Value of an Immediate Intravesical Instillation of Mitomycin C in Patients with Non-muscle-invasive Bladder Cancer: A Prospective Multicentre Randomised Study in 2243 patients.

BACKGROUND: The efficacy of an immediate single chemotherapy instillation after transurethral resection of a bladder tumour (TURBT) in patients with non-muscle-invasive bladder cancer (NMIBC) remains a topic of debate. Evidence is even more scarce when an immediate instillation is followed by adjuvant instillations. OBJECTIVE: To compare the effect of a mitomycin C (MMC) instillation within 24h to an instillation 2 wk after TURBT in patients with NMIBC with or without adjuvant instillations. DESIGN, SETTING, AND PARTICIPANTS: Between 1998 and 2003, 2844 NMIBC patients were randomised for immediate versus delayed MMC instillation after TURBT. Patients were categorised in low-risk (LOR), intermediate-risk (IMR), and high-risk (HIR) groups. Total numbers of instillations in these groups were 1, 9, and 15, respectively. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary end point was 3-yr recurrence risk for the IMR and HIR groups and 5-yr risk for the LOR group. Secondary outcomes were time to recurrence and incidence of adverse events. Analyses were performed with the log-rank test, Cox-regression, and χ2 test in SPSS. RESULTS AND LIMITATIONS: A total of 2243 patients were eligible on an intention-to-treat basis. Recurrence risks were 43% and 46% in the LOR group (5-yr follow-up, p=0.11), 20% and 32% in the IMR group (3-yr follow-up, p=0.037), and 28% and 35% in the HIR group (3-yr follow-up, p=0.007), for an immediate and a delayed instillation, respectively. For all patients, the recurrence risk was 27% (95% confidence interval [CI], 24-30) in the immediate and 36% (95% CI, 33-39) in the delayed instillation group (p<0.001) with a 27% reduction in relative recurrence risk (hazard ratio: 0.73, 95% CI, 0.63-0.85, p<0.001). The incidence of adverse events did not differ significantly between treatment groups (immediate instillation 25%, delayed instillation 22%, p=0.08). The risk groups in our study differ slightly from the current guidelines, which is a limitation of our study. CONCLUSIONS: An immediate, single instillation after TURBT reduces the recurrence risk in NMIBC patients, independent of the number of adjuvant installations. PATIENT SUMMARY: A single instillation of chemotherapy after the resection of non-muscle-invasive bladder cancer reduces the recurrence risk, even if patients are treated with an adjuvant schedule of instillations.

Is prostate-specific antigen a valid surrogate end point for survival in hormonally treated patients with metastatic prostate cancer? Joint research of the European Organisation for Research and Treatment of Cancer, the Limburgs Universitair Centrum, and AstraZeneca Pharmaceuticals.

PURPOSE: The long duration of phase III clinical trials of overall survival (OS) slows down the treatment-development process. It could be shortened by using surrogate end points. Prostate-specific antigen (PSA) is the most studied biomarker in prostate cancer (PCa). This study attempts to validate PSA end points as surrogates for OS in advanced PCa. PATIENTS AND METHODS: Individual data from 2,161 advanced PCa patients treated in studies comparing bicalutamide to castration were used in a meta-analytic approach to surrogate end-point validation. PSA response, PSA normalization, time to PSA progression, and longitudinal PSA measurements were considered. RESULTS: The known association between PSA and OS at the individual patient level was confirmed. The association between the effect of intervention on any PSA end point and on OS was generally low (determination coefficient, < 0.69). CONCLUSION: It is a common misconception that high correlation between biomarkers and true end point justify the use of the former as surrogates. To statistically validate surrogate end points, a high correlation between the treatment effects on the surrogate and true end point needs to be established across groups of patients treated with two alternative interventions. The levels of association observed in this study indicate that the effect of hormonal treatment on OS cannot be predicted with a high degree of precision from observed treatment effects on PSA end points, and thus statistical validity is unproven. In practice, non-null treatment effects on OS can be predicted only from precisely estimated large effects on time to PSA progression (TTPP; hazard ratio, < 0.50).

Relative importance of PSA in prostate cancer treatment.

METHODS AND MATERIALS: A retrospective study was conducted to (1) determine the relationship between baseline prostate-specific antigen (PSA) levels and initial treatment decisions for prostate cancer (surgery, hormone therapy, radiation, or watchful waiting) and (2) estimate the impact of PSA progression (doubling or three consecutive rises) on subsequent treatment decisions. Patient records (n=1116) from three community urology practices and a large academic health system were reviewed. Multivariate models were fitted to assess the relationship between initial treatment and baseline PSA, Gleason score, race, number of comorbid conditions and age and between PSA progression and time to subsequent therapy (adjusted for other factors). RESULTS: Baseline PSA was a significant predictor of initial treatment among men with localized disease with the likelihood of hormone therapy increasing with higher PSA levels and the likelihood of surgery decreasing steadily with higher PSA levels. PSA was the strongest predictor of hormone therapy as first choice followed by age. Age followed by PSA was the strongest predictor of surgery as first treatment as well as radiation therapy. Initial PSA levels did not predict the choice of watchful waiting. Patients with PSA progression were eight times (95% CI: 5.3-12.1) more likely to initiate a subsequent therapy than patients who did not have PSA progression when controlling for other predictors. CONCLUSIONS: In clinical practice, PSA significantly impacts the urologist's primary therapy choice and determines when they introduce subsequent treatments.

Prognostic and predictive factors in prostate cancer: historical perspectives and recent international consensus initiatives.

An understanding of prognosis in cancer medicine is important for patient care, research and cancer control programs. In prostate cancer, prognostic (predictive) factors are particularly important given the marked heterogeneity of this disease at clinical, morphologic and biomolecular levels. Clinical stage and histologic grade have historically played major roles in defining heterogeneity in prostate cancer. More recently, serum prostate-specific antigen measurement has assumed a significant prognostic role. Over the last two decades there has been an explosion of research into biomarkers, many of which have been purported to have prognostic significance. In this paper we present an overview of the various consensus initiatives that have transpired over the last dozen years. Criteria for evaluating prognostic factors and classifications of predictive factors have emerged that have proven useful and advanced our understanding of the biology of prostate cancer. The results of these consensus initiatives form a foundation on which the current international consultation on prognosis (prediction) in prostate cancer is built. Advances in our understanding of the new and promising prognostic factors will require a more rigorous evidence-based approach to the analysis of published studies. Furthermore, appropriate mathematical models for the analysis of the multiple factors that influence a prognostic system will have to be employed.

Prognostic and predictive factors and reporting of prostate carcinoma in prostate needle biopsy specimens.

The information provided in the surgical pathology report of a prostate needle biopsy of carcinoma has become critical in the subsequent management and prognostication of the cancer. The surgical pathology report should thus be comprehensive and yet succinct in providing relevant information consistently to urologists, radiation oncologists and oncologists and, thereby, to the patient. This paper reflects the current recommendations of the 2004 World Health Organization-sponsored International Consultation, which was co-sponsored by the College of American Pathologists. It builds on the existing work of several organizations, including the College of American Pathologists, the Association of Directors of Anatomic and Surgical Pathologists, the Royal Society of Pathologists, the European Society of Urologic Pathology and the European Randomized Study of Screening for Prostate Cancer.

Prognostic factors and reporting of prostate carcinoma in radical prostatectomy and pelvic lymphadenectomy specimens.

This paper, based on the activity of the Morphology-Based Prognostic Factors Committee of the 2004 World Health Organization-sponsored International Consultation, describes various methods of handling radical prostatectomy specimens for both routine clinical use and research purposes. The correlation between radical prostatectomy findings and postoperative failure is discussed in detail. This includes issues relating to pelvic lymph node involvement, detected both at the time of frozen section and in permanent sections. Issues of seminal vesicle invasion, including its definition, routes of invasion and relationship to prognosis, are covered in detail. The definition, terminology and incidence of extra-prostatic extension are elucidated, along with its prognostic significance relating to location and extent. Margins of resection are covered in terms of their definition, the etiology, incidence and sites of positive margins, the use of frozen sections to assess the margins and the relationship between margin positivity and prognosis. Issues relating to grade within the radical prostatectomy specimen are covered in depth, including novel ways of reporting Gleason grade and the concept of tertiary Gleason patterns. Tumor volume, tumor location, vascular invasion and perineural invasion are the final variables discussed relating to the prognosis of radical prostatectomy specimens. The use of multivariate analysis to predict progression is discussed, together with proposed modifications to the TNM system. Finally, biomarkers to predict progression following radical prostatectomy are described, including DNA ploidy, microvessel density, Ki-67, neuroendocrine differentiation, p53, p21, p27, Bcl-2, Her-2/neu, E-cadherin, CD44, retinoblastoma proteins, apoptotic index, androgen receptor status, expression of prostate-specific antigen and prostatic-specific acid phosphatase and nuclear morphometry.

Cell cycle perturbations and radiosensitization effects in a human prostate cancer cell line.

PURPOSE: To test the hypothesis that radiation-induced, transient G2/M arrest could potentially sensitize tumor cells to a subsequent, well-timed radiation dose. METHODS: PC-3 human prostate cancer cells were treated using either radiotherapy or (186)Re-labeled hydroxyethylidene diphosphonate ((186)Re-HEDP) treatment in different combinations. The resulting cell cycle shift and clonogenic cell death were analyzed by DNA flow cytometry and colony forming cell assay, respectively. RESULTS: Radiation doses of 4 Gy and 8 Gy induced a transient G2/M arrest, with a maximum after approximately 16 h. The presence of 2 mM pentoxifylline effectively abrogated this radiation-induced G2 M arrest, confirming a cell-cycle checkpoint-mediated effect. A second dose of 4 Gy, timed at the height of the G2/M arrest, significantly increased clonogenic cell-kill compared to delivery after a suboptimal interval (10 h, 20 h or 25 h after the first radiation fraction). Moreover, timed second doses of 2 Gy, 3 Gy or 4 Gy yielded improved normalized treatment effects compared to non-pretreated control. Radionuclide treatment of PC-3 cells, using (186)Re-HEDP (0.74 MBq/ml and 1.48 MBq/ml; total dose: 4.1 and 8.2 Gy, respectively) also induced a dose-dependent G2/M accumulation, which sensitized the cells to a subsequent external radiation dose of 2 Gy or 4 Gy. The observed pattern of cell-cycle shift towards a predominance of the G2/M phase is in line with the lack of functional p53 in this cell line. CONCLUSIONS: Radiation-induced cell-cycle shift was shown to effectively confer increased radiosensitivity to prostate tumor cells. Optimally timed combination of radiotherapy and radionuclide therapy could thus significantly increase treatment efficacy.

Use of prostate-specific antigen in the follow-up of patients with localized prostate cancer: results of a nationwide survey of urologists.

OBJECTIVES: To perform a nationwide survey of urologists' opinions and behavior regarding the use of prostate-specific antigen (PSA) in prostate cancer follow-up and secondary treatment. METHODS: A random sample of 300 urologists was interviewed. Content areas included defining recurrence in prostate cancer, factors that influence initiation of secondary treatment in this setting, and need for additional clinical trial information in recurrent prostate cancer. RESULTS: Seventy-eight percent of urologists indicated that absolute PSA levels were of high or very high importance when making follow-up decisions. When defining a rising PSA level, 83% of urologists surveyed use the American Society for Therapeutic Radiology and Oncology definition of failure. An additional 78% use PSA doubling time. When asked about the importance of rapidly reducing PSA levels after recurrence, 61% said it was of high or very high importance to them, but 81% said it was of high or very high importance to their patients. CONCLUSIONS: Results from the current study indicate that urologists consider PSA failure to be an important outcome in patients with prostate cancer. Researchers and policy makers need to consider this outcome when designing studies of prostate cancer.

A cross-sectional study of the international prostate symptom scores related to age and gender in Dutch adults reporting no voiding complaints.

OBJECTIVE: To determine the IPSS in a selected population reporting no voiding complaints. SUBJECTS AND METHODS: 1143 adults without voiding complaints were included. They were divided over both sexes and all decades. All subjects filled out questionnaires including the IPSS. Statistical analysis was aimed at relating the IPSS to age and gender. RESULTS: The IPSS in both sexes shows a gradual significant increase in consecutive age groups. Men in the third age decade have a mean score of 2.8, while men older than 70 years of age have a score of 7.0. In women these scores are 4.0 and 5.6 respectively. The increase is about equally caused by storage and voiding scores. The items addressing weak stream in men and nocturia and urgency in men and women are the major factors causing the correlation with age. Nearly 17% of all subjects have moderate symptom scores and 1% has severe scores. CONCLUSION: In both adult men and women reporting no voiding complaints the IPSS increases with age. This rise is more prominent in males.