Alfred Witjes

Prognostic factors and risk groups in T1G3 non-muscle-invasive bladder cancer patients initially treated with Bacillus Calmette-Guerin: results of a retrospective multicenter study of 2451 patients

BACKGROUND The impact of prognostic factors in T1G3 non-muscle-invasive bladder cancer (BCa) patients is critical for proper treatment decision making. OBJECTIVE To assess prognostic factors in patients who received bacillus Calmette-Guérin (BCG) as initial intravesical treatment of T1G3 tumors and to identify a subgroup of high-risk patients who should be considered for more aggressive treatment. DESIGN, SETTING, AND PARTICIPANTS Individual patient data were collected for 2451 T1G3 patients from 23 centers who received BCG between 1990 and 2011. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Using Cox multivariable regression, the prognostic importance of several clinical variables was assessed for time to recurrence, progression, BCa-specific survival, and overall survival (OS). RESULTS AND LIMITATIONS With a median follow-up of 5.2 yr, 465 patients (19%) progressed, 509 (21%) underwent cystectomy, and 221 (9%) died because of BCa. In multivariable analyses, the most important prognostic factors for progression were age, tumor size, and concomitant carcinoma in situ (CIS); the most important prognostic factors for BCa-specific survival and OS were age and tumor size. Patients were divided into four risk groups for progression according to the number of adverse factors among age ≥ 70 yr, size ≥ 3 cm, and presence of CIS. Progression rates at 10 yr ranged from 17% to 52%. BCa-specific death rates at 10 yr were 32% in patients ≥ 70 yr with tumor size ≥ 3 cm and 13% otherwise. CONCLUSIONS T1G3 patients ≥ 70 yr with tumors ≥ 3 cm and concomitant CIS should be treated more aggressively because of the high risk of progression. PATIENT SUMMARY Although the majority of T1G3 patients can be safely treated with intravesical bacillus Calmette-Guérin, there is a subgroup of T1G3 patients with age ≥ 70 yr, tumor size ≥ 3 cm, and concomitant CIS who have a high risk of progression and thus require aggressive treatment.

Randomized Phase III Study Comparing Paclitaxel–Bleomycin, Etoposide, and Cisplatin (BEP) to Standard BEP in Intermediate-Prognosis Germ-Cell Cancer: Intergroup Study EORTC 30983

PURPOSE To compare the efficacy of four cycles of paclitaxel-bleomycin, etoposide, and cisplatin (T-BEP) to four cycles of bleomycin, etoposide, and cisplatin (BEP) in previously untreated patients with intermediate-prognosis germ-cell cancer (GCC). PATIENTS AND METHODS Patients were randomly assigned to receive either T-BEP or standard BEP. Patients assigned to the T-BEP group received paclitaxel 175 mg/m(2) in a 3-hour infusion. Patients who were administered T-BEP received primary granulocyte colony-stimulating factor (G-CSF) prophylaxis. The study was designed as a randomized open-label phase II/III study. To show a 10% improvement in 3-year progression-free survival (PFS), the study aimed to recruit 498 patients but closed with 337 patients as a result of slow accrual. RESULTS Accrual was from November 1998 to April 2009. A total of 169 patients were administered BEP, and 168 patients were administered T-BEP. Thirteen patients in both arms were ineligible, mainly as a result of a good prognosis of GCC (eight patients administered BEP; six patients administered T-BEP) or a poor prognosis of GCC (one patient administered BEP; four patients administered T-BEP). PFS at 3 years (intent to treat) was 79.4% in the T-BEP group versus 71.1% in the BEP group (hazard ratio [HR], 0.73; CI, 0.47 to 1.13; P [log-rank test] = 0.153). PFS at 3 years in all eligible patients was 82.7% versus 70.1%, respectively (HR, 0.60; CI: 0.37 to 0.97) and was statistically significant (P = 0.03). Overall survival was not statistically different. CONCLUSION T-BEP administered with G-CSF seems to be a safe and effective treatment regimen for patients with intermediate-prognosis GCC. However, the study recruited a smaller-than-planned number of patients and included 7.7% ineligible patients. The primary analysis of the trial could not demonstrate statistical superiority of T-BEP for PFS. When ineligible patients were excluded, the analysis of all eligible patients demonstrated a 12% superior 3-year PFS with T-BEP, which was statistically significant.

The impact of re-transurethral resection on clinical outcomes in a large multicentre cohort of patients with T1 high-grade/Grade 3 bladder cancer treated with bacille Calmette-Guerin

To determine if a re‐transurethral resection (TUR), in the presence or absence of muscle at the first TUR in patients with T1‐high grade (HG)/Grade 3 (G3) bladder cancer, makes a difference in recurrence, progression, cancer specific (CSS) and overall survival (OS).

The effect of the time interval between diagnosis of muscle-invasive bladder cancer and radical cystectomy on staging and survival: A Netherlands Cancer Registry analysis

INTRODUCTION Data from single-center series suggest that a delay in time to radical cystectomy (RC) more than 3 months after diagnosis of muscle-invasive bladder cancer (MIBC) is associated with pathological upstaging and decreased survival. However, limited data is available from population-based studies. In this study, the effect of delayed RC was assessed in a nationwide cohort. MATERIALS AND METHODS Patients who underwent RC between 2006 and 2010 with primary clinical T2-T4N0M0 urothelial bladder cancer were selected using the Netherlands Cancer Registry database. Data from the Netherlands Cancer Registry was supplemented with data from the Nationwide Network and Registry of Histo- and Cytopathology database in case of incomplete information. The cohort was divided in patients who underwent RC ≤3 months (group I) vs. patients who underwent RC >3 months (group II). Median time from MIBC diagnosis to RC, variables associated with delayed RC >3 and the effect of delayed RC on staging and overall survival (OS) were evaluated in patients who underwent neoadjuvant therapy and patients who did not. RESULTS A total of 1,782 patients were included. Median follow-up time was 5.1 years for living patients and 1.3 years for deceased patients. Median time from MIBC diagnosis to RC was 50 days (interquartile range: 27 days) and 93% of patients underwent RC≤3 months. Patients older than 75 years (odds ratio [OR] = 0.50; 95% CI: 0.32-0.77), referred for RC (OR = 0.41; 95% CI: 0.26-0.69), and treated in a university hospital (OR = 0.34; 95% CI: 0.21-0.56) were less likely to undergo RC≤3 months. Pathologic upstaging rate (43.9% vs. 42.1%) and node-positive disease rate (20.2% vs. 21.7%) did not differ for group I and II. Delayed RC>3 months was not associated with decreased OS adjusting for confounding variables (hazard ratio = 1.16; 95% CI: 0.91-1.48; P = 0.25). Median time from MIBC diagnosis to RC in patients that received neoadjuvant therapy (n = 105) was 133 days (interquartile range: 62 days). Adjusting for confounding variables, delayed RC>3 months was not associated with OS (hazard ratio = 0.90; 95% CI: 0.45-1.82). CONCLUSIONS The vast majority of patient underwent RC within 3 months after diagnosis of MIBC, as recommended in the European Association of Urology MIBC guideline. Delayed RC for more than 3 months had no adverse effect on staging and survival.

1001 The impact of re-TUR on clinical outcomes in a large cohort of t1g3 patients treated with BCG

INTRODUCTION AND OBJECTIVES: Low risk non-muscle invasive bladder cancer (NMIBC) is an heterogeneous neoplasm, characterized by a high percentage of recurrences but a low tendency of progression. In this group of patients, overtreatment posts and impact in the quality of life and it implies high significant economical costs and an important deterioration of the quality of life, without evidence of improving their survival. Therefore, it seems reasonable to develop a program based on surveillance and monitoring of new recurrences. Our aim is to report our experience with low-risk bladder cancer patients under an active surveillance program after cancer recurrence, and to analyse which variables might help to predict progression. METHODS: From 2006 we have offered the option of active surveillance to all low risk tumours at time of recurrence. Follow-up included flexible cystoscopy and cytology every six months. TUR was performed when tumour size or number of lesions increased, at high grade cytology, when hematuria, tumour aspect worsened or patients’ choice. RESULTS: 68 patients were included. Mean age at recurrence was 71.5 years. Only 13,2% were female. Almost all patients received immediate postoperative mytomicin C (96%). Histological initial features were stage pTa in 48.5%, stage pT1a in 25%, pTx in 7.4% and PUNLMP in 17.6%; all were low grade. Mean time between TUR and recurrence was 33 months. The mean follow-up was 25,8 months. 32 (47%) patients underwent TUR after recurrence (mean time 20 months). Main cause of TUR (50%) was the increase of the number of lesions and tumor size, 18% due to hematuria, 6% to positive citology. Concerning recurrence features, 80% were single tumors and size was 5 mm in 60%. Seven patients (21.87%) progressed in stage (pTa to pT1a) (4) or grade (3). All patients with progression, tumor size was 5 mm or had positive cytology. None of our patients progressed to muscle invasive bladder cancer. CONCLUSIONS: Patients with recurrent, small, non muscleinvasive bladder tumours can be safely offered monitoring under an active surveillance protocol. Active surveillance can be safely considered in patients with less than 5mm recurrence or negative cytology.

Prognostic factors and risk groups in T1G3 patients initially treated with BCG: Results of a multicenter retrospective series in 1743 patients

Prognostic Factors And Risk Groups In T1g3 Patients Initially Treated With Bcg : Results Of A Multicenter Retrospective Series In 1743 Patients

VALUE OF 3 TESLA MULTI-MODALITY DIRECTED MR GUIDED BIOPSY TO DETECT PROSTATE CANCER IN PATIENTS AFTER AT LEAST TWO PREVIOUS NEGATIVE BIOPSIES AND ELEVATED PSA

(MRI), a novel platform that registers and fuses real-time US images with pre-procedure MRI was used. Feasibility and initial experience with MRUS fused targeted prostate biopsies with real time tracking performed outside MRI is described. METHODS: Under an IRB approved protocol patients with suspicion of prostate cancer (elevated PSA, history of prostate cancer) underwent a 3T endorectal-coil prostate MRI with T1, T2 weighted, dynamic contrast enhanced, diffusion weighted, and spectroscopy images. Lesions identified on MRI were scored for level of suspicion for cancer. A traditional 12-core US guided prostate biopsy was then performed. Subsequently, biopsies of MRI targeted lesions were performed using a custom probe and needle guide with spatial tracking within an electromagnetic field. Prostate US images were fused to MR images allowing for real-time US images and projected needle pathways on the corresponding MR location. RESULTS: 51 patients, mean age 62 (49-79) and mean PSA 8.1 (0.3 -46.9), underwent US-MR tracked fusion biopsy. 31 patients had prior prostate biopsy with 20 having known prostate cancer. 703 standard sextant biopsy cores and 352 tracked biopsy cores from 144 MRI targets were obtained. Core biopsies were analyzed by region (considered positive if at least 1 core at that region was positive). 18% (57/324) of the sextant regions and 25% (36/144) of the tracked regions were positive for cancer. 57% (29/51) of patients had positive biopsy with 19 (65%) on both sextant and tracked biopsy, 6 (21%) only positive on sextant biopsy and 4 (14%) on tracked biopsy only. Targets with increasing suspicion on MRI were more likely to be positive for cancer (see table). CONCLUSIONS: This phase I study demonstrates the feasibility and the clinical value (detecting 4 additional cases of cancer) of MR targeting of prostate lesions using real-time US images fused to preprocedure MRI and spatial tracking technology. Further studies are required to determine its role in cancer detection.

PD48-03 RISK FACTORS FOR RESIDUAL DISEASE AT RE-TUR IN T1G3 BLADDER CANCER

INTRODUCTION AND OBJECTIVES: Repeat TUR is both diagnostic and therapeutic in patients with T1 NMIBC. The depth of lamina propria invasion was shown to have the largest impact on T1 tumors prognosis. We intended to evaluate the influence of lamina propria invasion type at initial TUR on the re-staging pathology. METHODS: We reviewed from our prospectively maintained database all patients with a high-grade pT1 disease who underwent a re-staging TUR within 6 weeks at our center from January 2015 to May 2016. All pathology specimens were reviewed by a dedicated uropathologist. The characteristics of the lamina propria invasion were assessed according to the pathological report to identify focal invasion. The pathology of the second TUR was analyzed regarding the characteristics of the initial resection. RESULTS: We included 198 patients, with a median age of 70 years (interquartile range: 63-79). Muscle was present in the initial TUR specimen in 107 patients (54%). Pathology restaging was pT0 in 73 patients (37%), pTis in 44 (22%), pTa in 27 (14%), pT1 in 50 (25%) and pT2 in 4 (2%). Eighty-seven patients (44%) had tumors with minimal lamina propria invasion at initial TUR (53 specimens (27%) with focal invasion, 15 (7.6%) with superficial invasion and 19 (10%) with multifocal superficial invasion). Focal invasion was defined as few malignant cells in the lamina propria, superficial invasion as T1a and multifocal superficial invasion as multiple areas of T1a. Of the patients with minimal lamina propria invasion, residual disease was found in 20 patients (23%). However, none of those patients had T2 disease (Table 1). CONCLUSIONS: A significant number of patients with T1 tumors have residual disease at restaging TUR. This is not any different among patients with minimal lamina propria invasion. All patients with T1 tumors should undergo restaging TUR irrespective of the depth of penetration into the lamina propria.

Recurrence and progression according to stage at re-TUR in t1g3 bladder cancer patients treated with BCG: Not as bad as previously thought

INTRODUCTION AND OBJECTIVES: Intravesical induction immunotherapy with Bacille Calmette-Guerin (BCG) is the standard of care treatment for high risk non-muscle invasive bladder cancer (NMIBC). Despite this, rates of recurrence and progression to muscleinvasion remain unacceptably high. We sought to optimize immunologic response to intravesical induction immunotherapy with standardized BCG intradermal vaccination prior to induction, and herein report our two year outcomes. METHODS: BCG-naive patients with high-risk NMIBC who were candidates for BCG therapy were prospectively enrolled from 2014-2015. Patients who were PPD-negative were subsequently vaccinated with BCG in standard intradermal fashion, and 3 weeks later, standard induction immunotherapy with Tice BCG was performed. Urinary cytokines, BCG-specific T and mononuclear cells, and clinical outcomes were analyzed. RESULTS: 15 patients were enrolled and 13 completed the study; 5 controls were also enrolled. The median follow-up was 20.4 months (range: 28.1 to 14.8m). No patient experienced dose-limiting toxicity or a Grade 3+ adverse event. No patients progressed to muscleinvasive disease. 9 patients successfully converted PPD. 9 of 13 patients recurred in the lower tract (69.2%) and all were successfully salvaged. Immunologically, BCG-specific T cell lymphoproliferation was increased, as was IFN-g secretion, IFN-g ELISPOT response, and direct ex vivo IFN-g response. Flow cytometry demonstrated that BCG significantly enhanced CD4+ and CD8+ T cells in most patients. Compared to controls, primed patients exhibited an increase in IFN-g release in response to BCG ex vivo at both 3 months and 6 months after therapy. Priming resulted in an earlier and more robust increase in urinary IL-2, IL-17, and IL-8 compared to control patients suggesting a potential benefit from earlier and higher activation of local immune response. CONCLUSIONS: Vaccination with BCG prior to induction immunotherapy results in improved immunologic measurements and increased urinary cytokines associated with control of high-risk NMIBC. Priming may represent a method to increase the efficacy of BCG immunotherapy for high-risk NMIBC. Further study with dedicated multicenter clinical trials and long term follow-up is warranted.

MP56-16 THE IMPACT OF RE-TUR ON CLINICAL OUTCOMES IN A LARGE COHORT OF T1G3 PATIENTS TREATED WITH BCG.

INTRODUCTION AND OBJECTIVES: Low risk non-muscle invasive bladder cancer (NMIBC) is an heterogeneous neoplasm, characterized by a high percentage of recurrences but a low tendency of progression. In this group of patients, overtreatment posts and impact in the quality of life and it implies high significant economical costs and an important deterioration of the quality of life, without evidence of improving their survival. Therefore, it seems reasonable to develop a program based on surveillance and monitoring of new recurrences. Our aim is to report our experience with low-risk bladder cancer patients under an active surveillance program after cancer recurrence, and to analyse which variables might help to predict progression. METHODS: From 2006 we have offered the option of active surveillance to all low risk tumours at time of recurrence. Follow-up included flexible cystoscopy and cytology every six months. TUR was performed when tumour size or number of lesions increased, at high grade cytology, when hematuria, tumour aspect worsened or patients’ choice. RESULTS: 68 patients were included. Mean age at recurrence was 71.5 years. Only 13,2% were female. Almost all patients received immediate postoperative mytomicin C (96%). Histological initial features were stage pTa in 48.5%, stage pT1a in 25%, pTx in 7.4% and PUNLMP in 17.6%; all were low grade. Mean time between TUR and recurrence was 33 months. The mean follow-up was 25,8 months. 32 (47%) patients underwent TUR after recurrence (mean time 20 months). Main cause of TUR (50%) was the increase of the number of lesions and tumor size, 18% due to hematuria, 6% to positive citology. Concerning recurrence features, 80% were single tumors and size was 5 mm in 60%. Seven patients (21.87%) progressed in stage (pTa to pT1a) (4) or grade (3). All patients with progression, tumor size was 5 mm or had positive cytology. None of our patients progressed to muscle invasive bladder cancer. CONCLUSIONS: Patients with recurrent, small, non muscleinvasive bladder tumours can be safely offered monitoring under an active surveillance protocol. Active surveillance can be safely considered in patients with less than 5mm recurrence or negative cytology.