Treatment of Metastatic Urothelial Carcinoma After Previous Cisplatin-based Chemotherapy for Localized Disease: A Retrospective Comparison of Different Chemotherapy Regimens.

BACKGROUND: Optimal chemotherapy for patients who received cisplatin for localized urothelial carcinoma (UC) and develop metastatic disease is unclear. We compared the efficacy of platinum-based (PBC) versus non-platinum-based (NPBC) first-line chemotherapy for metastasis. PATIENTS AND METHODS: Data were collected from the Retrospective International Study of Cancers of the Urothelial Tract (RISC), a database of 3024 patients from 28 international academic centers from 2005 to 2012. Patient inclusion criteria included: (1) predominant UC; (2) any primary tumor site; (3) cT2-4, cN0-N2, cM0; (4) prior receipt of perioperative/radiation cisplatin-containing chemotherapy; and (5) receipt of cytotoxic chemotherapy in the first-line metastatic setting. Multivariate Cox proportional hazards models were used to show progression-free survival (PFS) and overall survival (OS) from the first day of chemotherapy for metastatic disease to date of censor. RESULTS: Eligibility criteria was met by 132 patients (n = 74 PBC; n = 58 NPBC). The median OS was 8.13 months (interquartile range, 4.87-16.64 months) and 8.77 months (interquartile range, 4.01-13.49 months) for PBC and NPBC, respectively. Neither OS (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.64-1.69; P = .87) nor PFS (HR, 0.86; 95% CI, 0.56-1.31; P = .48) differed for PBC versus NPBC. However, for patients who received chemotherapy more than a year after perioperative/radiation chemotherapy, OS was superior for PBC over NPBC (HR, 0.31; 95% CI, 0.10-0.92; P = .03). CONCLUSIONS: There is no significant outcome difference between PBC and NPBC in patients with metastatic UC who previously received cisplatin-based chemotherapy for localized disease. However, if over a year has elapsed, return to PBC is associated with superior OS.

Comparative Effectiveness of Treatment Strategies for Squamous Cell Carcinoma of the Bladder.

BACKGROUND: While there is established evidence supporting the use of radical cystectomy (RC) and perioperative chemotherapy for muscle-invasive urothelial carcinoma of the bladder, such evidence does not exist for squamous cell carcinoma. OBJECTIVE: We present the largest study to date of patients with squamous cell carcinoma and compare the effectiveness of possible treatment regimens for overall survival. DESIGN, SETTING, AND PARTICIPANTS: The National Cancer Data Base was queried for cases of localized, muscle-invasive pure squamous cell bladder cancer, classified as clinical stage T2/3N0M0. Permutations of surgery (RC), chemotherapy, and external beam radiation were selected. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A multinomial propensity score method was used to create treatment weights based on clinical characteristics predicting the probability of treatment receipt. These were then applied in weighted Cox proportional hazards models to assess the comparative effectiveness of treatments for overall survival, adjusting for age, TNM clinical stage, Charlson comorbidity index, race, sex, and facility and county level variables. RESULTS AND LIMITATIONS: A total of 828 cases were included, comprising 465 RC alone, 53 neoadjuvant chemotherapy+RC, 48 RC+adjuvant chemotherapy, 72 chemotherapy alone, 88 radiation alone, and 102 chemoradiation cases. On weighted regression, RC treatment with or without perioperative chemotherapy was associated with significantly better overall survival compared to the other treatment modalities; chemotherapy alone, radiation alone, and chemoradiation were associated with a hazard ratio (HR) of death of 2.43 (95% confidence interval [CI] 1.65-3.59), 4.78 (95% CI 3.33-6.86), and 1.61 (95% CI 1.16-2.25), respectively, compared to RC alone (all p<0.005). A combination of RC and neoadjuvant chemotherapy was comparable to RC alone, with HR of death 1.33 (95% CI 0.89-1.98). The combination of RC and adjuvant chemotherapy was also similar to RC alone (HR 1.11, 95% CI 0.66-1.85). These findings are limited by small numbers and the retrospective nature of the study. CONCLUSIONS: RC with or without perioperative chemotherapy should be considered an upfront therapy for squamous cell carcinoma of the bladder. PATIENT SUMMARY: Using a national database, we compared treatments for muscle-invasive squamous cell bladder cancer. Patients undergoing radical cystectomy with or without chemotherapy had longer survival. Radical cystectomy with or without chemotherapy should be the standard of care for this disease.

ENERGIZE: a Phase III study of neoadjuvant chemotherapy alone or with nivolumab with/without linrodostat mesylate for muscle-invasive bladder cancer.

Immune checkpoint inhibitors have revolutionized the treatment of patients with metastatic urothelial carcinoma. In cisplatin-eligible muscle-invasive bladder cancer (MIBC), cisplatin-based neoadjuvant chemotherapy (NAC) before radical cystectomy improves overall survival. Tumor PD-L1 expression increases in MIBC after NAC, suggesting potential synergy in combining PD1/PD-L1 inhibitors with NAC. IDO1 is overexpressed in bladder cancer and is associated with poor outcomes. Linrodostat mesylate (BMS-986205) - a selective, potent, oral IDO1 inhibitor - combined with nivolumab has demonstrated safety and preliminary evidence of clinical activity in metastatic urothelial carcinoma. Here, we discuss the rationale and trial design of the ENERGIZE, a Phase III trial investigating the efficacy of NAC in combination with nivolumab with or without linrodostat followed by postsurgery nivolumab or nivolumab with linrodostat in cisplatin-eligible patients with MIBC. Clinical trial registration number: NCT03661320.

The development of differentiation agents for the treatment of prostate cancer.

Given their novel mechanisms of action and relatively favorable toxicity profiles, differentiation agents have been the focus of much investigation in the field of oncology. Among the most well studied of these agents in prostate cancer have been the retinoids, vitamin D, peroxisome-proliferator-activated receptor gamma (PPARgamma) ligands, and, most recently, the histone deacetylase (HDAC) inhibitors. While the clinical activity of these agents has been limited, several obstacles to the development of these novel drugs have become apparent. A lack of validated measures of outcome and uncertainty regarding the appropriate disease states in which to test these agents have led to difficulty in trial design. Furthermore, a better understanding of the biologic targets and genes manipulated by these therapies is required such that more potent and selective drugs may be developed. By overcoming these obstacles, the full potential of this therapeutic class may be realized.

Use of nomograms for predicting survival in patients with castrate prostate cancer.

Given the heterogeneity of prognoses in patients with castrate metastatic prostate cancer, the ability to accurately predict survival is vital for optimal patient counseling, selection of treatments, clinical trial design, and interpretation of clinical data. Over the past 20 years, several prognostic models have been developed in an attempt to refine the clinician's predictive ability. Early models were based on patients with more advanced disease. They included variables that are no longer regularly encountered today and involved cumbersome calculations that were not practical for everyday use in the clinic. Recently, 2 point-based nomograms have been developed based on pretreatment variables measured on a routine basis. These models provide a user-friendly format in which to make sophisticated predictions of survival. These models have improved our ability to predict the outcomes of patients with castrate metastatic disease. However, further work to identify novel prognostic markers to improve the accuracy of these predictions is needed.