Effect of Concomitant pH-Elevating Medications with Pazopanib on Progression-Free Survival and Overall Survival in Patients with Metastatic Renal Cell Carcinoma.

BACKGROUND: Pazopanib is an oral tyrosine-kinase inhibitor that is approved by the U.S. Food and Drug Administration for treatment of metastatic renal cell carcinoma (mRCC). Pharmacokinetic data have shown that concomitant administration of pazopanib and esomeprazole, a proton pump inhibitor (PPI), leads to decreased area under the curve and thus decreased exposure of pazopanib by 40%. Despite the pharmacokinetic data published to date, the clinical significance and impact on patient outcomes resulting from decreased pazopanib exposure remains unknown. MATERIALS AND METHODS: In this retrospective, observational, cohort study, 90 patients with mRCC who either received pazopanib in combination with a PPI or histamine 2 receptor antagonist (H2RA; concurrent PPI/H2RA group) or who did not take concurrent pH-elevating medications (no PPI/H2RA group) were compared to determine if there was an impact on progression-free survival (PFS), the primary endpoint, and secondary endpoints, overall survival (OS) and safety. RESULTS: The differences between the PFS of 9.0 months and OS of 28.0 months for the concomitant PPI/H2RA group versus 11.0 months and 30.1 months, respectively, for the no PPI/H2RA group were not statistically significant. Rates of adverse events were similar between the concomitant PPI/H2RA and no PPI/H2RA groups. CONCLUSION: Concomitant PPI or H2RA usage was not shown to be associated with a reduction in PFS or OS for patients receiving pazopanib for mRCC, with a similar toxicity profile in each group. Based on the results of this retrospective cohort study and the palliative nature of the treatment of patients with mRCC, clinicians should consider allowing patients to remain on concomitant pazopanib and acid-reducing therapy. IMPLICATIONS FOR PRACTICE: Pazopanib is a preferred category-one first-line treatment for predominant clear cell metastatic renal cell carcinoma (mRCC). However, because of an aging demographic, coupled with patients with mRCC presenting with multiple comorbidities, including symptomatic dyspepsia or gastroesophageal reflux disease, patients are commonly required to take pazopanib concomitantly with a proton pump inhibitor (PPI) or a histamine 2 receptor antagonist (H2RA). Despite earlier pharmacokinetic reports suggesting that an alkaline pH may result in poorer absorption, this institutional retrospective study found no effect on clinical outcomes. These data suggest that concurrent treatment of mRCC with pazopanib and a PPI or H2RA may be safe in everyday practice.

NCCN Guidelines Insights: Antiemesis, Version 2.2017.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Antiemesis address all aspects of management for chemotherapy-induced nausea and vomiting. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Antiemesis, specifically those regarding carboplatin, granisetron, and olanzapine.

Predictors of unstable anticoagulation in African Americans.

OBJECTIVE: We sought to identify contributors to unstable anticoagulation in African Americans. PATIENTS AND METHODS: Sixty African Americans on warfarin were enrolled. Cytochrome P450 2C9 and vitamin K epoxide reductase genotypes and vitamin K intake were assessed, and clinical and dietary data during the 12 months prior to enrollment were collected. Data were compared between stable and unstable patients, classified based on the proportion of international normalized ratio (INR) values outside the therapeutic range. RESULTS: The median proportion of out-of-range INRs among study participants was 44%; 28 patients had a higher proportion of INRs out-of-range and were included in the unstable group, with the remaining constituting the stable group. The median (IQR) number of clinic visits/year was higher among unstable versus stable patients [18 (15-22) vs. 16 (13-19); P = 0.03]. Higher warfarin doses, lower adherence, vomiting or diarrhea, and use of antiinfective agents were more common among unstable patients. Genotype was not associated with anticoagulation stability. After regression analysis, only poor adherence and gastrointestinal illness remained predictive of unstable anticoagulation. In a control group of Caucasians of similar age and sex distribution, poor adherence, but not gastrointestinal illness, was associated with unstable anticoagulation. CONCLUSION: We conclude that poor warfarin adherence and gastrointestinal illness are major contributors to unstable anticoagulation in African Americans. Our data suggest that, similar to Caucasians, improving warfarin adherence rates may be an important mean to improve anticoagulation control in African Americans. In addition, close monitoring during acute illness may be particularly important in this population.

Interaction between warfarin and cranberry juice.

Warfarin is extensively used for anticoagulation to a target international normalized ratio of 2.0-3.0 for most indications or 2.5-3.5 for high-risk indications; however, many drugs and dietary supplements induce fluctuations in the international normalized ratio. Such fluctuations may lead to therapeutic failure or bleeding complications. Cranberry juice is increasingly used for the prevention and adjunctive treatment of urinary tract infections. The United Kingdom's Committee on Safety of Medicines has alerted clinicians to a potential interaction between warfarin and cranberry juice and has advised that patients avoid their concurrent use. Review and analysis of the literature revealed that ingestion of large volumes of cranberry juice destabilize warfarin therapy. Small amounts of juice are not expected to cause such an interaction. Clinicians should be aware of this potential interaction and monitor and counsel patients accordingly.

Correlation between KRAS mutation status and response to chemotherapy in patients with advanced non-small cell lung cancer☆.

OBJECTIVES: KRAS mutations are the most commonly found mutations in patients with non-small cell lung cancer (NSCLC) adenocarcinoma histology. The clinical implications of KRAS mutations in patients with advanced NSCLC are not well defined. We sought to determine if there is a correlation between KRAS mutation status, response to cytotoxic chemotherapy, and survival in patients with metastatic or recurrent NSCLC. MATERIALS AND METHODS: Patients with metastatic or recurrent NSCLC and tumor mutation analyses were analyzed for response to conventional chemotherapy. The presence or absence of tumor mutations was assessed with the SNaPshot assay, which detects >40 somatic mutations in eight genes, including KRAS. ALK fluorescence in-situ hybridization analysis was done separately. Associations between KRAS mutation status and response to chemotherapy and survival were assessed. RESULTS: We identified 80 patients with metastatic or recurrent NSCLC and a KRAS activating mutation, and we compared these patients to 70 patients who were pan negative (no detectable mutation by the SNaPshot assay and ALK negative). Patients with KRAS-mutant advanced NSCLC demonstrated a significantly shorter progression-free survival in response to first line chemotherapy (4.5 months versus 5.7 months, p=0.008) compared to pan-mutation negative patients. Overall survival was also significantly shorter in patients with KRAS-mutant advanced NSCLC compared to patients without KRAS activating mutations (8.8 months versus 13.5 months, p=0.038). CONCLUSIONS: Within this single institution retrospective analysis, patients with advanced NSCLC and a KRAS activating mutation exhibited inferior responses to cytotoxic chemotherapy and decreased survival compared to patients with advanced NSCLC and no KRAS mutation.

Prognostic impact of KRAS mutation subtypes in 677 patients with metastatic lung adenocarcinomas.

BACKGROUND: We previously demonstrated that patients with metastatic KRAS mutant lung cancers have a shorter survival compared with patients with KRAS wild-type cancers. Recent reports have suggested different clinical outcomes and distinct activated signaling pathways depending on KRAS mutation subtype. To better understand the impact of KRAS mutation subtype, we analyzed data from 677 patients with KRAS mutant metastatic lung cancer. METHODS: We reviewed all patients with metastatic or recurrent lung cancers found to have KRAS mutations over a 6-year time period. We evaluated the associations among KRAS mutation type, clinical factors, and overall survival in univariate and multivariate analyses. Any significant findings were validated in an external multi-institution patient dataset. RESULTS: Among 677 patients with KRAS mutant lung cancers (53 at codon 13, 624 at codon 12), there was no difference in overall survival for patients when comparing KRAS transition versus transversion mutations (p = 0.99), smoking status (p = 0.33), or when comparing specific amino acid substitutions (p = 0.20). In our dataset, patients with KRAS codon 13 mutant tumors (n = 53) had shorter overall survival compared with patients with codon 12 mutant tumors (n = 624) (1.1 versus 1.3 years, respectively; p = 0.009), and the findings were confirmed in a multivariate Cox model controlling for age, sex, and smoking status (hazard ratio: 1.52, 95% confidence interval: 1.11-2.08; p = 0.008). In an independent validation set of tumors from 682 patients with stage IV KRAS mutant lung cancers, there was no difference in survival between patients with KRAS codon 13 versus codon 12 mutations (1.0 versus 1.1 years, respectively; p = 0.41). CONCLUSIONS: Among individuals with KRAS mutant metastatic lung cancers treated with conventional therapy, there are no apparent differences in outcome based on KRAS mutation subtype.

Risk factors for treatment failure in patients receiving vancomycin for hospital-acquired methicillin-resistant Staphylococcus aureus pneumonia.

BACKGROUND: The rate of vancomycin failure in patients with hospital-acquired pneumonia (HAP) caused by methicillin-resistant Staphylococcus aureus (MRSA) has exceeded 40% in several studies. This observation was attributed initially to the lack of weight-based dosing and targeting of lower trough concentrations. However, a subsequent study demonstrated no additional benefit in patients who achieved trough vancomycin concentrations >15 mg/L compared with patients with concentrations between 5 and 15 mg/L. We sought to identify contributors to vancomycin failure in patients with MRSA HAP. METHODS: This was a retrospective study of patients in a surgical intensive care unit with MRSA HAP who received vancomycin between January 1, 2005, and July 31, 2007. Clinical outcomes, microbiological data, prior antibiotic exposure, ventilator days, co-morbidities, and demographics were compared in patients with clinical success and those with treatment failure. Their characteristics were compared using a two-sided Fisher exact test or Mann-Whitney U test, as appropriate for nominal or continuous data. RESULTS: More patients in the treatment failure group had received one or more doses of vancomycin within 90 days leading up to MRSA HAP (84% vs. 47%; p = 0.04). In addition, the duration of prior vancomycin exposure was significantly longer among patients in the treatment failure group (6 vs. 0 days; p < 0.05). There were no statistically significant differences in the percentages of patients who achieved a vancomycin trough concentrations > or =15 mg/dL within the first 48 h (28% vs. 17%; p = 0.69), 72 h (44% vs. 39%; p = 1.0), or 96 h (56% vs. 44%; p = 0.74) after starting treatment. Patients in the failure group had a significantly higher overall mortality rate (32% vs. 0; p = 0.02). CONCLUSIONS: These data suggest that patients who have recent exposure to vancomycin are at high risk for vancomycin failure and may benefit from an appropriate alternative when a diagnosis of MRSA HAP is made.