High-dose fotemustine in temozolomide-pretreated glioblastoma multiforme patients

Background: Glioblastoma multiforme (GBM) is a rare and deadly disease, with a reported average incidence rate of 3.19 cases per 100,000 inhabitants. Fotemustine, a third-generation nitrosourea with an alanine phosphor carrier that facilitates cellular penetration, has been extensively investigated in the setting of recurrent/progressive disease after initial treatment. Fotemustine is usually administered following a schedule consisting of 3 doses every week, followed by maintenance doses administered every 3 weeks. Methods: In this phase I/II trial, we aimed to assess whether the use of a biweekly regimen allowed administration of higher dose than the standard 100mg/m2 dose approved per label indication in a population of patients with recurrent GBM. In this phase I/II trial, fotemustine was administered intravenously over 1hour every 2 weeks at either 120 or 140mg/m2 doses for up to 1 year, until disease progression, unacceptable toxicity, or patient's request to withdraw from the study. The phase I part of the trial was conducted following the classic 3+3 study design. The phase II part of the trial was a single-arm study. The primary efficacy endpoint was the percentage of patients who had not progressed after 24 weeks (PFS-24). Results: Thirty-seven patients were enrolled in this phase I/II trial from August 2006 to November 2011. Treatment was well tolerated in the overall population. Main severe toxicity was grades 3 and 4 thrombocytopenia, which occurred in 4 of 6 patients treated at the 140mg/m2 dose level and in 3 of 31 patients treated at 120mg/m2. Median PFS and overall survival were 12.1 (1-40.2) weeks and 19.7 (1-102) weeks, respectively. Conclusion: We conclude that fotemustine can be safely administered at 120mg/m2 biweekly. The efficacy of such modified schedule and doses should be compared to the biweekly schedule at 80mg 2 and the standard weekly schedule at 80 to 100mg/m2

Prognostic Significance of Organ-Specific Metastases in Patients with Metastatic Upper Tract Urothelial Carcinoma

Background: Existing data on metastatic upper tract urothelial carcinoma (mUTUC) are limited. In this study, we investigated the prognostic value of site-specific metastases in patients with mUTUC and its association with survival outcomes. Methods: We retrospectively collected data from the Surveillance, Epidemiology and End Results (SEER) database between 2004 and 2016. Kaplan–Meier analysis with a log-rank test was used for survival comparisons. Multivariate Cox regression was employed to predict overall survival (OS) and cancer-specific survival (CSS). Results: 633 patients were selected in this study cohort. The median follow-up was 6 months (IQR 2–13) and a total of 584 (92.3%) deaths were recorded. Within the population presenting with a single metastatic organ site, the most common metastatic sites were distant lymph nodes, accounting for 36%, followed by lung, bone and liver metastases, accounting for 26%, 22.8% and 16.2%, respectively. In patients with a single metastatic organ site, the Kaplan–Meier curves showed significantly worse OS for patients with liver metastases vs. patients presenting with metastases in a distant lymph node (p < 0.001), bone (p = 0.023) or lung (p = 0.026). When analyzing CSS, statistically significant differences were detectable only between patients presenting with liver metastases vs. distant lymph node metastases (p < 0.001). Multivariate analyses showed that the presence of liver (OS: HR = 1.732, 95% CI = 1.234–2.430, p < 0.001; CSS: HR = 1.531, 95% CI = 1.062–2.207, p = 0.022) or multiple metastatic organ sites (OS: HR = 1.425, 95% CI = 1.159–1.753, p < 0.001; CSS: HR = 1.417, 95% CI = 1.141–1.760, p = 0.002) was an independent predictor of poor survival. Additionally, survival benefits were found in patients undergoing radical nephroureterectomy (RNU) (OS: HR = 0.675, 95% CI = 0.514–0.886, p = 0.005; CSS: HR = 0.671, 95% CI = 0.505–0.891, p = 0.006) and chemotherapy (CHT) (OS: HR = 0.405, 95% CI = 0.313–0.523, p < 0.001; CSS: HR = 0.435, 95% CI = 0.333–0.570, p < 0.001). Conclusions: A distant lymph node was the most common site of single-organ metastases for mUTUC. Patients with liver metastases and patients with multiple organ metastases exhibited worse survival outcomes. Lastly, CHT administration and RNU were revealed to be predictors of better survival outcomes in the mUTUC cohort