Abstract Background There are no prognostic factor publications on stage Ta–T1 non–muscle-invasive bladder cancer (NMIBC) treated with 1–3 yr of maintenance bacillus Calmette-Guérin (BCG). Objective ...To determine prognostic factors in NMIBC patients treated with 1–3 yr of BCG after transurethral resection of the bladder (TURB), to derive nomograms and risk groups, and to identify high-risk patients who should be considered for early cystectomy. Design, setting, and participants Data for 1812 patients were merged from two European Organization for Research and Treatment of Cancer randomized phase 3 trials in intermediate- and high-risk NMIBC. Intervention Patients received 1–3 yr of maintenance BCG after TURB and induction BCG. Outcome measurements and statistical analysis Prognostic factors for risk of early recurrence and times to late recurrence, progression, and death were identified in a training data set using multivariable models and applied to a validation data set. Results and limitations With a median follow-up of 7.4 yr, 762 patients recurred; 173 progressed; and 520 died, 83 due to bladder cancer (BCa). Statistically significant prognostic factors identified by multivariable analyses were prior recurrence rate and number of tumors for recurrence, and tumor stage and grade for progression and death due to BCa. T1G3 patients do poorly, with 1- and 5-yr disease-progression rates of 11.4% and 19.8%, respectively, and 1- and 5-yr disease-specific death rates of 4.8% and 11.3%. Limitations include lack of repeat transurethral resection in high-risk patients and exclusion of patients with carcinoma in situ. Conclusions NMIBC patients treated with 1–3 yr of maintenance BCG have a heterogeneous prognosis. Patients at high risk of recurrence and/or progression do poorly on currently recommended maintenance schedules. Alternative treatments are urgently required. Patient summary Non–muscle-invasive bladder cancer patients at high risk of recurrence and/or progression do poorly on currently recommended bacillus Calmette-Guérin maintenance schedules, and alternative treatments are urgently required. Trial registration Study 30911 was registered with the US National Cancer Institute clinical trials database (protocol ID: EORTC 30911). Study 30962 was registered at ClinicalTrials.gov, number NCT00002990; http://clinicaltrials.gov/ct2/show/record/NCT00002990.
Abstract Background The European Organization for Research and Treatment of Cancer (EORTC) risk scores are not validated in an independent patient population. Molecular grade (mG) based on fibroblast ...growth factor receptor 3 ( FGFR3 ) gene mutation status and MIB-1 expression was proposed as an alternative to pathologic grade in bladder cancer (BCa) 1. Objective To validate the EORTC risk score and to determine its relation to mG in a series with long-term follow-up as well as to determine reproducibility of pathologic grade and mG. Design, setting, and participants In this multicenter study, we included 230 patients with primary non–muscle-invasive BCa (NMIBC). Measurements Four uropathologists reviewed the slides. FGFR3 mutation status was examined by two assays. MIB-1 was assessed by immunohistochemistry. The EORTC risk scores for recurrence and progression were determined. Multivariable analyses were used to find prognostic factors. Results and limitations Median follow-up was 8.62 yr (interquartile range: 6.6–11.8). FGFR3 mutations were significantly related to favorable disease parameters, whereas altered MIB-1 was frequently seen with pT1, high grade, and high EORTC risk scores. EORTC risk scores were significant in multivariable analyses for recurrence and progression. In multivariable analyses for progression and disease-specific survival, the mG had independent significance. The addition of mG to the multivariable model for progression increased the predictive accuracy from 74.9% to 81.7% ( p < 0.001; Mantel-Haenszel test). The mG (89%) was more reproducible than the pathologic grade (41–74%). Conclusions We validated the EORTC risk scores for primary NMIBC in a clinical and biomarker setting. Next to EORTC risk score, mG proved highly reproducible and predictive. Our long-term results justify an independent prospective analysis of mG and EORTC risk scores.
Abstract Background Evidence from randomized trials on the effects of screening for prostate cancer (PCa) on disease-specific mortality accumulates slowly with increasing follow-up. Objective To ...assess data on PCa-specific mortality in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial. Design, setting, and participants A randomized controlled trial with randomization after signed, written informed consent (efficacy trial). In the period 1993–1999, a total of 42 376 men aged 54–74 yr were randomized to a screening arm (S-arm) ( n = 21 210 with screening every 4 yr, applying a total prostate-specific antigen PSA level cut-off ≥3.0 ng/ml as biopsy indication) or a control arm (C-arm) ( n = 21 166; no intervention). Outcome measurements and statistical analysis Number of PCas detected per arm depicted by predefined time periods and prognostic groups. PCa-specific mortality analyses using Poisson regression in age group 55–74 yr at randomization and separately in the predefined age group of 55–69 yr. Results and limitations After a median follow-up of 12.8 yr, 19 765 men (94.2%) were screened at least once and 2674 PCas were detected (of which 561 21.0% were interval PCas). In the C-arm, 1430 PCas were detected, resulting in an excess incidence of 59 PCas per 1000 men randomized (61 PCas per 1000 in age group 55–69 yr). Thirty-two percent of all men randomized have died. PCa-specific mortality relative-risk (RR) reductions of 20.0% overall (age: 55–74 yr; p = 0.042) and 31.6% (age: 55–69 yr; p = 0.004) were found. A 14.1% increase was found in men aged 70–74 yr (not statistically significant). Absolute PCa mortality was 1.8 per 1000 men randomized (2.6 per 1000 men randomized in age group 55–69 yr). The number needed to invite and number needed to manage were 565 and 33, respectively, for age group 55–74 yr, and 392 and 24, respectively, for age group 65–69 yr. Given the slow natural history of the disease, follow-up might be too short. Conclusions Systematic PSA-based screening reduced PCa-specific mortality by 32% in the age range of 55–69 yr. The roughly twofold higher incidence in the S-arm underlines the importance of tools to better identify those men who would benefit from screening.
Abstract Background Intravesical chemotherapy and bacillus Calmette-Guérin (BCG) reduce the recurrence rate in patients with stage Ta T1 urothelial bladder cancer; however, the benefit of BCG ...relative to chemotherapy for long-term end points is controversial, especially in intermediate-risk patients. Objective The aim of the study was to compare the long-term efficacy of BCG and epirubicin. Design, setting, and participants From January 1992 to February 1997, 957 patients with intermediate- or high-risk stage Ta T1 urothelial bladder cancer were randomized after transurethral resection to one of three treatment groups in the European Organization for Research and Treatment of Cancer Genito-Urinary Group phase 3 trial 30911. Intervention Patients received six weekly instillations of epirubicin, BCG, or BCG plus isoniazid (INH) followed by three weekly maintenance instillations at months 3, 6, 12, 18, 24, 30, and 36. Measurements End points were time to recurrence, progression, distant metastases, overall survival, and disease-specific survival. Results and limitations With 837 eligible patients and a median follow-up of 9.2 yr, time to first recurrence ( p < 0.001), distant metastases ( p = 0.046), overall survival ( p = 0.023), and disease-specific survival ( p = 0.026) were significantly longer in the two BCG arms combined as compared with epirubicin; however, there was no difference for progression. Three hundred twenty-three patients with stage T1 or grade 3 tumors were high risk, and the remaining 497 patients were intermediate risk. The observed treatment benefit was at least as large, if not larger, in the intermediate-risk patients compared with the high-risk patients. Conclusions In patients with intermediate- and high-risk stage Ta and T1 urothelial bladder cancer, intravesical BCG with or without INH is superior to intravesical epirubicin not only for time to first recurrence but also for time to distant metastases, overall survival, and disease-specific survival. The benefit of BCG is not limited to just high-risk patients; intermediate-risk patients also benefit from BCG. Trial registration This study was registered with the US National Cancer Institute clinical trials database protocol ID: EORTC-30911. http://www.cancer.gov/search/ViewClinicalTrials.aspx?cdrid=77075&version=HealthProfessional&protocolsearchid=6540260.
Abstract Context Currently, bacillus Calmette-Guérin (BCG) intravesical instillations are standard treatment for patients with high-grade non–muscle-invasive bladder cancer; however, no markers are ...available to predict BCG response. Objective To review the contemporary literature on markers predicting BCG response, to discuss the key issues concerning the identification of predictive markers, and to provide recommendations for further research studies. Evidence acquisition We performed a systematic review of the literature using PubMed and Embase databases in the period 1996–2010. The free-text search was extended by adding the following keywords: recurrence, progression, survival, molecular marker, prognosis, TP53, Ki-67, RB, fibronectin, immunotherapy, cytokine, interleukin, natural killer, macrophage, PMN, polymorphism, SNP, single nucleotide polymorphism, and gene signature. Evidence synthesis If thresholds for the detection of urinary interleukin (IL)-8, IL-18, and tumour necrosis factor apoptosis-inducing ligand levels are standardised, measurement of these cytokines holds promise in the assessment of BCG therapy outcome. Studies on immunohistochemical markers (ie, TP53, Ki-67, and retinoblastoma) display contradictory results, probably because of the small patient groups that were used and seem unsuitable to predict BCG response. Exploring combinations of protein levels might prove to be more helpful to establish the effect of BCG therapy. Single nucleotide polymorphisms, either in cytokines or in genes involved in DNA repair, need to be investigated in different ethnicities before their clinical relevance can be determined. Measurement of urinary IL-2 levels seems to be the most potent marker of all the clinical parameters reviewed. Conclusions IL-2 levels are currently the most promising predictive markers of BCG response. For future studies focusing on new biomarkers, it is essential to make more use of new biomedical techniques such as microRNA profiling and genomewide sequencing.
To evaluate the complication rates and possible risk factors of biopsy of the prostate, with the aim of improving patient counseling and the safety of the procedure. Biopsy of the prostate has to be ...a relatively safe procedure and the participants have to be well informed about the possible complications.
Within the biopsy protocol of the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer, we evaluated 5802 transrectal ultrasound-guided systematic sextant biopsies. All participants received prophylactic antibiotic therapy.
We performed 5802 biopsies. Hematuria lasting longer than 3 days and hematospermia were present after 22.6% and 50.4% of the procedures, respectively. More severe complications were far less frequent. Two hundred participants (3.5%) developed fever after biopsy. Urinary retention was seen 20 times (0.4%), and hospitalization was needed in 27 cases (0.5%). Twenty-five of these men were admitted because of signs of prostatitis and/or urosepsis. Risk factor analyses revealed that an earlier episode of prostatitis was significantly associated with hospital admission and pain after biopsy. Characteristics of prostatic hyperplasia, such as prostate volume, transition zone volume/total prostate volume ratio, and a higher International Prostate Symptom Score, were all predictors of urinary retention.
Minor complications are frequently seen but major complications are rare after prostate biopsy. Assessment of the risk factors before biopsy can help to improve the adequacy of counseling, and precautionary measures can be taken to minimize the risk of complications after the procedure. Transrectal ultrasound-guided sextant biopsy remains a safe procedure for the diagnosis of prostate cancer within the general population.
To quantify the residual geometric uncertainties after on-line corrections with intraprostatic fiducial markers, this study analyzed the deformation of the prostate and, in particular, the seminal ...vesicles relative to such markers.
A planning computed tomography (CT) scan and three repeat CT scans were obtained for 21 prostate cancer patients who had had three to four cylindrical gold markers placed. The prostate and whole seminal vesicles (clinical target volume CTV) were delineated on each scan at a slice thickness of 1.5 mm. Rigid body transformations (translation and rotation) mapping the markers onto the planning scan positions were obtained. The translation only (T(only)) or both translation and rotation were applied to the delineated CTVs. Next, the residue CTV surface displacements were determined using nonrigid registration of the delineated contours. For translation and rotation of the CTV, the residues represented deformation; for T(only), the residues stemmed from deformation and rotation. T(only) represented the residues for most currently applied on-line protocols. The patient and population statistics of the CTV surface displacements were calculated. The intraobserver delineation variation was similarly quantified using repeat delineations for all patients and corrected for.
The largest CTV deformations were observed at the anterior and posterior side of the seminal vesicles (population average standard deviation </=3 mm). Prostate deformation was small (standard deviation </=1 mm). The increase in these deviations when neglecting rotation (T(only)) was small.
Although prostate deformation with respect to implanted fiducial markers was small, the corresponding deformation of the seminal vesicles was considerable. Adding marker-based rotational corrections to on-line translation corrections provided a limited reduction in the estimated planning margins.
Currently, the use of two classification systems for bladder cancer grade is advocated in clinical guidelines because the WHO2004 classification has not been sufficiently validated with biological ...markers and follow-up. The slides of 325 primary non-muscle invasive bladder cancers from three hospitals were reviewed by one uro-pathologist in two separate sessions for the WHO1973 (G1, G2 and G3) and 2004 (papillary urothelial neoplasm of low malignant potential (LMP), low-grade (LG) and high-grade (HG)) classifications. FGFR3 status was examined with PCR-SNaPshot analysis. Expression of Ki-67, P53 and P27 was analyzed by immuno-histochemistry. Clinical recurrence and progression were determined. We performed validation and cross-validation of the two systems for grade with molecular markers and clinical outcome. Multivariable analyses were done to predict prognosis and pT1 bladder cancer. Grade review resulted in 88 G1, 149 G2 and 88 G3 lesions (WHO1973) and 79 LMP, 101 LG and 145 HG lesions (WHO2004). Molecular validation of both grading systems showed that FGFR3 mutations were associated with lower grades whereas altered expression (Ki-67, P53 and P27) was found in higher grades. Clinical validation showed that the two classification systems were both significant predictors for progression but not for recurrence. Cross-validation of both WHO systems showed a significant stepwise increase in biological (molecular markers) and clinical (progression) potential along the line: G1-LG-G2-HG-G3. The LMP and G1 categories had a similar clinical and molecular profile. On the basis of molecular biology and multivariable clinical data, our results support a four-tiered grading system using the 1973 and 2004 WHO classifications with one low-grade (LMP/LG/G1) category that includes LMP, two intermediate grade (LG/G2 and HG/G2) categories and one high-grade (HG/G3) category.
Fibroblast growth factor receptor 3 (FGFR3) and P53 mutations are frequently observed in bladder cancer. We here describe the distribution of FGFR3 mutations and P53 overexpression in 260 primary ...urothelial cell carcinomas. FGFR3 mutations were observed in 59% and P53 overexpression in 25%. Interestingly, FGFR3 and P53 alterations were mutually exclusive, because they coincided in only 5.7% of tumors. Consequently, we propose that they characterize two alternative genetic pathways in urothelial cell carcinoma pathogenesis. The genetic alterations were reflected in the pathology and the clinical outcome, i.e., FGFR3 mutations were found in low-stage/-grade tumors and were associated with a favorable disease course, whereas P53 alterations were tied to adverse disease parameters.
Abstract Background Although maintenance bacillus Calmette-Guérin (BCG) is the recommended treatment in high-risk non–muscle-invasive bladder cancer (NMIBC), its efficacy in older patients is ...controversial. Objective To determine the effect of age on prognosis and treatment outcome in patients with stage Ta T1 NMIBC treated with maintenance BCG. Design, setting, and participants A total of 957 patients with intermediate- or high-risk Ta T1 (without carcinoma in situ) NMIBC were randomized in European Organization for Research and Treatment of Cancer (EORTC) trial 30911 comparing six weekly instillations of epirubicin, BCG, and BCG plus isoniazid followed by three weekly maintenance instillations over 3 yr. Outcome measurements and statistical analysis Cox multivariate proportional hazards regression models were used to assess the relative importance of age for recurrence, progression, overall survival, and NMIBC-specific survival with adjustment for EORTC risk scores. Results and limitations Overall, 822 eligible patients were included: 546 patients in the BCG with or without INH arms and 276 in the epirubicin arm. In patients treated with BCG with or without INH, 34.1% were >70 yr of age and 3.7% were >80 yr. With a median follow-up of 9.2 yr, patients >70 yr had a shorter time to progression ( p = 0.028), overall survival ( p < 0.001), and NMIBC-specific survival ( p = 0.049) after adjustment for EORTC risk scores in the multivariate analysis. The time to recurrence was similar compared with the younger patients. BCG was more effective than epirubicin for all four end points considered, and there was no evidence that BCG was any less effective compared with epirubicin in patients >70 yr. Conclusions In intermediate- and high-risk Ta T1 urothelial bladder cancer patients treated with BCG, patients >70 yr of age have a worse long-term prognosis; however, BCG is more effective than epirubicin independent of patient age. Patient summary Intravesical bacillus Calmette-Guérin for non–muscle-invasive bladder cancer is less effective in patients >70 yr of age, but it is still more effective than epirubicin. Trial registration This study was registered with the US National Cancer Institute clinical trials database (protocol ID: EORTC 30911; http://www.cancer.gov/clinicaltrials/search/view?cdrid=77075&version=HealthProfessional&protocolsearchid=12442243#StudyIdInfo_CDR0000077075 ).
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