Intravesical chemotherapy for intermediate risk non-muscle invasive bladder cancer recurring after a first cycle of intravesical adjuvant therapy

Context: The therapeutic strategy in intermediate risk (IR) non-muscle invasive bladder cancer (NMIBC) recurring after intravesical therapy (IT) is not well defined. Most patients are usually retreated by Bacillus Calmette-Guerin (BCG). Aims: To evaluate the efficacy of intravesical chemotherapy (ICH) given at recurrence after the first cycle of ICH in IR-NMIBC recurring 6 months or later. Settings and Design: Retrospective analysis of the efficacy of ICH given after previous IT. Materials and Methods: The clinical files of IR-NMIBC patients recurring later than 6 months after transurethral resection (TUR) and IT and retreated by IT were reviewed. The patients should be at intermediate risk both initially and at the first recurrence. BCG should have been given at full dose. Cytology and cystoscopy were performed 3 monthly for 2 years and then 6 monthly. Statistical Analysis: The RFS was estimated by the Kaplan-Meier method and the differences between treatment groups were compared by log-rank test. Mann Whitney U-test was used to compare the parameters\u2032 distribution for median time to recurrence. Multivariate Cox proportional hazards models were used. Results: The study included 179 patients. The first IT was ICH in 146 (81.6%) and BCG in 33 (18.4%), re-IT was ICH in 112 (62.6%) and BCG in 67 (37.4%) patients. Median time to recurrence was 18 and 16 months after first and second IT (P = 0.32). At 3 years, 24 (35.8%) and 49 (43.8%) patients recurred after BCG and ICH, respectively (P = 0.90). No difference in RFS was found between BCG and ICH given after a first cycle of ICH (P = 0.23). Conclusions: Re-treatment with ICH could represent a legitimate option to BCG in patients harboring IR-NMIBC recurring after TUR and previous ICH. Prospective trials are needed

CHOICE OF ADJUVANT INTRAVESICAL THERAPY IN RECURRING INTERMEDIATE-RISK NMI-BC

Objective: The therapeutic strategy for patients affected by intermediate risk non-muscle invasive bladder cancer (NMIBC) recurring after intravesical therapy is not definitively established. Only few studies have been published on secondline intravesical therapy. BCG is advocated when intravesical chemotherapy fails and is often repeated. On the other hand, some patients that suffer recurrence repeat intravesical chemotherapy. A retrospective analysis of 179 intermediaterisk patients submitted to second-line intravesical therapy is reported. Patients and Methods: The clinical files of patients affected by intermediate risk NMI-BC and submitted to second-line adjuvant intravesical therapy were reviewed. Patients not receiving at least six instillations of BCG or intravesical chemotherapy after the first diagnosis and again after the transurethral resection (TUR) of the first recurrence were excluded. Only mitomycin c and epirubicin were accepted as chemotherapy. Only patients with intermediaterisk tumors with a recurrence-risk score between 5 and 9 according to the EORTC risk tables and in absence of Tis were selected. A multivariate analysis was performed for recurrence-free survival (RFS) and progression, considering first line intravesical therapy (BCG versus ICH), previous recurrence-free interval, tumor T category, G grade, multiplicity, second-line intravesical therapy (BCG versus ICH) and maintenance regimen. Results: The study included 179 patients. Chemotherapy was administered as first-line therapy in 131 (73.2%) and BCG in 48 (26.8%) patients. Second-line therapy was represented by BCG in 83 (46.4%) and chemotherapy in 96 (53.6%) patients, with maintenance of at least 12 months in 31% and 38% of patients, respectively. Of the 48 patients previously treated by BCG, 40 (83.3%) received BCG again, while of the 131 previously treated by chemotherapy, 88 (67.2%) repeated it and 43 (32.8%) received BCG. At a median follow-up of 29 months after the second TUR, 65 (36.3%) patients experienced recurrence, 25 (30.1%) and 40 (41.7%) after BCG and chemotherapy, respectively. Thirteen patients showed progression at a median interval of 19 months. At multivariate analysis, no statistically significant correlation was detected. Surprisingly, no statistical difference emerged in terms of recurrence-free interval between first- and second-line therapy and between BCG and chemotherapy as second-line therapy at recurrence after chemotherapy (p=0.28) Conclusion: Almost 65% of patients experiencing recurrence after intravesical chemotherapy received intravesical therapy again. No difference in efficacy was detected between firstand second-line therapies or between BCG and chemotherapy given at recurrence after chemotherapy

BIOMARKERS OF UROTHELIAL DAMAGE IN PATIENTS TREATED BY ADJUVANT INTRAVESICAL THERAPY

Introduction/Aim: Chemotherapy or BCG given intravesically to prevent recurrence after transurethral resection (TUR) of non-muscle invasive bladder cancer (NMI-BC) cause frequent, sometime severe, local toxicity. As a consequence, many patients do not complete the planned treatment (1). A major challenge for the urologists is to identify an early biomarker of urothelial damage to recognize and prevent local toxicity improving patient’s compliance. The purpose of our research was to investigate the relation between urothelial injury by intravesical treatment and the expression of potential biomarkers in urine and/or in barbotage solution. The urinary HB-EGF expression in interstitial cystitis has been analyzed by a few studies (2, 3). As a preliminary step, the variations of Fibronectin (FN), Epidermal Growth Factor- Receptor (EGF-R) and Heparin-binding Epidermal Growth Factor-like Growth Factor (HB-EGF) during intravesical therapy and after the administration of a solution with the potential role of urothelial repairing (hyaluronic acid and chondroitin sulphate) were investigated. Patients and Methods: the toxicity of intravesical therapy with mitomycin, epirubicin or BCG was classified in 3 grades (absent, moderate, severe). Urine and bladder washing solution during intravesical therapy in 55 patients after NMI-BC TUR and in 10 healthy controls for a total of 200 samples were collected. Total cellular RNA was isolated from the cell pellet using miRNeasy Mini Kit (Qiagen®). FN and EGF-R gene expression by Real Time quantitative PCR were analyzed. The expression of HB-EGF was measured in urine samples by ELISA (Abcam®). Results: In barbotage samples the FN gene expression and the EGF-R levels in our patients were respectively increased a median of 4.7 fold and decreased of 0.9 fold compared to controls. Before intravesical therapy and in absence of local toxicity, gene expression increased 1.9 fold for FN and 1.1 fold for EGF-R. In contrast, in patients with local toxicity due to intravesical therapy, the FN gene expression levels increased to a median of 5.82 fold, while EGF-R remained unchanged. The administration of hyaluronic acid and chondroitin sulphate solution decreased the mean FN gene expression from 3 to 0.6 fold, with concomitant symptomatic relief. HB-EGF protein median urine levels were 25.7 pg/ml in 13 patients before intravesical therapy and 18.9 pg/ml in 5 healthy controls. No significant variations in relation to the local toxicity. During therapy median HB-EGF protein levels in urine varied from 21.6 pg/ml in absence of toxicity to 25.7 pg/ml in case of severe toxicity to 18.5 pg/ml after hyaluronic acid and chondroitin sulphate solution. Preliminarily, the observed variations of HB-EGF, increasing no more than 1.2 fold compared to healthy controls, do not seem possible marker of urothelial damage. Discussion and Conclusion: EGF-R gene and HBEGF expressions do not seem to vary significantly in relation to local toxicity due to intravesical therapy. FN gene is overexpressed in presence of urothelial damage significantly reduced by intravesical hyaluronic acid and chondroitin sulphate solution administration, according with symptoms relief

PRELIMINARY DATA ON PSA CHANGES DURING INTRAVESICAL THERAPY FOR NON-MUSCLE INVASIVE BLADDER CANCER

Introduction/Aim: Many factors can cause an increase of PSA independently from the presence of prostate cancer . The objective was to evaluate the fluctuation of the serum levels of PSA during adjuvant intravesical chemotherapy or immunotherapy. An increase of PSA due to intravesical BCG and up to 3 months later has been reported (1). Patients and Methods: Patients treated with intravesical chemotherapy or immunotherapy for non- muscle invasive bladder cancer (NMIBC) were entered in the study. Serum samples were collected before starting intravesical therapy, during therapy (within 3rd and 6th instillation) and 30 days after the end of the 6-week induction regimen and during maintenance regimen when given. Patients with urinary tract infections, history of chronic prostatitis, elevated PSA before starting intravesical therapy, palpable prostate nodule or prostate cancer were not included. Results: Forty-five patients were studied, 34 receiving chemotherapy and 11 BCG. Thirty-three patients completed the induction regimen and in 12 more patients the research is ongoing. Out of the 33 evaluable patients, 23 received chemotherapy (mitomycin or epirubicin), while 10 immunotherapy (BCG Connaught). The pre-induction PSA mean level was 2.9 ng/ml.We observed a median PSA increase of 33,5% (p<0.0001) during therapy, in 18 (54.5%) patients. Twelve patients (36.3%) showed a median PSA decrease of 31.4% (p=0.3638). In two patients only (6%) PSA remained unchanged.We also observed a median increase of serum PSA levels of 87.4% at one month after the end of induction regimen. No significant difference between serum PSA level fluctuations induced by chemotherapy or BCG was detected: median increases during therapy and 30 days after the end were 91.7% and 149, 7% and 91.7% and 133% respectively (p<0.001). Discussion and Conclusion: Our preliminary study shows a clinically relevant increase of serum PSA levels in men undergoing both adjuvant intravesical BCG or chemotherapy. We confirm the results of the few studies reporting the increase of PSA during intravesical therapy with BCG or chemotherapy (2). The above mentioned variations should be considered when selecting patients undergoing prostate biopsy

A PROSPECTIVE STUDY ON THE INFLUENCE ON RECURRENCE OF QUITTING CIGARETTE SMOKING AT DIAGNOSIS OF PRIMARY NON MUSCLE INVASIVE BLADDER CANCER

Cigarette smoking is a known risk factor for bladder cancer (BC). Even if there is evidence that quitting decreases the incidence of BC it is still object of debate if quitting at first diagnosis could influence the outcome of primary non muscle invasive bladder cancer (NMIBC) reducing the risk of further recurrence. The aim of the present prospective study is to evaluate the outcome of smokers affected by primary NMI-BC in relation to their smoking habit after diagnosis