Nomogram Predicting Bladder Cancer-specific Mortality After Neoadjuvant Chemotherapy and Radical Cystectomy for Muscle-invasive Bladder Cancer: Results of an International Consortium.

BACKGROUND: Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) is associated with improved overall and cancer-specific survival. The post-NAC pathological stage has previously been reported to be a major determinant of outcome. OBJECTIVE: To develop a postoperative nomogram for survival based on pathological and clinical parameters from an international consortium. DESIGN, SETTING, AND PARTICIPANTS: Between 2000 and 2015, 1866 patients with MIBC were treated at 19 institutions in the USA, Canada, and Europe. Analysis was limited to 640 patients with adequate follow-up who had received three or more cycles of NAC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A nomogram for bladder cancer-specific mortality (BCSM) was developed by multivariable Cox regression analysis. Decision curve analysis was used to assess the model's clinical utility. RESULTS AND LIMITATIONS: A total of 640 patients were identified. Downstaging to non-MIBC (ypT1, ypTa, and ypTis) occurred in 271 patients (42 %), and 113 (17 %) achieved a complete response (ypT0N0). The 5-yr BCSM was 47.2 % (95 % confidence interval [CI]: 41.2-52.6 %). On multivariable analysis, covariates with a statistically significant association with BCSM were lymph node metastasis (hazard ratio [HR] 1.90 [95% CI: 1.4-2.6]; p < 0.001), positive surgical margins (HR 2.01 [95 % CI: 1.3-2.9]; p < 0.001), and pathological stage (with ypT0/Tis/Ta/T1 as reference: ypT2 [HR 2.77 {95 % CI: 1.7-4.6}; p < 0.001] and ypT3-4 [HR 5.9 {95 % CI: 3.8-9.3}; p < 0.001]). The area under the curve of the model predicting 5-yr BCSM after cross validation with 300 bootstraps was 75.4 % (95 % CI: 68.1-82.6 %). Decision curve analyses showed a modest net benefit for the use of the BCSM nomogram in the current cohort compared with the use of American Joint Committee on Cancer staging alone. Limitations include the retrospective study design and the lack of central pathology. CONCLUSIONS: We have developed and internally validated a nomogram predicting BCSM after NAC and radical cystectomy for MIBC. The nomogram will be useful for patient counseling and in the identification of patients at high risk for BCSM suitable for enrollment in clinical trials of adjuvant therapy. PATIENT SUMMARY: In this report, we looked at the outcomes of patients with muscle-invasive bladder cancer in a large multi-institutional population. We found that we can accurately predict death after radical surgical treatment in patients treated with chemotherapy before surgery. We conclude that the pathological report provides key factors for determining survival probability.

Concomitant CIS on TURBT does not impact oncological outcomes in patients treated with neoadjuvant or induction chemotherapy followed by radical cystectomy.

BACKGROUND: Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle invasive bladder cancer improves all-cause and cancer specific survival. We aimed to evaluate whether the detection of carcinoma in situ (CIS) at the time of initial transurethral resection of bladder tumor (TURBT) has an oncological impact on the response to NAC prior to radical cystectomy. PATIENTS AND METHODS: Patients were identified retrospectively from 19 centers who received at least three cycles of NAC or induction chemotherapy for cT2-T4aN0-3M0 urothelial carcinoma of the bladder followed by radical cystectomy between 2000 and 2013. The primary and secondary outcomes were pathological response and overall survival, respectively. Multivariable analysis was performed to determine the independent predictive value of CIS on these outcomes. RESULTS: Of 1213 patients included in the analysis, 21.8% had concomitant CIS. Baseline clinical and pathologic characteristics of the 'CIS' versus 'no-CIS' groups were similar. The pathological response did not differ between the two arms when response was defined as pT0N0 (17.9% with CIS vs 21.9% without CIS; p = 0.16) which may indicate that patients with CIS may be less sensitive to NAC or ≤ pT1N0 (42.8% with CIS vs 37.8% without CIS; p = 0.15). On Cox regression model for overall survival for the cN0 cohort, the presence of CIS was not associated with survival (HR 0.86 (95% CI 0.63-1.18; p = 0.35). The presence of LVI (HR 1.41, 95% CI 1.01-1.96; p = 0.04), hydronephrosis (HR 1.63, 95% CI 1.23-2.16; p = 0.001) and use of chemotherapy other than ddMVAC (HR 0.57, 95% CI 0.34-0.94; p = 0.03) were associated with shorter overall survival. For the whole cohort, the presence of CIS was also not associated with survival (HR 1.05 (95% CI 0.82-1.35; p = 0.70). CONCLUSION: In this multicenter, real-world cohort, CIS status at TURBT did not affect pathologic response to neoadjuvant or induction chemotherapy. This study is limited by its retrospective nature as well as variability in chemotherapy regimens and surveillance regimens.

Active surveillance for intermediate-risk prostate cancer.

BACKGROUND: Utilization of active surveillance (AS) for prostate cancer is increasing. Optimal selection criteria for this approach are undefined and questions remain on how best to expand inclusion beyond typical men with very low- or low-risk disease. We sought to review the current experience with AS for men with intermediate-risk featuresMethods:PubMed was queried for all relevant original publications describing outcomes for men with prostate cancer managed with AS. Outcomes for patients with intermediate-risk features as defined by the primary investigators were studied when available and compared with similar risk men undergoing immediate treatment. RESULTS: Cancer-specific survival for men managed initially with AS is similar to results published with immediate radical intervention. A total of five published AS series describe some outcomes for men with intermediate-risk features. Definitions of intermediate risk vary between studies. Men with Gleason 7 disease experience higher rates of clinical progression and are more likely to undergo treatment over time. Intermediate-risk men with Gleason 6 disease have similar outcomes to low-risk men. Men with Gleason 7 disease appear at higher risk for metastatic disease. Novel technologies including imaging and biomarkers may assist with patient selection and disease surveillance. CONCLUSIONS: The contemporary experiences of AS for men with intermediate-risk features suggest that although these men are at higher risk for eventual prostate-directed treatment, some are not significantly compromising chances for longer-term cure. Men with more than minimal Gleason pattern 4, however, must be carefully selected and surveyed for early signs of progression and may be at increased risk of metastases. Incorporating information from advanced imaging and biomarker technology will likely individualize future treatment decisions while improving overall surveillance strategies.

Pelvic lymphadenectomy in prostate cancer.

This review analyzes the anatomy of the prostate gland's lymphatic drainage, the optimal anatomic extend of pelvic lymph node dissection (PLND) and which dissection may be superior, who should undergo a PLND during prostatectomy, and its potential therapeutic benefits and complications. The prostate gland's lymphatic drainage can be variable, but frequently metastatic disease is found in the internal iliac chain. We conclude that the extended PLND yields the most lymph nodes and therefore may be superior. Some have demonstrated an unproven survival benefit after performing an extended PLND, possibly from removal of occult disease or from more accurate staging.

Elements regulating angiogenesis and correlative microvessel density in benign hyperplastic and malignant prostate tissue.

PURPOSE: To quantify the ex vivo production of proangiogenic proteins (vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (tPA)) and angiogenesis inhibitors (plasminogen activator inhibitor type-1 (PAI-1) and angiostatin) from epithelial and stromal components of primary prostate cancer (CaP) and benign prostatic hyperplasia (BPH) cultures. To perform microvessel density (MVD) counts on sections of BPH and CaP from the same prostatectomy specimens. SCOPE: Angiogenic cytokine expression was measured by immunoassays and in vitro angiostatin generating capacities assessed using immunoblotting. CaP and BPH tissue was immunostained using factor VIII antibody to determine MVD. CONCLUSIONS: Elements regulating angiogenesis are present in both primary cultures of CaP and BPH, suggesting that angiogenic ability is well established in the absence of carcinoma.

Regulation of u-PA gene expression in human prostate cancer.

u-PA contributes to CaP progression, especially in the metastatic androgen-insensitive state. In vitro, u-PA is expressed by androgen-insensitive, but not androgen-sensitive, CaP cell lines. We hypothesized that in androgen-sensitive CaP an activated ARE represses u-PA expression but in androgen-insensitive CaP this repression is lost and u-PA is upregulated through MAP kinase signaling pathways. To determine whether binding of the DHT-AR complex to AREs in the u-PA promoter region represses u-PA transcription in androgen-sensitive CaP, we studied 2 PC3 androgen-insensitive human CaP cell lines stably transfected with AR [PC3(AR)(2) and PC3(AR)(13)] and 1 mock-transfected cell line [PC3(M)]. In the presence of the synthetic androgen mibolerone, both PC3(AR)(2) and PC3(AR)(13), but not PC3(M), cells showed decreased u-PA expression as assayed by Western and Northern blotting. The AR inhibitor flutamide abrogated mibolerone's effect. Androgen regulation of a second gene, PSA, was also demonstrated in the PC3(AR)(2) cell line. To explore the pathway stimulating u-PA expression in CaP, we performed transient transfections in PC3(AR)(2) cells using u-PA promoter-regulated CAT reporter constructs. Compared to full-length u-PA promoter-CAT constructs, either deletion or mutation of the 5' AP-1 or PEA3 site reduced CAT expression. The location of androgen responsiveness in the u-PA promoter was not identified through the combination of promoter search and transient transfection assays, indicating that a more complicated mechanism is involved in the AR-mediated downmodulation of u-PA expression.

Differential expression of angiogenic cytokines by cell lines and primary cultures of human prostate cancer.

Studies on angiogenic cytokines usually are initially based upon their expression by available established cell lines. Our hypothesis is that established epithelial prostate cancer (CaP) cell lines do not accurately reflect angiogenic cytokine expression as compared to epithelial and stromal components of primary cultures generated from clinical CaP specimens. Serum free and growth factor free conditioned medium (CM) was collected from PC3, LNCaP, and their orthotopic selected prostate cancer sublines. Surgically acquired and pathologically confirmed neoplastic prostate tissue was selectively grown for selection of epithelial or stromal components, and CM was also collected. CM was assayed for urokinase (u-PA), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and tumor necrosis factor alpha (TNF-alpha). u-PA was expressed only by androgen independent cell lines, but was detectable in the epithelial and stromal cultures of androgen sensitive primary cultures. bFGF was not secreted by cell lines nor epithelial primary cultures. VEGF was universally expressed, but TNF-alpha was not secreted by cells lines nor primary cultures. These data suggest that the expression of angiogenic cytokines by established epithelial CaP cell lines does not reflect epithelial and stromal primary cultures.Prostate Cancer and Prostatic Diseases (2001) 4, 106-111