Real-world evaluation of upfront docetaxel in metastatic castrationsensitive 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.

Association of CYP2B6 Genotype with Survival and Progression Free Survival in Cyclophosphamide Treated Multiple Myeloma

Objective: Cyclophosphamide is a conventional pro-drug used in Multiple Myeloma (MM) and other malignancies. The highly polymorphic CYP2B6 is suggested as a major contributor in cyclophosphamide bioactivation, and GST enzymes are involved in detoxification. Polymorphisms of these enzymes may affect enzyme expression and function as well as treatment outcome. The aim of this study was to investigate the impact of the CYP2B6 SNPs G516T, A785G and C1459T, GSTP1 SNP Ile105Val, and GSTM1 and GSTT1 null variants, on the outcome for cyclophosphamide treated MM patients, in order to find markers of value for individualised therapy. Methods: We used allele specific PCR and Pyrosequencing to investigate the impact of CYP2B6 SNPs G516T, A785G and C1459T, GSTP1 Ile105Val, and GSTM1 and GSTT1 variants, on the outcome for 26 cyclophosphamide treated multiple myeloma patients. Results and Major Conclusion: The CYP2B6 785G carriers had significantly shorter progression free survival (p = 0.048*) and overall survival (p = 0.037*) with 785G/G patients having the worst outcome compared to patients carrying the wild type. A shorter progression free survival was also indicated in patients carrying both CYP2B6 516T & 785G (p = 0.068). These results indicate a predictive role of CYP2B6 SNPs, particularly A785G, in cyclophosphamide treatment.

Circulating inflammatory factors associated with worse long-term prognosis in colorectal cancer

AIM To investigate association of circulating inflammatory factors at the time of colorectal cancer(CRC) surgery with survival.METHODS Plasma levels from 174 CRC patients(69 females and 105 men), with median age 70 years(range 29-90), localized in the colon(n = 105) or rectum(n = 69), with stage Ⅰ(n = 24), stage Ⅱ(n = 54), stage Ⅲ(n = 67) and stage Ⅳ(n = 29) were measured using commercially available Bio-Plex Pro? Human Chemokine Panel 40-Plex, including 40 different chemokines, cytokines and interleukins. The prognostic association of each inflammatory factor was analysed as CRC-specific and total mortality.RESULTS Out of 174 patients, 66 died during the follow-up, 40 because of CRC specific mortality. High tertile levels of 8 factors were significantly associated with increased CRC-specific mortality, of which CCL1, CCL20, CCL24, CX3CL1, IL-4 and TNF-α remained significant in a multivariate Cox regression analysis. High tertile levels of 14 factors were associated with increased total mortality, of which CCL1, CCL15, CCL20, CX3CL1, CXCL13, IFN-γ, IL-2, IL-4 and IL-10 remained significant after adjustment for clinical covariates. For most of the inflammatory factors the association between higher tertile levels and an increased mortality in general appeared two years after surgery. High tertile levels of TNF-α and CCL24 were exclusively associated with CRC-specific mortality. The distribution of these factors were not associated with TNM stage with exception for CCL20.CONCLUSION High plasma levels of inflammatory factors are associated with increased risk of mortality among CRC patients and could be potential biomarkers for revealing prognosis.

Reflections on variability in the blood-breath ratio of ethanol and its importance when evidential breath-alcohol instruments are used in law enforcement

Variability in the blood-breath ratio(BBR)of alcohol is important,because it relates a mea-surement of the blood-alcohol concentration(BAC)with the co-existing breath-alcohol con-centration(BrAC).The BBR is also used to establish the statutory BrAC limit for driving from the existing statutory BAC limits in different countries.The in-vivo BBR depends on a host of analytical,sampling and physiological factors,including subject demographics,time after end of drinking(rising or falling BAC),the nature of the blood draw(whether venous or arterial)and the subject's breathing pattern prior to exhalation into the breath analyzer.The results from a controlled drinking study involving healthy volunteers(85 men and 15 women)from three ethnic groups(Caucasians,Hispanics and African Americans)were used to evaluate various factors influencing the BBR.Ethanol in breath was determined with a quantitative infrared analyzer(Intoxilyzer 8000)and BAC was determined by headspace gas chromatography(HS-GC).The BAC and BrAC were highly correlated(r = 0.948)and the BBR in the post-absorptive state was 2 382±119(mean ± SD).The BBR did not depend on gen-der(female:2 396±101 and male:2 380±123,P>0.05)nor on racial group(Caucasians 2 398±124,African Americans 2 344±119 and Hispanics 2 364±104,P>0.05).The BBR was lower in subjects with higher breath-and body-temperatures(P<0.05)and it also decreased with longer exhalation times into the breath-analyzer(P<0.001).In the post-absorptive state,none of the 100 subjects had a BBR of less than 2 100∶1.