Clinical Utility of Routine Cardiac Monitoring in Breast Cancer Patients Receiving Trastuzumab.

BACKGROUND: Trastuzumab targets the human epidermal growth factor receptor-2 (HER2). Cardiotoxicity is a potential adverse effect, manifesting as either an asymptomatic decline in left-ventricular ejection fraction or infrequently as largely reversible symptomatic heart failure (HF). Monitoring recommendations differ between product labeling and 2012 guidelines, and the clinical utility of serial cardiac monitoring in patients with metastatic breast cancer remains controversial. OBJECTIVE: The objectives of this study were to describe the frequency of monitoring, incidence of symptomatic or asymptomatic HF, overall effect on treatment, and cost of monitoring for cardiotoxicity. METHODS: We preformed an institutional review board-approved retrospective chart review of breast cancer patients receiving trastuzumab from January 1, 2009, through January 1, 2014, at an academic medical center. RESULTS: Out of 154 treatments, 72% were adjuvant, and 28% were metastatic. In the adjuvant setting, a mean of 4.5 (interquartile range [IQR] = 4-5) echocardiograms (echos) over a mean of 11.5 (IQR = 11-12) months were performed. In the metastatic setting, a mean of 3.1 (IQR = 1-5) echos over a mean of 20.2 (IQR = 9-31) months were performed. Symptomatic HF events occurred in 4 adjuvant (3.6%) and 2 metastatic patients (6.5%); 10 patients (6.5%) had a treatment interruption, with 9 (90%) tolerating restart of trastuzumab. Two patients (1.3%) changed treatment as a result of cardiotoxicity. Using population incidence of HER2-positive breast cancer, $13 million could be saved if monitoring were reduced by 1 echo per patient. CONCLUSIONS: Given the low incidence of clinically significant HF and cost of monitoring, less frequent monitoring may be justified.

Impact of Isotope Dilution Mass Spectrometry (IDMS) Standardization on Carboplatin Dose and Adverse Events.

BACKGROUND: When using area under the concentration-time curve-based strategies for dosing carboplatin, accurate estimation of glomerular filtration rate is required for determining dose. Commonly, the Cockcroft-Gault equation is used, which is dependent on measurement of serum creatinine (SCr). Because analysis of SCr changed to an isotope dilution mass spectrometry (IDMS) standard, we sought to determine the impact of this assay change on carboplatin dosing and related toxicity. METHODS: This was a single-center, retrospective chart review of adults treated with carboplatin between April 2008 and April 2010 divided into cohorts that initiated carboplatin before or after IDMS standardization. End points included grade 3 thrombocytopenia, decrease in platelet count, and hospitalization and were evaluated in cohorts based on concomitant chemotherapy. RESULTS: The chart review identified 158 patients, with 63 patients in the pre-IDMS group and 95 patients in the post-IDMS group. Average SCr (pre 1.01 mg/dl vs post 0.86 mg/dl, p<0.001) and average carboplatin dose (pre 580 mg vs post 703 mg, p<0.001) were significantly different between the groups. The frequency of grade 3 thrombocytopenia was not statistically significant across three partner chemotherapy cohorts before and after IDMS implementation. CONCLUSION: IDMS standardization led to an overall decrease in SCr with subsequent increase in carboplatin doses. However, no increase in recorded adverse events was observed, suggesting that the clinical relevance in toxicity from higher doses was minimal.

Mannitol to prevent cisplatin-induced nephrotoxicity in patients with squamous cell cancer of the head and neck (SCCHN) receiving concurrent therapy.

PURPOSE: The purpose of this study is to compare the incidence and severity of nephrotoxicity in patients receiving cisplatin with saline hydration vs. saline hydration with mannitol. METHODS: Retrospective chart review of all patients receiving a starting dose of cisplatin 100 mg/m(2) with concurrent radiation for SCCHN between January 1, 2009 and March 1, 2013. All patients received pre and post hydration each with 1 l of 0.9 % saline. The mannitol group received 12.5 g of mannitol in the prehydration fluid. The primary outcome was to compare the rate of grade 3 or greater serum creatinine (SCr) increase in patients receiving saline hydration vs. the addition of mannitol; additional parameters of interest included creatinine clearance, electrolyte disturbances, dose changes, and discontinuation of cisplatin. RESULTS: Data from 139 patients (80 % male) with a median age of 56 years (range 22 to 75 years) were collected; 88 received mannitol and 51 received saline alone. On multivariable analysis, the mannitol group was less likely to have grade 3 SCr increase than saline only group (OR 0.16; 95 % CI 0.04-0.65; p value = 0.01). There were no grade 4 SCr increase events. Rates of hypomagnesemia and hypokalemia were similar across groups. Grade 3 hyponatremia was more likely to occur in the mannitol group as compared to saline alone group (41 vs 22 %; p = 0.026). CONCLUSION: The addition of mannitol to saline hydration decreased the incidence of grade 3 increases in SCr in this cohort of patients and may increase rates of hyponatremia. Further investigations of methods to lessen cisplatin-induced nephrotoxicity are needed.

Melanoma: understanding relevant molecular pathways as well as available and emerging therapies.

Since 2011, 6 therapies, including cell signaling kinase inhibitors and immune checkpoint targeting antibodies, have been approved by the FDA for the treatment of melanoma. Due to advancements in research and a greater understanding of the role of the immune system in cancer as well as the molecular biology of melanoma tumors, novel therapies are emerging to combat and effectively manage melanoma tumors. Advances in research are resulting in prolonging rates of survival of patients with metastatic melanoma. Research is ongoing to gain deeper insight to discover (1) which patients are most likely to respond to and benefit from immunotherapy, (2) how to treat patients who have disease progression after treatment with targeted agents, and (3) how best to combine these approved immunologic therapies, targeted drugs, and emerging therapies, as well as their safety and efficacy.

Subcutaneous versus intravenous bortezomib: efficiency practice variables and patient preferences.

BACKGROUND: Subcutaneous bortezomib is noninferior in efficacy to intravenous bortezomib and is associated with a lower incidence of neuropathy in the treatment of multiple myeloma. However, there are no data assessing the effect of subcutaneous bortezomib administration on practice variables or patient preferences. OBJECTIVE: To quantify the difference in efficiency practice variables and patient preferences regarding subcutaneous versus intravenous bortezomib administration in patients with multiple myeloma. METHODS: This study was divided into 2 parts consisting of mutually exclusive patients: a retrospective efficiency study and a survey study. Patients' medical records were reviewed for efficiency data measures including length of infusion chair time and overall infusion center visit time in patients who received at least 6 doses of bortezomib. Patients who received at least 1 dose each of subcutaneous and intravenous administration were surveyed regarding preference, satisfaction, injection site reactions, and quality of life measures. A database was used to identify eligible patients for each portion of the study. RESULTS: A review of 92 medical records demonstrated a 38% reduction in chair time (143 vs 89 minutes; p < 0.001) and a 27% reduction in infusion center visit time (169 vs 123 minutes; p < 0.001) with subcutaneous versus intravenous administration of bortezomib. Of 47 eligible patients, 60% (28) completed the survey; 68% (19; p = 0.0002) of these patients preferred and were more satisfied with subcutaneous bortezomib administration. The overall incidence of injection site reactions was 39% (11) in the surveyed population and was not significantly different between the 2 preference groups. Limitations of the study include single-center design, small sample size, and nonvalidated survey. CONCLUSIONS: Subcutaneous administration of bortezomib is more time efficient for the patient and institution and is preferred by patients compared to intravenous bortezomib.

Publication of noninferiority clinical trials: changes over a 20-year interval.

STUDY OBJECTIVES: The primary objective was to evaluate the change in publication rate of noninferiority trials over a 20-year interval (1989-2009). Secondary objectives were to analyze the frequency of noninferiority trials by therapeutic category, the frequency of noninferiority trial publication by journal, the impact factors of the publishing journals, any potential special advantages of the study drug over the control, the funding sources of the trials, pharmaceutical industry affiliation of the authors, and the use of ghostwriters in the creation of manuscripts. DESIGN: Retrospective literature review of 583 articles. DATA SOURCES: PubMed (January 1989-December 2009) and EMBASE (first quarter 1989-fourth quarter 2009) databases. MEASUREMENTS AND MAIN RESULTS: A total of 583 articles of the results of randomized controlled clinical trials with a noninferiority study design that evaluated drug therapies, published in English, between 1989 and 2009, were included in the analysis. A consistent increase was noted in their yearly publication rates, with no trials published in 1989 versus 133 in 2009. One hundred twenty-six articles (21.6%) were in the therapeutic category of infectious diseases, followed by 78 (13.4%) in cardiology. Among the journals identified, The New England Journal of Medicine had the highest publication rate of trials with a noninferiority design, with 29 (5.0%) of the identified trials published in this journal. The median impact factor of the journals publishing noninferiority trials was 4.807 (interquartile range 3.064-7.5). The most common advantage of the study drug over the control was reduced duration of treatment or reduced pill burden (80 studies [22.9%]). A total of 425 trials (72.9%) listed the pharmaceutical industry as the only funding source. Among 369 trials with authors employed by the pharmaceutical industry, 101 (17.3%) disclosed an acknowledgment to an individual, other than those listed as authors, who contributed to writing the manuscript and who was affiliated with a medical information company and/or a pharmaceutical company (i.e., potential ghostwriters). CONCLUSION: The publication of noninferiority trials increased during the 20 years from 1989 until 2009, particularly in the therapeutic areas of infectious diseases and cardiology. Because of this growth, clinicians and researchers need to be familiar with the caveats of the noninferiority study design to appropriately interpret and design these clinical studies.

Epidermal growth factor receptor polymorphisms and risk for toxicity in paediatric patients treated with gefitinib.

PURPOSE: To investigate associations between germline genetic variations in the epidermal growth factor receptor (EGFR) and toxicity in paediatric patients treated with gefitinib. PATIENTS AND METHODS: Gefitinib treatment and toxicity data from five paediatric clinical trials were combined. EGFR genotypes evaluated included -191C>A, -216G>T, Arg497Lys and intron 1 CA sequence repeat number. The genetic variations were evaluated for associations with grade one or greater rash or diarrhoea during the first course of treatment. RESULTS: The analysis included 110 patients, 60 (55%) with grade one or greater rash and 47 (43%) with grade one or greater diarrhoea. Among patients with the -216 GG (n=51), GT (n=41) and TT (n=16) genotypes, grade one or greater rash occurred in 52.9%, 46.3% and 87.5% of patients (p=0.003, recessive model), respectively. Diarrhoea occurred in 27.5%, 58.5% and 43.8% of patients with respective GG, GT and TT genotypes (p=0.004, dominant model). The -191C>A, intron 1 CA repeat number and Arg497Lys genotypes were not significantly associated with either rash or diarrhoea. EGFR -216 and -191 polymorphisms were in linkage disequilibrium (D'=0.66, p=0.01). The haplotype (-191C, -216T) was associated with increased risk for rash (p=0.049), but was not more predictive of rash than the single -216 polymorphism. CONCLUSION: These findings indicate that EGFR -216G>T genotype is a predictive marker for the development of skin rash and diarrhoea in paediatric patients treated with gefitinib. Continued investigation of relationships between germline EGFR polymorphisms and the efficacy of EGFR inhibitors in paediatric patients is warranted.

Clinical pharmacokinetics of amifostine and WR1065 in pediatric patients with medulloblastoma.

PURPOSE: We evaluated the pharmacokinetics of amifostine and WR1065 in pediatric patients with newly diagnosed medulloblastoma to assess the influence of patient covariates, including demographics, clinical characteristics, and genetic polymorphisms, on amifostine and WR1065 pharmacokinetic parameters. EXPERIMENTAL DESIGN: We assessed the pharmacokinetics of amifostine and WR1065 in 33 children who received amifostine (1-minute infusion, 600 mg/m(2)) just before the start of and 3 hours into a 6-hour cisplatin infusion. Serial blood samples were collected after doses 1 (0 hour) and 2 (3 hours) of course 1. Amifostine and WR1065 were quantitated by high performance liquid chromatography with electrochemical detection. A pharmacokinetic model was simultaneously fit to amifostine and WR1065 plasma or whole blood concentration-versus-time data. The influence of demographic, biochemical, and pharmacogenetic covariates on amifostine and WR1065 disposition was evaluated. RESULTS: Body surface area was the primary size-based covariate for amifostine pharmacokinetics explaining 53% and 56% of interindividual variability in plasma and whole-blood amifostine clearance, respectively. The population-predicted values for amifostine clearance, volume, and apparent WR1065 clearance from the plasma data were 107 L/h/m(2), 5.53 L/m(2), and 30.6 L/h/m(2). The population-predicted values for amifostine clearance, volume, and apparent WR1065 clearance from whole blood data were 136 L/h/m(2), 7.23 L/m(2), and 12.5 L/h/m(2). CONCLUSIONS: These results support using body surface area for calculating doses of amifostine in children. Similar to data in adults, amifostine and WR1065 are rapidly cleared from plasma and whole blood in children.

Disparities in the use of chemotherapy and monoclonal antibody therapy for elderly advanced colorectal cancer patients in the community oncology setting.

BACKGROUND: The clinical trials on which the treatment of advanced colorectal (CRC) is based enroll few elderly patients. Furthermore, few investigations have determined the use and outcomes of the treatment of advanced CRC in practice. This study evaluated the treatment of advanced CRC in community oncology practices, focusing on age-related differences in treatment and outcome. METHODS: A national, retrospective chart review was conducted to evaluate the management of advanced CRC in 10 community practices across the U.S. All medical records of patients diagnosed with advanced CRC initiating chemotherapy treatment after January 1, 2003 through 2006 were included. The primary aim was to compare the proportion receiving doublet chemotherapy (irinotecan or oxaliplatin with a fluoropyrimidine) as initial therapy in young (age 65 years) patients. Additional aims included age-based comparisons of the addition of bevacizumab to chemotherapy, overall chemotherapy use, all-cause mortality, and toxicity-related events. RESULTS: Overall, 520 patients (56% elderly) received 6,253 cycles of chemotherapy. Of the younger patients, 84% received doublet chemotherapy first-line, compared with 58% of elderly patients (p < .001). The use of each of the medications--irinotecan, oxaliplatin, and bevacizumab--was lower in elderly patients (p < .001). Independent predictors of a higher risk for mortality were age >65 (adjusted hazards ratio [HR],1.19; 95% confidence interval [CI], 1.02-1.39) and performance status score >or=2 (HR, 1.65; 95% CI, 1.41-1.91). CONCLUSION: Elderly patients are less likely to receive first-line doublet chemotherapy than younger patients. Age and performance status are independent predictors of treatment and overall survival.

Paclitaxel and filgrastim for hematopoietic progenitor cell mobilization in patients with hematologic malignancies after failure of a prior mobilization regimen.

Paclitaxel and G-CSF have been evaluated for HPC mobilization in breast cancer and found to have tolerable toxicity with a predictable time to initiate leukapheresis. However, this approach has not been reported in patients with hematologic malignancies failing prior mobilization. We report a case-series of 26 adults given paclitaxel and G-CSF for HPC mobilization after failure of an initial mobilization. Patients received paclitaxel 250 mg/m(2) followed by G-CSF 10-16 mcg/kg/day. Compared to the initial regimen, paclitaxel mobilization produced greater CD34+ cell yields (median 1.53 x 10(6) CD34+ cells/kg vs. 0.79 x 10(6) CD34+ cells/kg, p = 0.004). Seventy-six percent of patients initiated leukapheresis on day 8, the remainder on day 9 or 10. Three patients developed febrile neutropenia resulting in one death prior to leukapheresis. Overall, 73% of patients proceeded with autologous HPC transplant. This case-series suggests paclitaxel may be an option for HPC mobilization in patients failing prior regimens.