[Show abstract][Hide abstract] ABSTRACT: Estimations of survival rates are diverse and the choice of the appropriate method depends on the context. Given the increasing interest in multiple imputation methods, we explored the interest of a multiple imputation approach in the estimation of cause-specific survival, when a subset of causes of death was observed.
By using European Randomized Study of Screening for Prostate Cancer (ERSPC), 20 multiply imputed datasets were created and analyzed with a Multivariate Imputation by Chained Equation (MICE) algorithm. Then, cause-specific survival was estimated on each dataset with two methods: Kaplan-Meier and competing risks. The two pooled cause-specific survival and confidence intervals were obtained using Rubin's rules after complementary log-log transformation. Net survival was estimated using Pohar-Perme's estimator and was compared to pooled cause-specific survival. Finally, a sensitivity analysis was performed to test the robustness of our constructed multiple imputation model.
Cause-specific survival performed better than net survival, since this latter exceeded 100 % for almost the first 2 years of follow-up and after 9 years whereas the cause-specific survival decreased slowly and than stabilized at around 94 % at 9 years. Sensibility study results were satisfactory.
On our basis of prostate cancer data, the results obtained by cause-specific survival after multiple imputation appeared to be better and more realistic than those obtained using net survival.
BMC Medical Research Methodology 12/2015; 15(1):54. DOI:10.1186/s12874-015-0048-4 · 2.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
COU-AA-301 trial has proved that abiraterone acetate (AA), a selective inhibitor of androgen biosynthesis, improved overall survival (OS) of patients with metastatic castration resistant prostate cancer (mCRPC) after a first line of docetaxel. Based on this result, a Temporary Authorization for Use (TAU) was performed between December 2010 and July 2011 to provide patients with mCRPC the opportunity to receive AA before its commercialization. The aim of this study was to evaluate safety and efficacy of AA treatment in this TAU.
Between December 2010 and July 2011, we conducted an ambispective, multicentric cohort study and investigated data from 20 centres participating to the AA TAU for patients presenting mCRPC and already treated by a first line of chemotherapy (CT). Statistical analyses of the data were performed using the Stata software v13 to identify predictive and prognostic factors.
Among the 408 patients, 306 were eligible with a follow-up at 3 years. Median OS was 37.1 months from beginning of CT and 14.6 months from AA introduction. 211 patients (69%) received ≥ 3 months of AA and 95 patients (31%) were treated less than 3 months. In the multivariate analyses, duration of AA was significantly correlated with PSA decrease at 3 months. Additionally, shorter time under AA treatment, presence of multiple sites of metastasis and previous hormonal treatment duration were three independent factors associated with poorer OS. At the time of analysis ten patients were still under treatment for more than 3 years.
Biochemical response monitored by PSA changes at 3 months is a strong predictive factor for AA treatment duration. Some high responders’ patients could beneficiate from AA for more than 3 years.
BMC Cancer 04/2015; 15(1). DOI:10.1186/s12885-015-1257-2 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Through a cross-sectional survey, we tried to assess whether practices of urologists and radiation oncologists are uniform when faced with similar clinical situations.
A self-administered questionnaire was mailed to all French urologists and radiation oncologists. Respondents were asked about their practices through 11 case scenarios. The scenarios cover most of localized prostate cancer situations and were gradually organized depending on prostate cancer progression risk and the age of the patient. The eight first scenarios address the situation of treatment-naive patients, and the last cases were about the management of patients after radical prostatectomy. Physicians were asked to choose a treatment modality for each case. The responses were first stratified according to the intention to treat: either curative-intent treatment or palliative. The curative-treatment modality chosen were afterward assessed. The responses to clinical scenarios were compared between the two specialties.
Concerning the intention to treat, practice patterns were overall consistent except in one case. Indeed, a higher rate of radiation oncologists prefer curative-intent treatment for intermediate-risk prostate cancer in aged patients: 57.4 versus 14.6 % (p < 0.001). Each medical specialist prefers the treatment that he himself delivers (p < 0.005). For intermediate-risk prostate cancer in 65-year-old patient: 96.5 % of urologists chose radical prostatectomy versus 37.7 % of radiation oncologists (p < 0.001). Fewer urologists (almost 14 %) compared to radiation oncologists (47.5 %) would prescribe adjuvant treatment after radical prostatectomy for T3a R0 prostate cancer with post-operative PSA undetectable (p < 0.001).
Significant differences were found in therapeutic approach between the two main specialties that deal with localized prostate cancer.
World Journal of Urology 03/2015; 33(11). DOI:10.1007/s00345-015-1543-2 · 2.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The development of personalized and non-invasive cancer therapies based on new targets combined with nanodevices is a major challenge in nanomedicine. In this work, the over-expression of a membrane lectin, the cation-independent mannose 6-phosphate receptor (M6PR), was specifically demonstrated in prostate cancer cell lines and tissues. To efficiently target this lectin a mannose-6-phosphate analogue was synthesized in six steps and grafted onto the surface of functionalized mesoporous silica nanoparticles (MSNs). These MSNs were used for in vitro and ex vivo photodynamic therapy to treat prostate cancer cell lines and primary cell cultures prepared from patient biopsies. The results demonstrated the efficiency of M6PR targeting for prostate cancer theranostic.
[Show abstract][Hide abstract] ABSTRACT: Urine markers have been studied extensively but there is a lack of blood prognostic markers in bladder cancer. MMP-7 is produced by stromal cells and by tumor cells and is overexpressed in a variety of epithelial and mesenchymal tumors. In this study, we assessed with an immunoassay we developed, the prognostic value of serum MMP-7 in a series of patients with advanced bladder cancer.
Serum samples were collected from 56 patients with advanced bladder cancer who were treated at the Montpellier Cancer Institute between March 2003 and December 2004. MMP-7 was quantified in serum samples by using a homogeneous sandwich fluoroimmunoassay we developed based on the time resolved amplified cryptate emission (TRACE) technology.
The median overall survival of the study population was 2.2 years (95% CI, 1.4 to 3.0) with 1- and 5-year survival rates of 73% (95% CI, 59% to 82%) and 25% (95% CI, 14% to 37%), respectively. High MMP-7 serum levels were associated with poor survival. Using a cut-off value of 11.5 ng/mL, the median overall survival was 3.0 years (95% CI, 1.5 to 5.1) for patients with MMP-7 serum level <11.5 ng/mL and 1.3 years (95% CI, 0.8 to 2.5) for patients with serum level ?11.5 ng/mL. Multivariate analysis identified high MMP-7 serum concentration as an independent prognostic factor for survival in patients with advanced bladder cancer (R?=?2.1, 95% CI, 1.1 to 4.4).
Our results show that the MMP-7 serum concentration is an independent prognostic factor in patients with locally advanced and or metastatic bladder cancer.
Clinical and Translational Medicine 10/2014; 3(1). DOI:10.1186/s40169-014-0031-4
[Show abstract][Hide abstract] ABSTRACT: Background
The European Randomised study of Screening for Prostate Cancer (ERSPC) has shown significant reductions in prostate cancer mortality after 9 years and 11 years of follow-up, but screening is controversial because of adverse events such as overdiagnosis. We provide updated results of mortality from prostate cancer with follow-up to 2010, with analyses truncated at 9, 11, and 13 years.
ERSPC is a multicentre, randomised trial with a predefined centralised database, analysis plan, and core age group (55–69 years), which assesses prostate-specific antigen (PSA) testing in eight European countries. Eligible men aged 50–74 years were identified from population registries and randomly assigned by computer generated random numbers to screening or no intervention (control). Investigators were masked to group allocation. The primary outcome was prostate cancer mortality in the core age group. Analysis was by intention to treat. We did a secondary analysis that corrected for selection bias due to non-participation. Only incidence and no mortality data at 9 years’ follow-up are reported for the French centres. This study is registered with Current Controlled Trials, number ISRCTN49127736.
With data truncated at 13 years of follow-up, 7408 prostate cancer cases were diagnosed in the intervention group and 6107 cases in the control group. The rate ratio of prostate cancer incidence between the intervention and control groups was 1·91 (95% CI 1·83–1·99) after 9 years (1·64 [1·58–1·69] including France), 1·66 (1·60–1·73) after 11 years, and 1·57 (1·51–1·62) after 13 years. The rate ratio of prostate cancer mortality was 0·85 (0·70–1·03) after 9 years, 0·78 (0·66–0·91) after 11 years, and 0·79 (0·69–0·91) at 13 years. The absolute risk reduction of death from prostate cancer at 13 years was 0·11 per 1000 person-years or 1·28 per 1000 men randomised, which is equivalent to one prostate cancer death averted per 781 (95% CI 490–1929) men invited for screening or one per 27 (17–66) additional prostate cancer detected. After adjustment for non-participation, the rate ratio of prostate cancer mortality in men screened was 0·73 (95% CI 0·61–0·88).
In this update the ERSPC confirms a substantial reduction in prostate cancer mortality attributable to testing of PSA, with a substantially increased absolute effect at 13 years compared with findings after 9 and 11 years. Despite our findings, further quantification of harms and their reduction are still considered a prerequisite for the introduction of populated-based screening.
Each centre had its own funding responsibility.
The Lancet 08/2014; 384(9959). DOI:10.1016/S0140-6736(14)60525-0 · 45.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Prostate biopsy side effects have a role in the controversy over screening for prostate cancer. We measured the precise incidence of infection after prostate biopsy and determined risk factors.
Materials and methods:
We performed a prospective, multicenter study in France from April to June 2013. All prostate biopsies done during this period were included in study. A web based questionnaire was used to identify patient characteristics, biopsy methods and postoperative infectious episodes. External audit helped ensure data completeness. The primary outcome was the post-biopsy infection rate. We determined risk factors for infectious complications using univariate and multivariate analysis.
The study included 2,718 patients, of whom 6% reported receiving antibiotics in the previous 6 months and 7.4% had a history of prostatitis. Recommended antibiotic prophylaxis consisting of 2 fluoroquinolone tablets 2 hours before examination for prostate biopsy was noted in 78.3% of cases. Post-biopsy sepsis was found in 76 subjects (2.8%). On multivariate analysis predictors of post-biopsy sepsis were noncompliance with antibiotic prophylaxis guidelines (OR 2.3, 95% CI 1.4-3.9, p = 0.001), antibiotic treatment in the previous 6 months (OR 2.1, 95% CI 1.1-3.9, p = 0.015) and a history of prostatitis (OR 1.7, 95% CI 1.2-2.4, p = 0.002).
In this study the incidence of post-prostate biopsy sepsis was 2.8% and no deaths were reported. Risk factors identified on multivariate analysis were noncompliance with antibiotic prophylaxis according to guidelines, antibiotic treatment in the previous 6 months and a history of prostatitis.
The Journal of Urology 07/2014; 193(1). DOI:10.1016/j.juro.2014.07.086 · 4.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Prostate cancer is the most common cancer in male in most Western countries, including France. Despite a significant morbidity and mortality to a lesser extent, the etiology of prostate cancer remains largely unknown. Indeed, the only well-established risk factors to date are age, ethnicity and a family history of prostate cancer. We present, here, the rationale and design of the EPIdemiological study of Prostate CAncer (EPICAP), a population-based case-control study specifically designed to investigate the role of environmental and genetic factors in prostate cancer. The EPICAP study will particularly focused on the role of circadian disruption, chronic inflammation, hormonal and metabolic factors in the occurrence of prostate cancer.
EPICAP is a population-based case-control study conducted in the departement of Herault in France. Eligible cases are all cases of prostate cancers newly diagnosed in 2012-2013 in men less than 75 years old and residing in the departement of Herault at the time of diagnosis. Controls are men of the same age as the cases and living in the departement of Herault, recruited in the general population.The sample will include a total of 1000 incident cases of prostate cancer and 1000 population-based controls over a 3-year period (2012-2014).The cases and controls are face-to-face interviewed using a standardized computed assisted questionnaire. The questions focus primarily on usual socio-demographic characteristics, personal and family medical history, lifestyle, leisure activities, residential and occupational history. Anthropometric measures and biological samples are also collected for cases and controls.
The EPICAP study aims to answer key questions in prostate cancer etiology: (1) role of circadian disruption through the study of working hours, chronotype and duration/quality of sleep, (2) role of chronic inflammation and anti-inflammatory drugs, (3) role of hormonal and metabolic factors through a detailed questionnaire, (4) role of individual genetic susceptibility of genes involved in biological pathways of interest. The EPICAP study will also allow us to study prognostic factors and tumor aggressiveness.Taken together, the EPICAP study will provide a comprehensive framework to go further in the understanding of prostate cancer occurrence and its prognosis.
BMC Cancer 02/2014; 14(1):106. DOI:10.1186/1471-2407-14-106 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The evaluation kits PSA conducted in 2004 by AFSSAPS resumed in 2012 using the same methodology to update the performance of assays available on the French market. Preference should be given to equimolar and accurate assays of PSA for uniform clinical use and correct kinetic monitoring.
[Show abstract][Hide abstract] ABSTRACT: Concomitant treatment with radiation therapy and cisplatin (CDDP) remains the gold standard for bladder preservation in the treatment of muscle-invasive bladder cancer (MIBC). We present the long-term results of a phase 1 clinical trial to assess the association of twice-weekly gemcitabine with CDDP and radiation therapy in this setting.
Patients with pT2-pT4N0M0 MIBC without hydronephrosis or diffuse carcinoma in situ were enrolled in this study. After maximal transurethral resection of the bladder tumor, patients received concomitant radiation therapy (63 Gy in 1.8 fractions) and chemotherapy (CDDP 20 mg/m²/day over 4 days every 21 days and gemcitabine twice a week). The starting dose of gemcitabine was 15 mg/m² with dose escalation to 20, 25, and 30 mg/m². The primary endpoint was the maximum tolerated dose (MTD). Secondary endpoints included toxicity and tumor control.
Fourteen patients were enrolled. Dose-limiting toxicity occurred in 2 patients treated with 30 mg/m² gemcitabine (grade 4 thrombocytopenia and severe impairment of World Health Organization performance status, respectively). Nine patients received the complete chemoradiation therapy protocol. The recommended dose of gemcitabine was 25 mg/m². The median follow-up time was 53 months, and the overall and disease-specific 5-year survival rates were 62% and 77%, respectively. Among the patients who received the complete treatment, bladder-intact survival was 76% at 5 years, and the median overall survival was 69.6 months.
This regimen was well tolerated. The gemcitabine MTD was 25 mg/m². Bladder preservation and disease control were promising. A multicenter phase 2 randomized trial is ongoing.
International journal of radiation oncology, biology, physics 12/2013; 88(4). DOI:10.1016/j.ijrobp.2013.11.016 · 4.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To assess oncologic outcomes after salvage radiotherapy (SRT) without androgen deprivation therapy (ADT) in patients with persistently detectable PSA after radical prostatectomy (RT).
Two hundred and one patients who failed to achieve an undetectable PSA received SRT without ADT. The primary endpoint was failure to SRT that was defined by clinical progression or use of second-line ADT. Clinicopathological parameters, 6-week PSA level, PSAV and pre-SRT PSA levels were assessed using time-dependent analyses.
Median postoperative 6-week PSA and pre-SRT PSA levels were 0.25 and 0.48 ng/mL, respectively. Median time between surgery and SRT was 7 months. Failure to SRT was reported in 42.8 % of cases with the need for second-line ADT in 26.9 % of cases. Pre-SRT PSA was strongly correlated with postoperative 6-week PSA (p < 0.001) but not with PSAV. The risk of SRT failure was increased by threefold in case of Gleason score 8-10 (p = 0.036) or pT3b cancer (p = 0.006). Risk group classification based on these prognostic factors improved SRT failure prediction. Survival curves confirmed that 5-year ADT-free survival rates were significantly influenced by PSAV (p = 0.002) and pre-SRT PSA (p = 0.030).
In patients with persistently detectable PSA after RP and selected for local salvage treatment, SRT offers good oncologic clinical outcomes. The most powerful pathologic predictive factors of SRT failure include a pT3b stage, a Gleason score 8 or more cancer and high PSAV and pre-SRT PSA levels. Patients having a high PSAV >0.04 ng/mL/mo would be potentially better candidates for a systemic therapy due to a high SRT failure rate.
World Journal of Urology 11/2013; 32(5). DOI:10.1007/s00345-013-1214-0 · 2.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Present national estimations of the incidence and mortality trends in urological cancers in France between 1980 and 2012.
Francim database and French Register of Cancers.
Analysis of the current data shows a regular increase of the incidence of renal cancer in men and women (7 781 cases in men and 3 792 in women in 2012). For bladder cancer, trends are divergent. There is a small reduction in incidence for men and an increase for women (9 549 cases in men and 2416 in women in 2012). Testicular cancer is still increasing slightly (2 317 incidental cases in 2012). The incidence of prostate cancer experienced a huge increase up until 2005, and thereafter it decreased sharply, though it is difficult to discern whether this drop (which was observed up until 2008) continued at the same rate after that point (56 841 incidences in 2012 based on the rates calculated for 2009).
The analyses by organ database show that there are significant variations in the incidence of urological cancers, particularly for prostate cancer, which shows that both the natural history of urological tumours and the methods of detection have an impact on incidence.
[Show abstract][Hide abstract] ABSTRACT: The sub Comittee prostate of the CCAFU established guidelines for diagnostic, treatment, evaluation and standart of care of prostate cancer.
Guidelines 2010 were updated based on systematic literature search performed by the sub-Comittee in Medline and PubMed databases to evaluate references, levels of evidence and grade of recommandation.
Pathological examination of the tissue specimens was defined specifically for Gleason score according to ISP 2005 recommandations. Prostate and pelvis RMN became the reference in terms of radiological exam. Individual and early diagnosis of prostate cancer was defined and role of PSA was precised. Active surveillance became one of the standart of care of low-risk tumors, radical prostatectomy remained one of the options for all risk group tumors, length of hormonotherapy in association with radiotherapy was precised according to the risk group. Side effects of hormonotherapy treament needed specific supervision ; hormonotherapy had no indication in case of non metastatic tumors and intermittent hormonotherapy in metastatic tumors. New hormonal drugs in pre and post chemotherapy and bone target drugs opened new therapeutics pathways.
From 2010 to 2013, standarts of care of prostate cancer were modified because of results of prospective studies and new therapeutics. They allowed precise treatments for each specific clinical situation. In the future, multidisciplinary treatments for high risk tumors, time of adjuvant treatment and sequencies of new hormonal treatment had to be defined.
[Show abstract][Hide abstract] ABSTRACT: The analytical and clinical validation of new biomarkers for the early detection of prostate is necessary. (-2)proPSA, total PSA and free PSA values are used to calculate a standardized PHI index linked to a higher probability of a positive biopsy in patients with PSA levels between 3-4 and 10 ng/L, the gray zone for prostate cancer diagnosis. The purpose of this study is to validate the analytical performance of the (-2)proPSA and to determine the predictive value of PHI for the early detection of prostate cancer. Analytical performances are correct. It is not necessary to dilute samples before analysis. The stability of (-2)proPSA is good until at least 3 hours at room temperature before centrifugation. The study of the PSAT, PSAL, (-2)proPSA and PHI values in a population of patients consulting for an early prostate cancer diagnosis shows that the index PHI is the most powerful predictive marker of cancer with an area under ROC curve of 0.70, whereas it is only 0.56 for total PSA.
[Show abstract][Hide abstract] ABSTRACT: To evaluate whether microarray analysis could find a molecular signature for pathologic staging and/or grading.
Prospective multicentric study conducted from September 2007 to May 2008 (108 bladder tumours (45 pTa, 35 pT1 and 28> pT1). Microarray analysis was performed with Agilent Technologies Human Whole Genome 4 x 44K oligonucleotide microarrays and used a method of "dual colour" type versus a reference consisting of a pool of tumours. From the lists of genes provided by the BrB Class Comparison analyses, we validated the microarray results of 38 selected differentially expressed genes by RT-QPCR in another bladder tumour cohort (n = 95).
The cluster "superficial vs invasive stage" properly classified 92.9% of invasive stages and 66.3% of superficial stages. Among the superficial tumours, the cluster analysis showed that pT1b tumours were closer to invasive stages than pT1a tumours. We also found molecular differences between low and high-grade superficial tumours. However these differences were less clear-cut than the one observed for staging.
We confirm that the histopathological classification into subgroups pTa, pT1a and pT1b may have a translation in a "molecular signature" with a continuous progression of deregulation (overexpression or repression of these genes) from superficial (pTa) to more invasive (pT1a then b) stage.
BJU International 07/2013; 113(2). DOI:10.1111/bju.12364 · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this mini-review, we focus on different strategies to bring nanotools specifically to cancer cells. We discuss about a better targeting of tumor, combining the characteristics of tumor environment, the increase in nanoparticles life time, the biomarkers overexpressed on cancer cell and different physical methods for non invasive therapies. Here we detail the necessity of a synergy between passive and active targeting for an actual specificity of cancer cells.
Current Medicinal Chemistry 01/2013; 20(15). DOI:10.2174/0929867311320150002 · 3.85 Impact Factor