[show abstract][hide abstract] ABSTRACT: Several large randomized controlled trials have provided evidence that neoadjuvant chemotherapy (NC) improves outcomes in patients with muscle-invasive urothelial bladder cancer (MIBC) who undergo radical cystectomy (RC). We sought to analyze the study design, methods and observations in these trials to identify patient subgroups that appeared most likely to benefit and discover distinguishing features from those groups that did not obtain improved outcomes.
We analyzed the initial and updated methods and results of the four main prospective trials of NC (SWOG, MRC, and Nordic I and II) and subsequent meta-analyses that have been the basis for advocating the use of NC in all patients with MIBC who undergo RC.
The group that demonstrated the greatest apparent benefit were those patients who were free of cancer at the time of RC (pT0). These patients had markedly improved overall and disease-specific survivals compared to those with residual disease. However, these improvements occurred regardless of whether downstaging from MIBC to pT0 was seen with transurethral resection (TUR) alone (control group) or with TUR+NC. Thus, the major benefit from NC appeared to be the greater number of patients achieving pT0 in the chemotherapy group. In focusing on this, we explored limitations in these studies which may have influenced these outcomes. We also considered the potential for overtreatment of patients not likely to benefit from chemotherapy regimens. Finally, we employed risk stratification techniques to offer a decision tree model in the selection of patients for NC that conceivably could maximize oncologic outcomes and minimize overtreatment.
In the four main NC trials and their subsequent meta-analyses, pT0 patients in each group experienced similar survival, far exceeding those in both groups that did not achieve pT0 status. The benefit from NC appeared to be the larger number of patients than in the TUR-only group that were downstaged to pT0, suggesting that variables other than NC may have influenced outcomes. Therefore, employing strategies to selectively administer NC to certain at-risk patients has the potential to maintain improved bladder cancer outcomes while reducing overtreatment and its associated toxicities.
The Journal of urology 11/2013; · 4.02 Impact Factor
[show abstract][hide abstract] ABSTRACT: To study the impact of prognostic factors (liver metastasis [LM], anemia [Hb<10 g/dl], ECOG-performance status [PS] ≥1, time from prior chemotherapy [TFPC]) on the activity of second-line therapy for advanced urothelial carcinoma (UC).
Twelve phase II trials evaluating second-line chemotherapy and/or biologics (n=748) in patients with progressive disease were pooled. Progression-free survival (PFS) was defined as tumor progression or death from any cause. PFS at 6 months (PFS6) was defined from the date of registration and calculated using the Kaplan-Meier method. Response rate (RR) was defined using RECIST 1.0. A nomogram predicting PFS6 was constructed using the RMS package in R (www.r-project.org).
Data regarding progression, Hb, LM, PS and TFPC were available from 570 patients in 9 phase II trials. The overall median PFS was 2.7 months (mo), PFS6 was 22.2% (95% CI: 18.8-25.9) and RR was 17.5% (95% CI: 14.5%-20.9%). For every unit increase in risk group, the hazard of progression in 6 mo increased by 41% and the odds of response decreased by 48%. A nomogram was constructed to predict PFS6 on an individual patient level. The model was internally validated and displayed acceptable calibration performance.
PFS6 and RR vary as a function of baseline prognostic factors in patients receiving second-line therapy for advanced UC. A nomogram incorporating prognostic factors facilitates the evaluation of outcomes across phase II trials enrolling heterogeneous populations and helps select suitable agents for phase III testing.
[show abstract][hide abstract] ABSTRACT: Second-line systemic therapy for advanced urothelial carcinoma (UC) has substantial unmet needs, and current agents show dismal activity. Second-line trials of metastatic UC have used response rate (RR) and median progression-free survival (PFS) as primary endpoints, which may not reflect durable benefits. A more robust endpoint to identify signals of durable benefits when investigating new agents in second-line trials may expedite drug development. PFS at 6 months (PFS6) is a candidate endpoint, which may correlate with overall survival (OS) at 12 months (OS12) and may be applicable across cytostatic and cytotoxic agents.
Ten second-line phase II trials with individual patient outcomes data evaluating chemotherapy or biologics were combined for discovery, followed by external validation in a phase III trial. The relationship between PFS6/RR and OS12 was assessed at the trial level using Pearson correlation and weighted linear regression, and at the individual level using Pearson chi-square test with Yates continuity correction.
In the discovery dataset, a significant correlation was observed between PFS6 and OS12 at the trial (R(2) = 0.55, Pearson correlation = 0.66) and individual levels (82%, Қ = 0.45). Response correlated with OS12 at the individual level less robustly (78%, Қ = 0.36), and the trial level association was not statistically significant (R(2) = 0.16, Pearson correlation = 0.37). The correlation of PFS6 (81%, Қ = 0.44) appeared stronger than the correlation of response (76%, Қ = 0.17) with OS12 in the external validation dataset.
PFS6 is strongly associated with OS12 and appears more optimal than RR to identify active second-line agents for advanced UC.
Clinical Genitourinary Cancer 09/2013; · 1.43 Impact Factor
[show abstract][hide abstract] ABSTRACT: Standard chemotherapy with gemcitabine and cisplatin in advanced urothelial cancer of the bladder results in median overall survival of 14 months (1). Triplet chemotherapy regimens or high-dose chemotherapy failed to improve OS (2-4). The success of targeted therapies in some tumor entities as renal cell cancer, hepatocellular carcinoma or breast cancer led to studies in almost all other tumor entities. Based on the fact that these novel agents bind to specific receptors it seemed rationale to choose a target overexpressing its specific receptor in the tumor to be treated. In urothelial cancer the vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR) and Her-2/neu , a transmembrane tyrosine-kinase growth factor receptor, are known to be overexpressed in a substantial amount (5-9).
[show abstract][hide abstract] ABSTRACT: The evaluation of lesions detected in prostate magnetic resonance imaging (MRI) with increased signal intensity (SI) on high b-value diffusion-weighted images as a sign of malignancy.
One hundred and three consecutive patients with prostate MRI examination and MRI-guided in-bore biopsy were retrospectively included in the study. MRI-guided in-bore biopsy histologically confirmed prostate cancer in 50 patients (n = 92 lesions). The other 53 patients (n = 122 lesions) had negative bioptical results.
In patients with histologically confirmed prostate cancer, 46 of the 92 lesions had visually increased SI on the high b-value images compared with the peripheral zone (SI = +27 ± 16%) or the central gland (SI = +37 ± 19%, P < 0.001 respectively). In patients with a negative biopsy, ten of the 122 lesions had visually increased SI (compared with the peripheral zone, SI = +29 ± 18%, and with the central gland, SI = +41 ± 15%, P < 0.001 respectively). Neither the apparent diffusion coefficient (ADC) values nor the Gleason Score of lesions with increased SI were significantly different from lesions without increased SI.
Visually increased SI on the high b-value images of diffusion-weighted imaging using standard b-values is a sign of malignancy but can occasionally also be a feature of benign lesions. However, it does not indicate more aggressive tumours.
• Diffusion weighted magnetic resonance imaging is increasingly used to diagnose prostatic cancer • Reduced signal intensity (SI) on apparent diffusion coefficient (ADC) mapping is characteristic • Prostatic tumours usually exhibit increased SI on high b-value images • But benign lesions can also yield increased SI on high b-value images.
[show abstract][hide abstract] ABSTRACT: To estimate potential malignant lesions within the prostate gland, the usage of a scoring system has recently been proposed by a European consensus meeting.
To prospectively investigate a scoring system for functional prostate magnetic resonance imaging (MRI) using in-bore MR-guided prostate biopsy at 3-T.
Prostate MRI examinations of 59 patients (between February 2011 and May 2012) with no known prostate cancer, elevated prostate specific antigen (PSA) level, and unsuspicious digital rectal examination were included in the study. In each patient up to three lesions were defined and scored using a 5-point scoring system for each MR sequence (T2-weighted images, diffusion-weighted imaging, dynamic contrast-enhanced imaging). Following MRI-guided in-bore biopsy these lesions were correlated to the histopathological findings.
A total number of 144 lesions were defined in 59 patients. In 28 patients (51 lesions) MR-guided in-bore biopsy was positive for tumor (Gleason grade 6 or higher). A cut-off limit of 10 or more points in summation of the individual scores of all three sequences was used, leading to a 90% sensitivity, 63% specificity, 58% positive predictive value, and 92% negative predictive value.
A simple 5-point scoring system of functional prostate MRI achieves excellent sensitivity and moderate specificity for directing 3-T-guided prostate biopsy relative to the histopathological findings.
[show abstract][hide abstract] ABSTRACT: The prognostic impact of response to prior chemotherapy independent of performance status (PS), hemoglobin (Hb), liver metastasis (LM), and time from prior chemotherapy (TFPC) in the context of second-line therapy for advanced urothelial carcinoma (UC) is unknown.
Six phase II trials evaluating second-line therapy (n = 504) were pooled. Patients who received prior therapy for metastatic disease were eligible for analysis if Hb, LM, PS, and TFPC were available. Response by Response Evaluation Criteria in Solid Tumors 1.0 to first-line therapy was recorded. Progression-free survival (PFS) and overall survival (OS) were calculated from the date of registration using the Kaplan-Meier method.
A total of 275 patients were evaluable for analysis. Patients received gemcitabine-paclitaxel, cyclophosphamide-paclitaxel, pazopanib, docetaxel plus vandetanib/placebo, or vinflunine (2 trials). Those with prior response (n = 111) had a median OS of 8.0 months (95% confidence interval [CI], 6.8-9.4), compared with 5.9 months (95% CI, 5.0-6.6) for those without prior response (n = 164). Those with prior response had a median PFS of 3.0 months (95% CI, 2.6-4.0) compared with 2.6 months (95% CI, 2.0-2.8) in patients without response. Multivariable analysis did not reveal a significant independent impact of prior response on PFS and OS.
Best prior response in patients receiving prior chemotherapy for metastatic disease did not confer an independent prognostic impact with second-line therapy for advanced UC. Given that the setting of prior chemotherapy (metastatic or perioperative) has not appeared significant in a prior study, patients who received prior chemotherapy in perioperative or metastatic settings may be enrolled in the same second-line trial stratified for PS, Hb, LM, and TFPC.
Clinical Genitourinary Cancer 06/2013; · 1.43 Impact Factor
[show abstract][hide abstract] ABSTRACT: OBJECTIVES: The recent European Society of Urogenital Radiology (ESUR) guidelines for evaluation and reporting of prostate multiparametric magnetic resonance imaging (mp-MRI) include the Prostate Imaging Reporting and Data System (PI-RADS). The aim of this study was to investigate the inter-reader agreement of this scoring system. METHODS: One hundred and sixty-four lesions in 67 consecutive patients with elevated prostate-specific antigen and previously negative trans-rectal ultrasound (TRUS)-guided biopsy were scored retrospectively by three blinded readers using PI-RADS. Mp-MRI was performed at 3 T using T2-weighted, diffusion-weighted and dynamic contrast-enhanced imagings (T2WI, DWI, DCE-MRI). Histology of all lesions was obtained by in-bore MRI-guided biopsy. Cohen's kappa statistics were calculated for all readers. RESULTS: Inter-reader agreement for all lesions was good to moderate (T2WI, κ = 0.55; DWI, κ = 0.64; DCE-MRI, κ = 0.65). For tumour lesions it was good (T2WI, κ = 0.66; DWI, κ = 0.80; DCE-MRI, κ = 0.63) and for benign lesions moderate to good (T2WI, κ = 0.46; DWI, κ = 0.52; DCE-MRI, κ = 0.67). Using an overall PI-RADS score with a threshold of ≥10, we achieved a sensitivity of 85.7 %, and negative predictive value of 90.1 % for biopsied lesions. CONCLUSION: PI-RADS score shows good to moderate inter-reader agreement and enables standardised evaluation of prostate mp-MRI, with high sensitivity and negative predictive value. KEY POINTS : • The European Society of Urogenital Radiology recently published guidelines for prostate MRI. • We have evaluated inter-reader agreement of ESUR scoring for multiparametric prostate MRI. • PI-RADS shows good to moderate inter-reader agreement and is clinically applicable. • PI-RADS achieves in our series high sensitivity and negative predictive value for biopsied lesions. • PI-RADS can be used as standardised scoring system in prostate cancer detection.
[show abstract][hide abstract] ABSTRACT: Background AZD4877 is a potent inhibitor of the mitotic spindle kinesin, Eg5. Early-phase clinical studies in a broad range of cancers showed that AZD4877 is well tolerated. This Phase II study evaluated the efficacy, safety and pharmacokinetics (C(max)) of AZD4877 in patients with previously treated advanced urothelial cancer (ClinicalTrials.gov identifier NCT00661609). Patients and methods AZD4877 25 mg was administered once-weekly for 3 weeks of each 4-week cycle until disease progression, death, unacceptable toxicity or withdrawal. The primary objective was to determine the objective response rate (RECIST). Recruitment was to be halted if ≤2 of the first 20 evaluable patients achieved an objective tumor response. C(max) was assessed on days 1 and 8 of cycle 1. Results None of the first 20 patients evaluable for efficacy achieved an objective response; enrollment was therefore halted. During this initial analysis, a further 21 patients were recruited. Overall, 39 patients were evaluable for efficacy, including one with confirmed partial response (PR) and seven patients with stable disease for ≥8 weeks (including one unconfirmed PR). The most commonly reported treatment-related adverse events (TRAEs) were neutropenia (22 patients), fatigue (12), leukopenia (7) and constipation (6); the most commonly reported grade ≥3 TRAE was neutropenia (21). Four patients had serious TRAEs. On days 1 and 8, the geometric mean C(max) of AZD4877 was 138 ng/ml (CV = 75 %) and 144 ng/ml (CV = 109 %), respectively. Conclusions AZD4877 was generally tolerable in patients with advanced urothelial cancer. Given the limited clinical efficacy, further development of AZD4877 in urothelial cancer is not planned.
Investigational New Drugs 01/2013; · 3.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Outcomes for patients in the second-line setting of advanced urothelial carcinoma (UC) are dismal. The recognized prognostic factors in this context are Eastern Cooperative Oncology Group (ECOG) performance status (PS) >0, hemoglobin level (Hb) <10g/dl, and liver metastasis (LM). OBJECTIVES: The purpose of this retrospective study of prospective trials was to investigate the prognostic value of time from prior chemotherapy (TFPC) independent of known prognostic factors. DESIGN, SETTING, AND PARTICIPANTS: Data from patients from seven prospective trials with available baseline TFPC, Hb, PS, and LM values were used for retrospective analysis (n=570). External validation was conducted in a second-line phase 3 trial comparing best supportive care (BSC) versus vinflunine plus BSC (n=352). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cox proportional hazards regression was used to evaluate the association of factors, with overall survival (OS) and progression-free survival (PFS) being the respective primary and secondary outcome measures. RESULTS AND LIMITATIONS: ECOG-PS >0, LM, Hb <10g/dl, and shorter TFPC were significant prognostic factors for OS and PFS on multivariable analysis. Patients with zero, one, two, and three to four factors demonstrated median OS of 12.2, 6.7, 5.1, and 3.0 mo, respectively (concordance statistic=0.638). Setting of prior chemotherapy (metastatic disease vs perioperative) and prior platinum agent (cisplatin or carboplatin) were not prognostic factors. External validation demonstrated a significant association of TFPC with PFS on univariable and most multivariable analyses, and with OS on univariable analyses. Limitations of retrospective analyses are applicable. CONCLUSIONS: Shorter TFPC enhances prognostic classification independent of ECOG-PS >0, Hb <10g/dl, and LM in the setting of second-line therapy for advanced UC. These data may facilitate drug development and interpretation of trials.
[show abstract][hide abstract] ABSTRACT: In November 2011, the Third European Consensus Conference on Diagnosis and Treatment of Germ-Cell Cancer (GCC) was held in Berlin, Germany. This third conference followed similar meetings in 2003 (Essen, Germany) and 2006 (Amsterdam, The Netherlands) [Schmoll H-J, Souchon R, Krege S et al. European consensus on diagnosis and treatment of germ-cell cancer: a report of the European Germ-Cell Cancer Consensus Group (EGCCCG). Ann Oncol 2004; 15: 1377-1399; Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ-cell cancer: a report of the second meeting of the European Germ-Cell Cancer Consensus group (EGCCCG): part I. Eur Urol 2008; 53: 478-496; Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ-cell cancer: a report of the second meeting of the European Germ-Cell Cancer Consensus group (EGCCCG): part II. Eur Urol 2008; 53: 497-513]. A panel of 56 of 60 invited GCC experts from all across Europe discussed all aspects on diagnosis and treatment of GCC, with a particular focus on acute and late toxic effects as well as on survivorship issues.The panel consisted of oncologists, urologic surgeons, radiooncologists, pathologists and basic scientists, who are all actively involved in care of GCC patients. Panelists were chosen based on the publication activity in recent years. Before the meeting, panelists were asked to review the literature published since 2006 in 20 major areas concerning all aspects of diagnosis, treatment and follow-up of GCC patients, and to prepare an updated version of the previous recommendations to be discussed at the conference. In addition, ∼50 E-vote questions were drafted and presented at the conference to address the most controversial areas for a poll of expert opinions. Here, we present the main recommendations and controversies of this meeting. The votes of the panelists are added as online supplements.