RT) remains a subject for debate. To ...determine whether salvage radiotherapy (SRT) upon early prostate-specific antigen (PSA) relapse is equivalent to immediate adjuvant radiotherapy (ART) post RP. Material and methods 130 patients receiving ART and 89 receiving SRT were identified. All had an undetectable PSA after RP. Homogeneous subgroups were built based on the status (±) of lymphatic invasion (LVI) and surgical margins (SM), to allow a comparison of ART and SRT. Biochemical disease-free survival (bDFS) was calculated from the date of surgery and from the end of RT. The multivariate analysis was performed using the Cox Proportional hazard model. Results In the SM−/LVI− and SM+/LVI− groups, SRT was a significant predictor of a decreased bDFS from the date of surgery, while in the SM+/LVI+ group, there was a trend towards significance. From the end of RT, SRT was also a significant predictor of a decreased bDFS in three patient groups: SM−/LVI−, SM+/LVI− and SM+/LVI+. Gleason score >7 showed to be another factor on multivariate analysis associated with decreased bDFS in the SM−/LVI− group, from the date of surgery and end of RT. Preoperative PSA was a significant predictor in the SM−/LVI− group from the date of RP only. Conclusions Immediate ART post RP for patients with high risk features in the prostatectomy specimen significantly reduces bDFS after RP compared with early SRT upon PSA relapse.
Abstract Background Urinary prostate cancer gene 3 ( PCA3 ) represents a promising novel marker of prostate cancer detection. Objective To test whether urinary PCA3 assay improves prostate cancer ...(PCa) risk assessment and to construct a decision-making aid in a multi-institutional cohort with pre–prostate biopsy data. Design, setting, and participants PCA3 assay cut-off threshold analyses were followed by logistic regression models which used established predictors to assess PCa-risk at biopsy in a large multi-institutional data set of 809 men at risk of harboring PCa. Measurements Regression coefficients were used to construct four sets of nomograms. Predictive accuracy (PA) estimates of biopsy outcome predictions were quantified using the area under the curve of the receiver operator characteristic analysis in models with and without PCA3 . Bootstrap resamples were used for internal validation and to reduce overfit bias. The extent of overestimation or underestimation of the observed PCa rate at biopsy was explored graphically using nonparametric loss-calibration plots. Differences in PA were tested using the Mantel-Haenszel test. Finally, nomogram-derived probability cut-offs were tested to assess the ability to identify patients with or without PCa. Results and limitations PCA3 was identified as a statistically independent risk factor of PCa at biopsy. Addition of a PCA3 assay improved bootstrap-corrected multivariate PA of the base model between 2% and 5%. The highest increment in PA resulted from a PCA3 assay cut-off threshold of 17, where a 5% gain in PA (from 0.68 to 0.73, p = 0.04) was recorded. Nomogram probability–derived risk cut-off analyses further corroborate the superiority of the PCA3 nomogram over the base model. Conclusions PCA3 fulfills the criteria for a novel marker capable of increasing PA of multivariate biopsy models. This novel PCA3 -based nomogram better identifies men at risk of harboring PCa and assists in deciding whether further evaluation is necessary.
PDF
