Jouko Viitanen

Factors Explaining Recurrence in Patients Undergoing Chemoimmunotherapy Regimens for Frequently Recurring Superficial Bladder Carcinoma

OBJECTIVES To study the factors determining new recurrences in patients with frequently recurring superficial bladder tumors. METHODS Of all 205 eligible patients, each received 5 weekly intravesical instillations of mitomycin C (MMC), with the first instillation given perioperatively. This was followed, according to randomization, by BCG instillations alone or by alternating instillations of interferon-alpha and BCG monthly for up to 1 year. Impact of 12 variables on time to first recurrence was retrospectively studied with the Cox multiple hazards regression and Kaplan-Meier analysis. RESULTS Type of regimen was the most significant factor determining new recurrences, with preceding recurrence rate being the most important prognostic factor. Timing of the first MMC was the third significant predictor in the main multivariate analysis, with more than a two-fold relative risk for a new recurrence if the first MMC instillation was given later than on day 0. CONCLUSION Preceding recurrence rate, most accurately reflects, in patients with frequently recurring tumors, the inherent risk for new recurrences. This risk can be considerably reduced by use of an effective chemoimmunotherapy regimen, and in addition, by inclusion of an early perioperative chemotherapy instillation in such a regimen.

The FinnProstate Study VII: Intermittent Versus Continuous Androgen Deprivation in Patients With Advanced Prostate Cancer

PURPOSE We conducted a randomized trial to compare intermittent and continuous androgen deprivation in patients with advanced prostate cancer. We studied time to progression, overall and prostate cancer specific survival, and time to treatment failure. MATERIALS AND METHODS Between May 1997 and February 2003, 852 men with locally advanced or metastatic prostate cancer were enrolled to receive androgen deprivation therapy for 24 weeks. Patients in whom prostate specific antigen decreased to less than 10 ng/ml, or by 50% or more if less than 20 ng/ml at baseline, were randomized to intermittent or continuous androgen deprivation. In the intermittent therapy arm androgen deprivation therapy was withdrawn and resumed again for at least 24 weeks based mainly on prostate specific antigen decrease and increase. RESULTS There were 298 patients who did not meet the randomization criteria. The remaining 554 patients were randomized, with 274 (49.5%) to intermittent androgen deprivation and 280 (50.5%) to the continuous androgen deprivation arm. Median followup was 65.0 months. Of these patients 392 (71%) died, including 186 (68%) in the intermittent androgen deprivation arm and 206 (74%) in the continuous androgen deprivation arm (p=0.12). There were 248 prostate cancer deaths, comprised of 117 (43%) in the intermittent androgen deprivation and 131 (47%) in the continuous androgen deprivation arm (p=0.29). Median times from randomization to progression were 34.5 and 30.2 months in the intermittent androgen deprivation and continuous androgen deprivation arms, respectively. Median times to death (all cause) were 45.2 and 45.7 months, to prostate cancer death 45.2 and 44.3 months, and to treatment failure 29.9 and 30.5 months, respectively. CONCLUSIONS Intermittent androgen deprivation is a feasible, efficient and safe method to treat advanced prostate cancer compared with continuous androgen deprivation.

Advanced Prostate Cancer Treated with Intermittent or Continuous Androgen Deprivation in the Randomised FinnProstate Study VII: Quality of Life and Adverse Effects

BACKGROUND Intermittent dosing may reduce the adverse events (AEs) of androgen-deprivation therapy (ADT). OBJECTIVE To compare intermittent androgen deprivation (IAD) and continuous androgen deprivation (CAD) with regard to health-related quality of life (QoL). DESIGN, SETTING, AND PARTICIPANTS A total of 852 men with advanced prostate cancer (PCa) were enrolled to receive goserelin acetate 3.6 mg every 28 d for 24 wk. A total of 554 patients whose prostate-specific antigen (PSA) decreased to <10 ng/ml or by ≥50% (<20 ng/ml at baseline) were randomised to IAD or CAD. INTERVENTION In the IAD arm, ADT was resumed for at least 24 wk whenever PSA increased >20 ng/ml or above baseline. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS QoL was monitored with a validated Cleary 30-item questionnaire and analysed by the Mann-Whitney U test, 0.5 standard deviation rule, and repeated measures analysis of variance. AEs and adverse drug reactions (ADRs) were analysed by the chi-square test. RESULTS AND LIMITATIONS Median follow-up was 65 mo. Significant differences in QoL emerged in activity limitation, physical capacity, and sexual functioning, favouring IAD. No significant differences emerged in the prevalence of AEs: 87 patients in the IAD arm (31.8%) and 95 in the CAD arm (33.9%) had cardiovascular (CV) AEs (p=0.59), with 25 (9.1%) and 29 (10.4%) withdrawn (p=0.62), and 21 (7.7%) and 24 (8.6%) dying because of a CV event (p=0.70), respectively; bone fractures occurred in 19 (6.9%) and 15 (5.4%) patients (p=0.44), respectively. Hot flushes or night sweats were the most common ADRs (47.1% vs 50.4%; p=0.44). Erectile dysfunction (15.7% vs 7.9%; p=0.042) and depressed mood (2.2 vs 0%; p=0.032) were more common in the IAD arm. CONCLUSIONS IAD showed benefits in the treatment of advanced PCa with respect to QoL. The prevalence of AEs was not significantly lower with IAD. TRIAL REGISTRATION ClinicalTrials.gov, NCT00293670.

Analysis of false-positive BTA stat test results in patients followed up for bladder cancer

OBJECTIVES To evaluate the role of a positive BTA stat Test result in patients with negative cystoscopic findings. METHODS Five hundred one consecutive patients in follow-up for bladder cancer were studied. A voided urine sample was obtained before cystoscopy and split for culture, cytology, and BTA stat testing. In the case of a positive BTA stat Test, but negative cystoscopic findings, patients underwent additional investigations. RESULTS Of 501 patients, 133 (26.5%) had bladder cancer recurrence at cystoscopy, of which the BTA stat Test detected 71 (53.4%); only 21 of the cases (17.9%) were detected by cytologic examination. Of the remaining 368 patients with no visible tumor at cystoscopy, 96 (26.1%) had a positive BTA stat Test result. Fifty-five of those (57.3%) underwent intravenous urography or renal ultrasound and random biopsies, and an additional 9 recurrences (16.4%) were detected. Of those 46 patients who had a true false-positive BTA stat Test, 3 (3 of 43, 7.0%) had recurrence at the next follow-up cystoscopy, 4 (8.7%) had a urine infection, and 8 (17.4%) had ongoing intravesical instillations; the latter two percentages were significantly higher than among those with true-negative BTA stat Test results (0% and 6.8%, respectively). CONCLUSIONS Patients with a positive BTA stat Test result but negative cystoscopic findings have about a 16% risk of an undetected recurrence. False-positive results may be due to present instillation treatment and urine infection, and the predictive value of a BTA stat Test for subsequent recurrence seems relatively low.

Finnish Multicenter Study Comparing Intermittent to Continuous Androgen Deprivation for Advanced Prostate Cancer: Interim Analysis of Prognostic Markers Affecting Initial Response to Androgen Deprivation

PURPOSE Intermittent androgen deprivation has been proposed to prolong hormone sensitivity and improve quality of life in patients with advanced prostate cancer. The FinnProstate Study VII has been performed to identify patients who might benefit from intermittent androgen deprivation. In this interim analysis we evaluated which prognostic markers affect the initial response to androgen deprivation therapy. MATERIALS AND METHODS A total of 856 men with locally advanced or metastatic prostate cancer were enrolled and given androgen deprivation therapy for 24 weeks to ensure hormone sensitivity. Patients with hormone sensitive prostate cancer were randomized 1:1 to continuous androgen deprivation or intermittent androgen deprivation. The randomization criteria were prostate specific antigen decrease to less than 10 ng/ml or by more than 50% if less than 20 ng/ml at baseline. RESULTS There were 292 patients (34%) who did not meet the randomization criteria (group 1). The remaining 564 patients (66%) were randomized to intermittent androgen deprivation or continuous androgen deprivation (group 2). Mean prostate specific antigen (834 vs 151 ng/ml), mean alkaline phosphatase (793 vs 292 IU/l), proportion of T4 tumors (37% vs 24%), poorly differentiated cancers (39% vs 26%), metastatic disease (82% vs 51%) and number of skeletal hot spots in M1 disease (more than 5 hot spots 72% vs 42%) were significantly higher in group 1 than in group 2. CONCLUSIONS Patients with the most advanced prostate cancer and poorest prognosis do not show adequate biochemical prostate specific antigen response to androgen deprivation therapy but should be assessed for eligibility to receive nonendocrine treatment.

Prognostic Value of CD44 Standard, Variant Isoforms 3 and 6 and ·–Catenin Expression in Local Prostate Cancer Treated by Radical Prostatectomy

Objective: The clinical and histological data of prostate cancer patients were compared with the expression of CD44 standard (CD44s), variant isoforms CD44v3, CD44v6 and α–catenin. The prognostic value of these adhesion molecules was also analysed.Patients and Methods: We analysed the clinical and histological data of 87 prostate cancer patients treated by radical prostatectomy in two Finnish hospitals. The mean (SD) age of the patients at diagnosis was 64 years (6) and the mean follow–up was 3 years (8). Immunohistochemistry was used to detect the expression of CD44s and its v3 (CD44v3) and v6 (CD44v6) isoforms and α–catenin.Results: The mean (SD) fractions of positively stained cancer cells were 38 (38), 10 (22), 56 (41) and 93% (17) for CD44s, CD44v3, CD44v6 and α–catenin, respectively. Low fractions of CD44s– and CD44v6–positive cancer cells were related to high preoperative prostate–specific antigen (PSA) levels (p<0.05 for both). Low fraction of CD44s positive cancer cells was linked with presence of seminal vesicle invasion (p = 0.07), surgical margin positivity (p = 0.09), high Gleason score (p = 0.04) and high mitotic index (p = 0.02). Low fraction of CD44v3–positive cancer cells was related to positive surgical margins (p = 0.05), high Gleason score (p = 0.04), presence of perineural infiltration (p = 0.02) and absence of tumour–infiltrating lymphocytes (p = 0.02). Low fraction of CD44v6–positive cancer cells was related to high pT classification (p = 0.07), capsule invasion (p = 0.03), positive surgical margins (p = 0.05), high Gleason score (p = 0.008), perineural infiltration (p = 0.0001) and high mitotic index (p = 0.001). α–Catenin expression was not related to any of the clinicopathological variables included in this study. Gleason score (p = 0.001), pT classification (p = 0.007), perineural infiltration (p = 0.01) and the fraction of CD44v3–positive cancer cells (p = 0.04) were predictors of PSA failure in univariate analysis. pT category (p = 0.012), Gleason score (p = 0.02) and expression of CD44v3 (p = 0.0003) were independent predictors of PSA failure.Conclusions: The expression of CD44s, CD44v3 and CD44v6 is related to tumour differentiation. The expression of CD44v3 independently predicts PSA failure in addition to Gleason score and pT category during a short–term follow–up.

Long-term Outcome of Patients with Frequently Recurrent Non–muscle-invasive Bladder Carcinoma Treated with One Perioperative Plus Four Weekly Instillations of Mitomycin C Followed by Monthly Bacillus Calmette-Guérin (BCG) or Alternating BCG and Interferon-α2b Instillations: Prospective Randomised FinnBladder-4 Study

BACKGROUND Recurrent TaT1 non-muscle-invasive bladder cancer (NMIBC) patients should be treated with immediate instillation of chemotherapy after transurethral resection of bladder tumour followed by instillation therapy. OBJECTIVE To present long-term results of a study exploring the effect of initial mitomycin C (MMC) instillations followed by two types of immunotherapy for patients with frequently recurring NMIBC. DESIGN, SETTING, AND PARTICIPANTS Between 1992 and 1996, 236 patients with frequently recurring TaT1 grade 1-2 NMIBC were enrolled in the prospective randomised multicentre FinnBladder-4 study. INTERVENTION One perioperative plus four weekly instillations of MMC followed by monthly bacillus Calmette-Guérin (BCG) or alternating BCG and interferon (IFN)-α2b instillations for up to 1 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Primary end points were time to first recurrence and time to progression. Secondary end points were disease-specific mortality and overall survival. The principal statistical methods were the proportional subdistribution hazards model and Cox proportional hazards model plus cumulative incidence and Kaplan-Meier analyses. RESULTS AND LIMITATIONS The median follow-up was 10.3 yr (maximum: 19.8 yr) in the MMC-BCG group and 8.6 yr (maximum: 19.8 yr) in the MMC-BCG/IFN group. The probability of recurrence was significantly lower in the MMC-BCG group than in the MMC-BCG/IFN group (43% vs 78% at 10 yr and 45% vs 80% at 15 yr, respectively; hazard ratio: 2.86; 95% confidence interval, 1.98-4.13; p<0.001). There were no significant differences in the probability of progression, disease-free mortality, or overall survival. CONCLUSIONS Perioperative plus four weekly MMC instillations followed by monthly BCG, instead of alternating BCG and IFN-α2b instillations, significantly reduce long-term recurrence. PATIENT SUMMARY We demonstrated in non-muscle-invasive bladder cancer patients with exceptionally frequent recurrences that the risk of long-term recurrence was reduced from 78-80% to 43-45% if one perioperative plus four weekly mitomycin C instillations were followed by monthly bacillus Calmette-Guérin (BCG) instillations for 1 yr instead of alternating instillations of BCG and interferon-α2b. TRIAL REGISTRATION The registration was not considered necessary at this stage of the follow-up because the study was initiated as early as in 1992 and the last randomisation took place in 1996, before the current requirements concerning study registrations were implemented.

Comparison of intermittent and continuous androgen deprivation and quality of life between patients with locally advanced and patients with metastatic prostate cancer: a post hoc analysis of the randomized FinnProstate Study VII

Abstract Objective. The aim of the study was to compare intermittent (IAD) and continuous (CAD) androgen deprivation therapy (ADT) between locally advanced (M0) and metastatic (M1) prostate cancer, and the effect of ADT on the quality of life. Material and methods. In total, 852 men with advanced prostate cancer were enrolled to receive goserelin acetate for 24 weeks. Of these, 554 patients whose prostate-specific antigen (PSA) decreased to less than 10 ng/ml or by at least 50% (<20 ng/ml at baseline) were randomized to IAD or CAD. In the IAD arm, ADT was resumed for at least 24 weeks whenever PSA increased to greater than 20 ng/ml or above baseline. Results. Median follow-up time was 65 months. Median times from randomization to progression, death, prostate cancer death and treatment failure in M0 and M1 patients were 46.8 and 21.4, 57.6 and 40.3, 59.5 and 40.7, and 41.9 and 20.0 months, respectively (p < 0.001). No significant differences emerged between IAD and CAD. ADT showed a beneficial effect on pain, activity limitation and social functioning in M1 patients, and a deleterious effect on physical capacity in M0 patients and on sexual functioning in both groups. IAD offered extra benefit for activity limitation, social functioning and recovery of sexual functioning. Conclusions. IAD is as efficient as CAD in treatment of locally advanced and metastatic prostate cancer. ADT improves quality of life in M1 patients, with IAD offering extra benefit.

Transurethral Prostatectomy in Patients with Preoperative Bacteriuria: Double-Blind Study with Oral Fleroxacin and Cefalexin

We compared oral fleroxacin and cefalexin in the prevention of postoperative infectious complications after transurethral prostatectomy (TURP) in patients with preoperative bacteriuria. 95 patients underwent TURP due to benign prostatic hyperplasia with preoperative bacteriuria . The therapy consisted of 7 days of oral fleroxacin 400 mg once a day or cefalexin 500 mg three times daily. After 2 weeks, 62% of the urine samples were sterile in the fleroxacin group but only 37% in the cefalexin group (p = 0.047). Patients in the cefalexin group had also statistically significantly more symptoms of urinary tract infections. After 6 weeks, the bacterial eradication rate was 53% in the fleroxacin group and 37% in the cefalexin group. There were no septicemias. TURP can be performed with reasonable safety with this oral anbiotic therapy.