Tapani Liukkonen

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.

Prognostic Value of MIB-1 Score, p53, EGFr, Mitotic Index and Papillary Status in Primary Superficial (Stage pTa/T1) Bladder Cancer: A Prospective Comparative Study

Objective: A prospective randomized study was undertaken to determine whether cell proliferation indices (M/V index, MIB1), papillary status, the expression of p53 and epidermal growth factor receptor (EGFr) have prognostic value in superficial (pTa–pT1) bladder cancer (SBC). Methods: 207 patients with primary SBC were followed up over a period of 4.9 (range 3.7–6.0) years. M/V index and papillary status were assessed by light microscopy, and expression of MIB1, p53 and EGFr was assessed by immunohistochemistry. The results of histopathological analyses were related to the survival data of the patients. Results: Using univariate analysis, stage (p < 0.001), grade (p < 0.001), papillary status (p < 0.001), MIB1 (p < 0.001), M/V index (p < 0.001), EGFr (p < 0.001) and p53 (p = 0.002) were significant predictors of progression. Using multivariate analysis, MIB-1 score and papillary status were independent predictors of progressive disease and cancer-specific survival. Tumor grade was the only independent predictor of recurrence. Conclusion: Evaluation of tumor cell proliferation rate by M/V index or by MIB1 immunohistochemistry and assessment of papillary status by light microscopy are useful prognostic tools in tailoring treatment and follow-up schedule of patients with SBC.

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.

WEEKLY MITOMYCIN C FOLLOWED BY MONTHLY BACILLUS CALMETTE-GUERIN OR ALTERNATING MONTHLY INTERFERON-α2B AND BACILLUS CALMETTE-GUERIN FOR PROPHYLAXIS OF RECURRENT PAPILLARY SUPERFICIAL BLADDER CARCINOMA

PURPOSE We evaluated alternatives to bacillus Calmette-Guerin (BCG) monotherapy using a new combination of chemotherapy and immunotherapy for recurrent superficial bladder carcinoma. MATERIALS AND METHODS A total of 236 patients with frequently recurrent stage Ta or T1 bladder tumors were enrolled in our prospective, randomized, multicenter Finnbladder IV study. The initial mitomycin C instillation was instilled in all patients perioperatively after transurethral resection, followed by 4 weekly instillations of mitomycin C. Thereafter patients were randomized to receive monthly for up to 1 year BCG only or interferon-alpha2b and BCG alternating monthly. Primary end points were time to initial recurrence, recurrence rate (number of recurrences per patient-year) and recurrence index (number of recurrent tumors per patient-year). RESULTS Of the 236 randomized patients 205 were eligible for study with a median overall followup of 30.7 months. Monthly BCG was superior to alternating monthly interferon-alpha and/or BCG with respect to time to initial recurrence (log rank test p <0.00001) as well as recurrence rate (0.4 versus 0.9, p <0.00001) and index (0.9 versus 3.0, p <0.00001). Side effects were limited. CONCLUSIONS Monthly BCG given for up to 1 year preceded by perioperative and an additional 4 weekly mitomycin C instillations is a well tolerated mode of instillation therapy, providing excellent tumor control comparable to that of the best reported instillation regimens. No benefit was obtained by alternating interferon-alpha2b with BCG.

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.

Suspicious Urine Cytology (Class III) in Patients with Bladder Cancer: Should it be Considered as Negative or Positive?

Objectives: Urine cytology is the gold standard in the diagnosis and follow-up of bladder cancer. Cytology, however, exhibits variable sensitivity depending on tumour grade and interpretation of urine specimens is highly dependent on the skill of the examiner. Positive cytology, classes IV and V by Papanicolaou classification, is a strong predictor for coexisting or subsequent malignancy, while the role of suspicious cytology, class III, is controversial. The objective of the study was to evaluate the role of the suspicious finding in cytological analysis, and whether it should be considered as a negative or positive sign for coexisting malignancy. Material and Methods: Six hundred and fifty-two consecutive patients with bladder cancer were studied in a prospective multicenter trial. One hundred and fifty-one of the patients were newly diagnosed, and the remaining 501 patients were under follow-up. A voided urine sample was obtained prior to TURB or prior to routine follow-up cystoscopy in those under the surveillance and split for culture and cytology. The cytopathological results were analyzed by a central review and only patients with samples available for review analysis were included. Sensitivity and specificity, as well as positive (PPV) and negative (NPV) predictive values of urine cytology were calculated by classifying the class III samples as negative or positive. Results: A total of 570 patients were evaluable. One hundred and twenty nine (22.6%) were newly diagnosed and 441 were under follow-up, of whom 117 (26.5%) had recurrence. Cytology was classified as suspicious in 33/129 (25.6%) patients with primary tumour, and in 41/441 (9.3%) of those under the follow-up, of whom 20 (48.8%) had recurrence. Sensitivity increased from to 31.0% to 56.6% in primary tumours ( p < 0.001) and from 17.8% to 34.7% in recurrent tumours ( p < 0.001) if class III was determined as positive, whereas the specificity decreased from 96.6% to 90.1% ( p < 0.001). Accordingly, the NPV increased from 76.3% to 79.1% and the PPV decreased from 65.6% to 56.2%. Conclusions: The poor sensitivity of voided urine cytology improved significantly when suspicious samples were determined as positive while the specificity remained high, a clear advantage compared with most of the new tumour marker tests. In addition, nearly half of the follow-up patients with suspicious class III cytology had recurrence implying that this patient category is at substantial risk for co-existing malignancy. Therefore, it is recommended that suspicious class III cytology together with class IV and V specimens should be considered positive.

Current concepts in the role of intravesical instillations in the therapy and prophylaxis of superficial transitional-cell cancer of the bladder

SummaryA survey on superficial, local urinary bladder cancer, its prognostic factors, and instillation treatments is presented on the basis of experience with approximately 1,000 patients over a period of 20 years, experimental investigations, and the literature. Personal opinions and practical recommendations are presented in 11 conclusive theses.

Intravesical Bacillus Calmette-Guérin Versus Combination of Epirubicin and Interferon-α2a in Reducing Recurrence of Non–Muscle-invasive Bladder Carcinoma: FinnBladder-6 Study

BACKGROUND Patients with non-muscle-invasive bladder cancer (NMIBC) belonging to the intermediate-risk group should be treated with intravesical instillations to prevent recurrence and progression. OBJECTIVE We compared the outcome of a monthly maintenance bacillus Calmette-Guérin (BCG) regimen with that of epirubicin (EPI) and interferon-α2a (IFN) in patients with NMIBC. DESIGN, SETTING, AND PARTICIPANTS Our prospective randomized multicenter study comprised 229 eligible patients with frequently recurrent TaT1 grade 1-2 or low-grade NMIBC enrolled between 1997 and 2008. INTERVENTIONS The four-arm study involved a single perioperative instillation of EPI plus five weekly instillations of BCG or EPI/IFN, followed by 11 monthly instillations in the 1-yr BCG or EPI/IFN maintenance arms, further followed by four additional quarterly instillations in the two 2-yr maintenance arms. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Time to recurrence, progression, disease-specific survival, and overall mortality were analyzed using the Kaplan-Meier and cumulative incidence analyses plus the Cox and proportional subdistribution hazards models. RESULTS AND LIMITATIONS The median follow-up time was 7.5 and 7.4 yr in the BCG and EPI/IFN groups, respectively. The probability of recurrence was significantly lower in the BCG group than in the EPI/IFN group. The probability was 39% versus 72% at 7.4 yr, respectively (hazard ratio [HR]: 0.41; 95% confidence interval [CI], 0.28-0.60; p<0.001). There was no significant difference in the probability of progression or in overall survival. However, there was a significant difference in disease-specific mortality in favor of the BCG group (HR: 0.20; 95% CI, 0.04-0.91; p=0.04). CONCLUSIONS The monthly maintenance BCG regimen showed excellent efficacy and was significantly better in preventing recurrence than a similar regimen of EPI/IFN-α2a. PATIENT SUMMARY A monthly bacillus Calmette-Guérin (BCG) regimen showed excellent efficacy and was significantly better in preventing recurrence than a similar regimen of epirubicin and interferon-α2a. TRIAL REGISTRATION Registration was not considered necessary at this stage of the follow-up because the study was initiated as early as in 1997, before the current requirements concerning study registrations were implemented.

Metabolic Consequences of Urinary Intestinal Diversion

Urinary intestinal diversion can produce metabolic disturbances of which the main and most specific is reabsorption of urinary water and electrolytes by the intestinal mucosa. This reabsorption can produce a metabolic hyperchloremic acidosis, usually without clinical consequences. Other complications are more rare and less specific. The main factor which favors these metabolic disorders is stagnation of urine in the intestine, especially when there is incomplete emptying of the urinary intestinal segment.