Laura S. Mertens

Multicenter Assessment of Neoadjuvant Chemotherapy for Muscle-invasive Bladder Cancer

BACKGROUND The efficacy of neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (BCa) was established primarily with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), with complete response rates (pT0) as high as 38%. However, because of the comparable efficacy with better tolerability of gemcitabine and cisplatin (GC) in patients with metastatic disease, GC has become the most commonly used regimen in the neoadjuvant setting. OBJECTIVE We aimed to assess real-world pathologic response rates to NAC with different regimens in a large, multicenter cohort. DESIGN, SETTING, AND PARTICIPANTS Data were collected retrospectively at 19 centers on patients with clinical cT2-4aN0M0 urothelial carcinoma of the bladder who received at least three cycles of NAC, followed by radical cystectomy (RC), between 2000 and 2013. INTERVENTION NAC and RC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary outcome was pathologic stage at cystectomy. Univariable and multivariable analyses were used to determine factors predictive of pT0N0 and ≤pT1N0 stages. RESULTS AND LIMITATIONS Data were collected on 935 patients who met inclusion criteria. GC was used in the majority of the patients (n=602; 64.4%), followed by MVAC (n=183; 19.6%) and other regimens (n=144; 15.4%). The rates of pT0N0 and ≤pT1N0 pathologic response were 22.7% and 40.8%, respectively. The rate of pT0N0 disease for patients receiving GC was 23.9%, compared with 24.5% for MVAC (p=0.2). There was no difference between MVAC and GC in pT0N0 on multivariable analysis (odds ratio: 0.89 [95% confidence interval, 0.61-1.34]; p=0.6). CONCLUSIONS Response rates to NAC were lower than those reported in prospective randomized trials, and we did not discern a difference between MVAC and GC. Without any evidence from randomized prospective trials, the best NAC regimen for invasive BCa remains to be determined. PATIENT SUMMARY There was no apparent difference in the response rates to the two most common presurgical chemotherapy regimens for patients with bladder cancer.

Impact of 18F‐fluorodeoxyglucose (FDG)‐positron‐emission tomography/computed tomography (PET/CT) on management of patients with carcinoma invading bladder muscle

To evaluate the clinical impact of 18F‐fluorodeoxyglucose (FDG)‐positron‐emission tomography/computed tomography (PET/CT) scanning, compared with conventional staging with contrast‐enhanced CT imaging (CECT).

FDG-Positron Emission Tomography/Computerized Tomography for Monitoring the Response of Pelvic Lymph Node Metastasis to Neoadjuvant Chemotherapy for Bladder Cancer

PURPOSE We evaluated FDG-positron emission tomography/computerized tomography for monitoring the response of pelvic lymph node metastasis to neoadjuvant chemotherapy for bladder cancer. We compared this to contrast enhanced computerized tomography. MATERIALS AND METHODS Included in study were 19 consecutive patients with lymph node positive bladder cancer who underwent FDG-positron emission tomography/computerized tomography and contrast enhanced computerized tomography before and after a median of 4 cycles (range 2 to 4) of neoadjuvant chemotherapy between September 2011 and April 2012. Metabolic response was assessed according to EORTC (European Organisation for Research and Treatment of Cancer) recommendations based on the change in FDG uptake on FDG-positron emission tomography/computerized tomography. Radiological response was assessed on contrast enhanced computerized tomography according to RECIST (Response Evaluation Criteria in Solid Tumors) 1.1. All patients underwent pelvic lymph node dissection. Histopathological evaluation served as the gold standard for the nodal response. RESULTS Before neoadjuvant chemotherapy, hypermetabolic FDG uptake was seen in all 19 patients, which matched the lymph node metastasis. Evaluating the nodal response with positron emission tomography/computerized tomography was feasible in all patients. On histopathology 16 patients were responders, including 14 with a complete pathological response of the lymph nodes. Positron emission tomography/computerized tomography and contrast enhanced computerized tomography correctly distinguished responders from nonresponders (18 of 19 patients or 94.7% and 15 of 19 or 78.9%) and complete responders from patients with residual disease (13 of 19 or 68.4% and 12 of 19 or 63.2%, respectively). CONCLUSIONS Although no definitive conclusions can be drawn from these preliminary data, positron emission tomography/computerized tomography appears feasible for evaluating the nodal response to neoadjuvant chemotherapy and distinguishing responders from nonresponders.

Prostate Sparing Cystectomy for Bladder Cancer: 20-Year Single Center Experience

PURPOSE We evaluated long-term oncologic and functional results after prostate sparing cystectomy for bladder cancer. MATERIALS AND METHODS A total of 120 patients with cT1-4N0-3 bladder cancer were treated with prostate sparing cystectomy between 1994 and 2013, of whom 110 had a followup of 2 years or greater and were eligible for analysis. To rule out tumor in the bladder neck, prostatic urethra or prostate cancer all patients underwent preoperative transurethral biopsy of the bladder neck and prostatic urethra, prostate specific antigen measurement and transrectal ultrasound with biopsies. We assessed oncologic outcomes (disease specific and recurrence-free survival), recurrence rates, prostate cancer and functional results (continence, voiding, and erectile and ejaculatory function). RESULTS Mean patient ± SD age was 56.2 ± 8.3 years and median followup was 77.0 months (IQR 57-116). Two and 5-year disease specific survival rates were 76.2% and 66.5%, 2 and 5-year recurrence-free survival rates were 71.2% and 66.6%, and distant and local recurrence rates were 34.2% and 10.0%, respectively. One local recurrence was in the remnant prostatic urothelium. Prostate cancer was diagnosed in 2.7% of cases. Complete daytime and nighttime continence was achieved in 96.2% and 81.9% of patients, and erectile function and antegrade ejaculation were intact in 89.7% and 35.5%, respectively. CONCLUSIONS Our long-term data show that prostate sparing cystectomy is an oncologically safe procedure with excellent functional results in a subset of carefully selected patients with bladder cancer without evidence of urothelial carcinoma in the prostatic urethra/bladder neck and no prostate cancer.

Occult lymph node metastases in patients with carcinoma invading bladder muscle: incidence after neoadjuvant chemotherapy and cystectomy vs after cystectomy alone.

To investigate the effect of neoadjuvant chemotherapy (NAC) on the incidence of lymph node (LN) metastases in clinically node‐negative (cN0) patients with carcinoma invading the bladder muscle (MIBC).

18F-fluorodeoxyglucose–Positron Emission Tomography/Computed Tomography Aids Staging and Predicts Mortality in Patients With Muscle-invasive Bladder Cancer

OBJECTIVE To investigate the association between extravesical (18)F-fluorodeoxyglucose (FDG) avid lesions on FDG-positron emission tomography/computed tomography (PET/CT) and mortality in patients with muscle-invasive bladder cancer. METHODS An international, bi-institutional cohort study of 211 patients with muscle-invasive bladder cancer who underwent staging CT and FDG-PET/CT imaging. On the basis of the presence of extravesical FDG-avid lesions suspicious for malignancy on PET/CT images, patients were divided into a PET/CT-positive and PET/CT-negative group. Data on staging and mortality were retrospectively analyzed from prospective databases. Kaplan-Meier analyses were performed to compare overall (OS) and disease-specific survival (DSS) between the groups. Multivariable Cox regression models were used to investigate the association between extravesical PET/CT lesions and mortality. Extravesical lesions suspicious for malignancy on conventional CT were included in the models. RESULTS Of the 211 patients, 98 (46.4%) had 1 or more extravesical lesions on PET/CT, 113 (53.5%) had a negative PET/CT. Conventional CT revealed extravesical lesions in 51 patients (24.4%). Median follow-up was 18 months. Patients with a positive PET/CT had a significantly shorter OS and DSS (median OS: 14 vs 50 months, P = .001; DSS: 16 vs 50 months, P <.001). In multivariable analysis, the presence of extravesical lesions on PET/CT was an independent prognostic indicator of mortality (OS: hazard ratio = 3.0, confidence interval 95% 1.7-5.1). This association was not statistically significant for conventional CT (hazard ratio = 1.6 (95% confidence interval 0.9-2.7). CONCLUSION On the basis of our results, the presence of extravesical FDG-avid lesions on PET/CT might be considered an independent indicator of mortality.

Carboplatin based induction chemotherapy for nonorgan confined bladder cancer--a reasonable alternative for cisplatin unfit patients?

PURPOSE We investigated induction carboplatin based chemotherapy in patients with nonorgan confined urothelial carcinoma who were considered unfit for cisplatin. A comparison was made with patients who received induction cisplatin based combination chemotherapy. MATERIALS AND METHODS We identified 167 patients with nonorgan confined urothelial carcinoma who received induction cisplatin based combination chemotherapy (126) or gemcitabine and carboplatin (41) at our hospital between 1990 and 2010. Of the patients 124 completed 4 cycles of cisplatin based combination chemotherapy or gemcitabine and carboplatin. Clinical response (ycTNM) was evaluated according to RECIST (Response Evaluation Criteria in Solid Tumors) 1.1. Radical cystectomy and bilateral extended pelvic lymph node dissection were performed in 106 patients. A pathological complete response was defined as no evidence of disease (ypT0N0). Disease specific survival was analyzed using the Kaplan-Meier method. Multivariate analysis was performed. RESULTS Complete clinical response rates did not differ significantly among the treatment groups. A pathological complete response was seen in 33.7% of specimens in the cisplatin based combination chemotherapy group vs 30.3% in the gemcitabine and carboplatin group (p = 0.808). We found no significant difference in disease specific survival between patients who started cisplatin based combination chemotherapy and those who started gemcitabine and carboplatin. For patients who completed 4 cycles and underwent radical cystectomy there was also no significant difference in disease specific survival between the groups. On multivariate analysis a pathological complete response was the only variable significantly associated with disease specific survival (p <0.045). CONCLUSIONS Induction gemcitabine and carboplatin for nonorgan confined urothelial carcinoma achieves clinical and pathological response rates, and survival outcomes comparable to those of the cisplatin based combination chemotherapy schemes. Our data suggest that a carboplatin based regimen can be considered a reasonable alternative for cisplatin unfit patients in the preoperative setting.

Tumor heterogeneity of fibroblast growth factor receptor 3 (FGFR3) mutations in invasive bladder cancer: implications for perioperative anti-FGFR3 treatment

BACKGROUND Fibroblast growth factor receptor 3 (FGFR3) is an actionable target in bladder cancer. Preclinical studies show that anti-FGFR3 treatment slows down tumor growth, suggesting that this tyrosine kinase receptor is a candidate for personalized bladder cancer treatment, particularly in patients with mutated FGFR3. We addressed tumor heterogeneity in a large multicenter, multi-laboratory study, as this may have significant impact on therapeutic response. PATIENTS AND METHODS We evaluated possible FGFR3 heterogeneity by the PCR-SNaPshot method in the superficial and deep compartments of tumors obtained by transurethral resection (TUR, n = 61) and in radical cystectomy (RC, n = 614) specimens and corresponding cancer-positive lymph nodes (LN+, n = 201). RESULTS We found FGFR3 mutations in 13/34 (38%) T1 and 8/27 (30%) ≥T2-TUR samples, with 100% concordance between superficial and deeper parts in T1-TUR samples. Of eight FGFR3 mutant ≥T2-TUR samples, only 4 (50%) displayed the mutation in the deeper part. We found 67/614 (11%) FGFR3 mutations in RC specimens. FGFR3 mutation was associated with pN0 (P < 0.001) at RC. In 10/201 (5%) LN+, an FGFR3 mutation was found, all concordant with the corresponding RC specimen. In the remaining 191 cases, RC and LN+ were both wild type. CONCLUSIONS FGFR3 mutation status seems promising to guide decision-making on adjuvant anti-FGFR3 therapy as it appeared homogeneous in RC and LN+. Based on the results of TUR, the deep part of the tumor needs to be assessed if neoadjuvant anti-FGFR3 treatment is considered. We conclude that studies on the heterogeneity of actionable molecular targets should precede clinical trials with these drugs in the perioperative setting.

Detecting primary bladder cancer using delayed (18)F-2-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography imaging after forced diuresis.

Objective: The aim of this study was to evaluate the use of delayed pelvic 18F-2-fluoro-2-deoxy-D-glucose-positron emission tomography combined with the computed tomography (FDG-PET/CT) imaging, according to a standardized protocol including, pre-hydration and forced diuresis, for the detection of primary bladder cancer. Materials and Methods: We evaluated 38 consecutive patients with primary cT1-4 bladder cancer. They underwent standard FDG-PET/CT followed by delayed pelvic imaging after administration of 20 mg furosemide intravenously and extra oral water intake of 0.5 L. Two observers, blinded for patient data, scored both image sets for tumor visibility using a 3-point ordinal scale: (1) negative; (2) indeterminate; (3) positive. FDG-PET/CT findings were compared with histopathology and/or follow-up imaging. Results: The procedure was completed successfully in 37/38 patients and the reference standard revealed a bladder tumor in 26/37 patients. Delayed PET/CT images showed reduction of urinary bladder activity to (near) background levels in 17 of 37 cases (45.9%). Standard PET/CT detected hyper-metabolic bladder lesions in 15/37 patients (40.5%) of which 8 were indeterminate. Delayed FDG-PET/CT showed hyper-metabolic bladder lesions in 30/37 (81.1%) patients, of which 5 were indeterminate. When indeterminate lesions were considered positive, the sensitivity of standard and delayed PET/CT was 46% versus 88%, respectively. The specificity was 72% versus 36%. When indeterminate lesions were considered negative, the sensitivity of standard and delayed PET/CT was 23% and 85%. The specificity was 93% versus 73%. Conclusions: Our data suggest that delayed pelvic FDG-PET/CT imaging after forced detects more primary bladder tumors than standard FDG-PET/CT protocols. However, indeterminate bladder lesions on delayed PET/CT remain a problem and should be interpreted cautiously in order to avoid false positive results.

Lymph node count at radical cystectomy does not influence long-term survival if surgeons adhere to a standardized template

INTRODUCTION Multiple bladder cancer studies report that the number of removed lymph nodes (lymph node count [LNC]) at radical cystectomy (RC) is positively associated with survival. Although these reports suggest that LNC can be used as a proxy for surgical quality, all studies used variable or inconsistent pelvic lymph node dissection (PLND) templates. We therefore wished to establish whether LNC at RC influences survival if surgeons adhere to a standardized PLND template. MATERIALS AND METHODS We included 274 patients who underwent RC from January 2005 until December 2012. All RCs were performed in either one of 2 hospitals (hospital A or B) by the same 4 urologists (all from hospital A) and a standardized PLND template was applied. PLND specimens were processed by 2 independent pathology departments (hospital A and B). We used Cox regression analysis to investigate the prognostic value of LNC adjusted for patient characteristics. We also compared LNC between hospitals and surgeons and investigated the effect of both the variables on overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS). RESULTS Median LNC was 17 (interquartile range = 12). At a median follow-up of 64.3 months, there was no association between LNC and OS (P = 0.328), CSS (P = 0.645), or DFS (P = 0.450). Median LNC was higher in hospital B than in hospital A (20.0 vs. 16.0, P = 0.003). Median LNC varied significantly among surgeons (12-20, P<0.001). Neither the hospital of surgery nor the surgeon performing PLND influenced OS (P = 0.771 and P = 0.982, respectively), CSS (P = 0.310 and P = 0.691, respectively), or DFS (P = 0.256 and P = 0.296, respectively). CONCLUSION If surgeons adhere to a standardized template, LNC at RC does not affect long-term survival.