Activity and safety of KEES - an oral multi-drug chemo-hormonal metronomic combination regimen in metastatic castration-resistant prostate cancer.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) remains a therapeutic challenge and evidence for late-line treatments in real-life is limited. The present study investigates the efficacy and safety of an oral metronomic chemo-hormonal regimen including cyclophosphamide, etoposide, estramustine, ketoconazole and prednisolone (KEES) administered in a consecutive biweekly schedule. METHODS: A retrospective cohort study in two Swedish regions was conducted. Overall (OS) and progression-free survival (PFS), biochemical response rate (bRR) and toxicities were analyzed. RESULTS: One hundred and twenty-three patients treated with KEES after initial treatment with at least a taxane or an androgen-receptor targeting agents (ARTA) were identified. Of those, 95 (77%) had received both agents and were the primary analysis population. Median (95% CI) OS and PFS in the pre-treated population were 12.3 (10.1-15.0) and 4.4 (3.8-5.5) months, respectively. Biochemical response, defined as ≥ 50% prostate-specific antigen (PSA) reduction, occurred in 26 patients (29%), and any PSA reduction in 59 (65%). PFS was independent of prior treatments used, and KEES seemed to be effective in late treatment lines. The bRR was higher compared to historical data of metronomic treatments in docetaxel and ARTA pre-treated populations. In multivariable analyses, performance status (PS) ≥ 2 and increasing alkaline phosphatase (ALP) predicted for worse OS. Nausea, fatigue, thromboembolic events and bone marrow suppression were the predominant toxicities. CONCLUSIONS: KEES demonstrated meaningful efficacy in heavily pre-treated CRPC patients, especially those with PS 0-1 and lower baseline ALP, and had an acceptable toxicity profile.

Real-world evaluation of upfront docetaxel in metastatic castration-sensitive prostate cancer.

BACKGROUND: The majority of patients with newly diagnosed metastatic prostate cancer (PC) initially respond to androgen deprivation therapy (ADT) and are classified as metastatic castration-sensitive PC (mCSPC). Following months to years of ADT, the disease tends to become resistant to ADT. Recent randomized phase-III trials demonstrated a survival benefit with the addition of upfront docetaxel to ADT in mCSPC. Following its implementation in routine care, this combined treatment strategy requires more detailed evaluation in a real-world setting. AIM: To assess the real-world outcome and safety of upfront docetaxel treatment in mCSPC. METHODS: A multicenter retrospective cohort study in the Southeast Health Care Region of Sweden was performed. This region includes approximately 1.1 million citizens and the oncology departments of Linköping, Jönköping, and Kalmar. All patients given upfront docetaxel for mCSPC from July 2015 until December 2017 were included. The primary endpoint was progression-free survival (PFS) at 12 mo, and the secondary endpoints were PFS at 24 mo, overall survival (OS), treatment intensity, adverse events, and unplanned hospitalizations. Exploratory analyses on potential prognostic parameters were performed. RESULTS: Ninety-four patients were eligible and formed the study cohort. PFS at 12 and 24 mo was 75% (95%CI: 66-84) and 58% (46-70), respectively. OS at 12 and 24 mo was 93% (87-99) and 86% (76-96). A total of 91% of patients (n = 86) were given docetaxel according to the standard protocol of 75 mg/m2 every 3 wk (6 cycles), while 9% (n = 8) received a modified protocol of 50 mg/m2 every 2 wk (9 cycles). The average overall dose intensity for those commencing standard treatment was 91%. Univariate Cox regression analyses show that baseline PSA > 180 vs < 180 and the presence of distant metastases vs locoregional lymph node metastases were only negative prognostic factors (HR 2.86, 95%CI: 1.39-5.87, P = 0.0041 and 3.36, 95%CI: 1.03-10.96, P = 0.045). Following multivariate analysis, statistical significance remained for PSA (2.51, 95%CI: 1.21-5.19, P = 0.013) but not for metastatic status (2.60, 95%CI: 0.78-8.65, P = 0.12). Febrile neutropenia was recorded in 21% (n = 20) of patients, and 26% (n = 24) had at least one episode of unplanned hospitalization under and up to 30 d after the treatment course. CONCLUSION: Results from this study support the implementation of upfront docetaxel plus ADT as part of the standard of care treatment strategy in mCSPC.

Validation of a point-of-care instrument for bedside glutamine screening in the intensive care unit.

BACKGROUND: A point-of-care instrument developed for measuring glutamine levels in cell cultures was validated for bedside use in the ICU setting and compared with a standard HPLC technique to measure plasma glutamine. The aim was to evaluate the instrument for absolute measurements and for screening purposes. METHODS: Consecutive blood samples were obtained from one hundred adult ICU patients 3-5 days apart during their ICU stay. Each sample was divided into 3 aliquots, out of which two were used for analyses of plasma and whole blood glutamine by the point-of-care instrument, and one was used for analysis of plasma glutamine concentration by the gold standard HPLC technique. Comparisons were performed by Bland-Altman analyses. RESULTS: Comparison of the initial plasma sample of each subject (n = 100), between the point of care instrument and HPLC analysis revealed a systematic bias of -221 µmol/L. Comparisons between plasma and whole blood on the point-of-care instrument revealed comparable results. After pragmatic adjustments for the measured bias and hematocrit, whole blood analyses during ICU stay (n = 316) compared with HPLC plasma analyses showed a line of identity of -34 µmol/L and limits of agreement between 288 and -355 µmol/L. CONCLUSION: When compared to the HPLC gold standard in particular, the lines of agreement indicate that the point-of-care instrument is not suitable for quantitative plasma or whole blood glutamine concentration measurements. For screening purposes the instrument may be useful in order to identify patients with hypoglutaminemia and hyperglutaminemia and the tested accuracy was high enough for safe supplementation of glutamine to patients with low plasma values measured with the device. The point-of-care instrument may also serve as a screening tool for scientific studies.

Plasma Glutamine Concentrations in Liver Failure.

BACKGROUND: Higher than normal plasma glutamine concentration at admission to an intensive care unit is associated with an unfavorable outcome. Very high plasma glutamine levels are sometimes seen in both acute and chronic liver failure. We aimed to systematically explore the relation between different types of liver failure and plasma glutamine concentrations. METHODS: Four different groups of patients were studies; chronic liver failure (n = 40), acute on chronic liver failure (n = 20), acute fulminant liver failure (n = 20), and post-hepatectomy liver failure (n = 20). Child-Pugh and Model for End-stage Liver Disease (MELD) scores were assessed as indices of liver function. All groups except the chronic liver failure group were followed longitudinally during hospitalisation. Outcomes were recorded up to 48 months after study inclusion. RESULTS: All groups had individuals with very high plasma glutamine concentrations. In the total group of patients (n = 100), severity of liver failure correlated significantly with plasma glutamine concentration, but the correlation was not strong. CONCLUSION: Liver failure, regardless of severity and course of illness, may be associated with a high plasma glutamine concentration. Further studies are needed to understand whether high glutamine levels should be regarded as a biomarker or as a contributor to symptomatology in liver failure.

Plasma glutamine concentration after intensive care unit discharge: an observational study.

INTRODUCTION: Low plasma glutamine concentration at ICU admission is associated with unfavorable outcomes. The prediction of plasma glutamine concentration after ICU discharge on outcomes has not been characterized. In the recent Scandinavian Glutamine Trial, a survival advantage was seen with glutamine supplementation as long as patients stayed in the ICU. It was therefore hypothesized that the glutamine level may drop at ICU discharge, indicative of a sustained glutamine deficiency, which may be related to outcome. METHODS: Fully fed ICU patients intravenously supplemented with glutamine for >3 days were studied at ICU discharge and post ICU. In study A, plasma glutamine level was followed every 5 to 7 days post ICU of the remaining hospital stay and compared to the level on the day of ICU discharge (n=63). In study B, plasma glutamine level 24 to 72 hours after ICU discharge was related to 12-month all-cause mortality (n=100). RESULTS: Post-ICU plasma glutamine levels were within normal range and were not found to be predictive for mortality outcome. Plasma glutamine level at discharge, on the other hand, was within normal limits but higher in nonsurvivors. In addition, it was adding prediction value to discharge SOFA scores for post-ICU mortality. CONCLUSIONS: Post-ICU glutamine levels are not indicative of glutamine depletion. The relation between plasma glutamine concentration and glutamine availability during critical illness is not well understood, and needs to be studied further to define the possible role for glutamine supplementation.