Effect of single agent high-dose methotrexate-related acute kidney injury on length of hospitalization and relative dose intensity in adult patients with central nervous system lymphoma.

Purpose Grade ≥3 adverse effects prolong hospitalization and reduce chemotherapy dose intensity. The purpose of this study was to evaluate the rate and severity of high-dose methotrexate-related acute kidney injury and analyze its effect on hospital length of stay and relative chemotherapy dose intensity. Methods This was a retrospective cohort analysis. Patients receiving ≥1 dose of high-dose methotrexate were analyzed for acute kidney injury and length of stay. Patients receiving ≥6 cycles of induction therapy were included in the analysis of relative chemotherapy dose intensity. Chi squared analysis was used to determine the differences between dichotomous data; Student's t-test for parametric data and Mann-Whitney U test for non-parametric data for continuous variables. Statistical analyses were performed with IBM SPSS Statistics (version 21). Results Twenty-six patients and 194 treatment encounters were identified. Thirteen patients were evaluated for relative chemotherapy dose intensity. Grade ≥3 acute kidney injury occurred in four patients (15% of patients; 2% of encounters). There were no grade 5 adverse events. Mean length of stay for encounters with grade ≥3 acute kidney injury was almost three times longer than for those with ≤ grade 2 acute kidney injury (p = 0.041). Mean relative chemotherapy dose intensity was reduced approximately in half for patients experiencing grade ≥3 acute kidney injury (p < 0.01). The most common adverse events were hypokalemia and nausea. Proton pump inhibitors were the most frequently co-administered medications with the potential to affect high-dose methotrexate pharmacokinetics. Conclusion At our cancer program, the rate of grade ≥3 acute kidney injury with high-dose methotrexate is similar to that reported by others. Grade ≥3 acute kidney injury following high-dose methotrexate administration significantly prolonged length of stay and reduced relative chemotherapy dose intensity.

Hepatocyte growth factor (HGF) autocrine activation predicts sensitivity to MET inhibition in glioblastoma.

Because oncogene MET and EGF receptor (EGFR) inhibitors are in clinical development against several types of cancer, including glioblastoma, it is important to identify predictive markers that indicate patient subgroups suitable for such therapies. We investigated in vivo glioblastoma models characterized by hepatocyte growth factor (HGF) autocrine or paracrine activation, or by MET or EGFR amplification, for their susceptibility to MET inhibitors. HGF autocrine expression correlated with high phospho-MET levels in HGF autocrine cell lines, and these lines showed high sensitivity to MET inhibition in vivo. An HGF paracrine environment may enhance glioblastoma growth in vivo but did not indicate sensitivity to MET inhibition. EGFRvIII amplification predicted sensitivity to EGFR inhibition, but in the same tumor, increased copies of MET from gains of chromosome 7 did not result in increased MET activity and did not predict sensitivity to MET inhibitors. Thus, HGF autocrine glioblastoma bears an activated MET signaling pathway that may predict sensitivity to MET inhibitors. Moreover, serum HGF levels may serve as a biomarker for the presence of autocrine tumors and their responsiveness to MET therapeutics.

Reduced time for urinary alkalinization before high-dose methotrexate with preadmission oral bicarbonate.

PURPOSE: Hydration and urinary alkalinization are essential for reducing renal dysfunction with high dose methotrexate (HDMTX). This report presents an analysis of institutional methods used to achieve adequate urinary alkalinization and output for patients receiving single agent HDMTX. Renal and metabolic parameters of tolerance were examined. METHODS: Medical records of adult patients receiving HDMTX during the calendar years of 2008-2009 were retrospectively reviewed to determine the time to achieve urine pH > 7. Number of hospital days, bicarbonate dose, ordered hydration rate, urine output, and urine pH were assessed. A survival analysis model was run for time to urine pH > 7 using preadmission oral bicarbonate as a predictor variable and including a frailty term. Observational statistics were performed for other parameters. RESULTS: The analysis included 79 encounters for ten patients. Urine pH > 7 was achieved more rapidly in patients receiving preadmission oral bicarbonate (P = 0.012). The number of patients receiving HDMTX on the same day as admission was greater for those receiving preadmission oral bicarbonate (47%) in comparison to those who did not (2%), and they spent less time in the hospital. A standard regimen for hydration and urinary alkalinization based on this project is reported. The nature and frequency of adverse events were as expected for this treatment. CONCLUSION: At our institution, the time to achieve urinary alkalinization was reduced for patients receiving preadmission oral bicarbonate which facilitated chemotherapy infusion on the same day as admission and decreased the number of calendar days that patients stayed in the hospital.

Cost savings from dose rounding of biologic anticancer agents in adults.

PURPOSE: The purpose of this project was to determine the cost savings related to a dose-rounding process for adult biologic anticancer agents. METHODS: Biologic anticancer agents prepared by the inpatient pharmacy were identified retrospectively through completed chemotherapy preparation checklists and medication orders on file in the pharmacy or by the clinical pharmacist for adult oncology from the medical records of patients in her practice. The specific products screened for evaluation were aldesleukin, bevacizumab, cetuximab, denileukin diftitox, gemtuzumab, rituximab, and trastuzumab. Data collected included drug name, ordered dose, rounded dose, and product vials not wasted. Specific drug costs were provided by the department's purchasing office. The project was reviewed and approved by the institutional review board to allow retrospective data collection from patient records. Cost savings were evaluated retrospectively for the time period of January 1, 2005 through March 31, 2005. RESULTS: One hundred and twenty-six orders for biologic anticancer agents were processed by the pharmacy department during the 3-month time period of data collection. Dose rounding could reduce drug wastage for 42% of these orders. Potential cost savings from dose rounding was $24,434 for the 3-month interval evaluated. However, nonadherence to dose rounding for 29 rituximab orders decreased the actual cost savings to $15,922. Individual staff education was reinforced to address nonadherence. CONCLUSION: Routine dose rounding of biologic anticancer agents to an amount within 10% of the ordered dose achieved cost savings through reduction of drug wastage at our institution.

Increased risk of metabolic syndrome, diabetes mellitus, and cardiovascular disease in men receiving androgen deprivation therapy for prostate cancer.

Prostate cancer is the leading cancer diagnosis and second leading cause of cancer-related mortality for men in the United States. Due to the increased prevalence of prostate cancer in men older than 50 years, men at risk for prostate cancer represent the same population of men who are at greatest risk for metabolic syndrome, diabetes mellitus, and coronary artery disease (CAD). In addition to risk factors for CAD that are applicable to the general population, men with prostate cancer can be at increased risk for CAD due to long-term androgen deprivation therapy (ADT) administered as treatment for prostate cancer. Men undergo ADT by medical (drug therapy) or surgical (castration) means. Luteinizing hormone-releasing hormone (LHRH) agonists are the primary drug therapies used for ADT. Commercially available LHRH agonists are goserelin, histrelin, leuprolide, and triptorelin. Body composition changes, hyperlipidemia, insulin resistance, metabolic syndrome, and acute coronary syndrome are all reported adverse effects of ADT, which are consequences of reduced levels of circulating testosterone. Metabolic and body composition changes associated with ADT arise within months of beginning medical ADT and persist after discontinuation of therapy. To better understand the increased risk of metabolic syndrome, diabetes, and heart disease in patients undergoing ADT for prostate cancer, we performed a MEDLINE search (1986-2008) to identify pertinent studies and reports. Additional citations were obtained from the articles retrieved from the literature search. We found that the increased risk for serious cardiovascular disease becomes evident within months of beginning ADT. Pharmacists should provide counseling to these patients on primary disease prevention. Men receiving ADT should be monitored routinely for signs and symptoms of metabolic syndrome, diabetes, and CAD. Healthy lifestyle practices should be encouraged, and physical therapy should be considered for these patients.

Phase II trial to evaluate gemcitabine and etoposide for locally advanced or metastatic pancreatic cancer.

Prior studies suggest that tumor cell lines harboring RAS mutations display remarkable sensitivity to gemcitabine and etoposide. In a phase II clinical trial of patients with locally advanced or metastatic pancreatic cancer, we evaluated the response rate to a combination of these drugs. Forty chemo-naïve patients with nonresectable and histologically confirmed pancreatic cancer were accrued. Patients received gemcitabine 1,000 mg/m(2) (days 1 and 8) and etoposide 80 mg/m(2) (days 8, 9, and 10; 21-day cycle). The primary end point was radiological response rate. Secondary objectives were determination of overall survival, response duration (time to progression), quality of life, toxicity, and CA 19-9 biomarker response. In 35 evaluable patients, 10 exhibited a radiological partial response and 12 had stable disease in response to treatment. Twenty patients exhibited a >20% decrease in CA 19-9 biomarker levels. Median overall survival was 6.7 months for all patients (40) and 7.2 months for evaluable patients (35). Notably, four patients survived for longer than 1 year, with two patients surviving for more than 2 years. Median time to progression for evaluable patients was 3.1 months. The median overall survival for locally advanced patients was 8.8 months and 6.75 months for metastatic patients. One-year survival was 10% for all patients and 11.4% for evaluable patients. Quality of life improved in 12 patients and remained stable in 3 of the evaluable patients. The primary dose-limiting toxicities were hematologic toxicity and fatigue. These results show that the gemcitabine and etoposide combination is generally well-tolerated and exhibits a response rate similar to other published studies.

Locally advanced prostate cancer treated with concomitant radiation and 5-fluorouracil: Southwest Oncology Group Study 9024.

PURPOSE: Radiation is considered the standard treatment for locally advanced (T3 and T4) prostate cancer but cure with radiation alone is infrequent. Studies have shown that adding androgen ablation improves the results but there is still much room for improvement. We performed a phase II multi-institutional study to explore the feasibility of concomitant chemoradiotherapy. MATERIALS AND METHODS: Eligible patients had prostate cancer with clinical evidence of invasion through the prostatic capsule or into the seminal vesicles without evidence of nodal or distant metastasis. Prior prostatectomy was not allowed and patients could not be candidates for surgical resection due to medical reasons or refusal of surgery. Radiation consisted of 7,020 cGy in 39 fractions. Continuous infusion 5-fluorouracil at a dose of 200 mg/m2 daily was started on day 1 and continued 7 days weekly until the last day of radiation. RESULTS: All 30 eligible patients were evaluated for toxicity. Diarrhea was the most common toxicity with grade 3 and 4 diarrhea in 2 and 1 patients, respectively. The only other grade 4 toxicity was hemorrhagic cystitis in 1 patient. There was 1 incident each of grade 3 stomatitis, congestive heart failure, edema, proctitis and hematuria. No patient with grade 3 or 4 toxicity required treatment delay. Ten patients (33%) achieved a negative biopsy and 13 (43%) achieved prostate specific antigen less than 1.0 ng/ml. Six patients (20%) achieved a complete response, defined as negative biopsy and prostate specific antigen less than 1.0 (95% CI 8 to 39). Patients without any biopsies or without prostate specific antigen followup were assumed to be nonresponders. CONCLUSIONS: Toxicity was acceptable. The modest response rate indicates that better chemotherapy that improves local and systemic failure is necessary to improve the results. This study confirms the feasibility of a combined chemoradiotherapy approach.