Docetaxel or pemetrexed with or without cetuximab in recurrent or progressive non-small-cell lung cancer after platinum-based therapy: a phase 3, open-label, randomised trial.

BACKGROUND: Available preclinical and phase 2 clinical data suggest that the addition of cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor (EGFR), to chemotherapy might improve outcome in patients with advanced non-small-cell lung cancer (NSCLC). We aimed to assess whether the addition of cetuximab to chemotherapy improved progression-free survival in patients with recurrent or progressive NSCLC after platinum-based therapy. METHODS: In this unmasked, open-label randomised phase 3 trial we enrolled patients with metastatic, unresectable, or locally advanced NSCLC from 121 sites in Canada and the USA. Eligible patients were those aged 18 years or older who had experienced progressive disease during or after one previous platinum-based regimen. Initially, patients were randomly assigned to receive either pemetrexed (500 mg/m(2)) or docetaxel (75 mg/m(2)) and then randomly assigned within each group to receive their chemotherapy with or without cetuximab (400 mg/m(2) at first dose and 250 mg/m(2) weekly thereafter) until disease progression or unacceptable toxicity. However, after a change in the standard of care, investigators chose whether to treat with pemetrexed or docetaxel on a patient-by-patient basis. The primary analysis was changed to compare progression-free survival with cetuximab plus pemetrexed versus pemetrexed, on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT00095199. FINDINGS: Between Jan 10, 2005, and Feb 10, 2010, we enrolled 939 patients; data for one patient was accidentally discarded. Of the remaining 938 patients, 605 received pemetrexed (301 patients with cetuximab and 304 alone) and 333 received docetaxel (167 in combination with cetuximab and 166 alone). Median progression-free survival with cetuximab plus pemetrexed was 2·9 months (95% CI 2·7-3·2) versus 2·8 months (2·5-3·3) with pemetrexed (HR 1·03, 95% CI 0·87-1·21; p=0·76). The most common grade 3-4 adverse events with cetuximab plus pemetrexed were fatigue (33 [11%] of 292 patients), acneiform rash (31 [11%]), dyspnoea (29 [10%]), and decreased neutrophil count (28 [10%]), and with pemetrexed alone were dyspnoea (35 [12%] of 289 patients), decreased neutrophil count (26 [9%]), and fatigue (23 [8%]). A significantly higher proportion of patients in the cetuximab plus pemetrexed group (119 [41%] of 292 patients) experienced at least one serious adverse event than those patients in the pemetrexed group (85 [29%] of 289 patients; p=0·0054). Nine (3%) of 292 treated patients in the cetuximab and pemetrexed group died of adverse events compared with five (2%) of 289 treated patients in the pemetrexed alone group. INTERPRETATION: The use of cetuximab is not recommended in combination with chemotherapy in patients previously treated with platinum-based therapy. FUNDING: Eli Lilly and Company and ImClone Systems LLC, a wholly owned subsidiary of Eli Lilly and Company.

Randomized phase III trial of gemcitabine-based chemotherapy with in situ RRM1 and ERCC1 protein levels for response prediction in non-small-cell lung cancer.

PURPOSE: We evaluated the efficacy of gemcitabine versus gemcitabine and carboplatin in patients with advanced non-small-cell lung cancer (NSCLC) and a performance status (PS) of 2 and assessed if tumoral RRM1 and ERCC1 protein levels are predictive of response to therapy. PATIENTS AND METHODS: A randomized phase III trial was conducted in community-based oncology practices. Tumor specimens were collected a priori and shipped to a single laboratory for blinded determination of in situ RRM1 and ERCC1 protein expression levels by an automated quantitative immunofluorescent-based technology. RESULTS: One hundred seventy patients were randomly assigned. Overall median survival was 5.1 months for gemcitabine and 6.7 months for gemcitabine and carboplatin (P = .24). RRM1 (range, 5.3 to 105.6; median, 34.1) and ERCC1 (range, 5.2 to 131.3; median, 34.7) values were significantly and inversely correlated with disease response (r = -0.41; P = .001 for RRM1; r = -0.39; P = .003 for ERCC1; ie, response was better for patients with low levels of expression). A model for response prediction that included RRM1, ERCC1, and treatment arm, was highly predictive of the treatment response observed (P = .0005). We did not find statistically significant associations between survival and RRM1 or ERCC1 levels. CONCLUSION: Single-agent chemotherapy remains the standard of care for patients with advanced NSCLC and poor PS. Quantitative analysis of RRM1 and ERCC1 protein expression in routinely collected tumor specimens in community oncology practices is predictive of response to gemcitabine and gemcitabine and carboplatin therapy. Oncologists should consider including in situ expression analysis for these proteins into their therapeutic decisions.

Selenium accumulation in prostate tissue during a randomized, controlled short-term trial of l-selenomethionine: a Southwest Oncology Group Study.

PURPOSE: Epidemiologic and clinical data suggest that selenium could prevent prostate cancer, but it has not been shown that supplemental selenium leads to an increased concentration of selenium in prostate tissue compared with adjacent tissue. EXPERIMENTAL DESIGN: We conducted a randomized, controlled, short-term trial of l-selenomethionine (SeMet) versus observation in men with organ-confined prostate cancer. The primary endpoint was the measurement of selenium concentration in prostate tissue and seminal vesicle (SV). We assessed baseline selenium levels in serum and in toenail specimens (reflecting long-term intake) and post-intervention selenium levels in serum, and in prostate and SV tissues using hydride generation atomic fluorescence spectroscopy. RESULTS: Sixty-six eligible patients were randomly assigned to the SeMet (n = 34) or observation (n = 32) arm; both arms had similar baseline patient characteristics. Baseline serum selenium was similar in the two groups (P = 0.64). Baseline toenail selenium levels were slightly higher in the SeMet group than in the control group (P = 0.07). After the intervention, the mean serum selenium level increased 15% in the SeMet arm and was higher than in the observation arm (P = 0.001). The selenium concentration in prostate tissue was 22% higher in the SeMet arm (n = 26) than in the observation arm (n = 25; 1.80 versus 1.47 ppm; P = 0.003, Wilcoxon rank sum test) and remained significantly higher after adjusting for chronic selenium intake (P = 0.021, ANCOVA). SV selenium concentration was similar in both groups (P = 0.384) and was lower than in prostate tissue. CONCLUSIONS: The present study is the first to show that selenium taken as oral supplementation accumulates preferentially in the human prostate gland as opposed to the SV. These findings support the hypothesis that oral selenium supplementation may contribute to the cancer preventive effects of selenium.

Research and commentary: Change in exercise tolerance, activity and sleep patterns, and quality of life in patients with cancer participating in a structured exercise program.

PURPOSE/OBJECTIVES: To investigate the feasibility of an exercise program patterned after a phase II cardiac rehabilitation program to improve selected physiologic and psychological parameters of health in patients with cancer. DESIGN: Prospective, repeated measures study. SETTING: Two major military medical centers in the southwestern United States. SAMPLE: 62 patients diagnosed with cancer within the previous two years. Ages ranged from 24-83 (meanX = 59). Half of the participants were male and half were female. Minorities made up 29% of the sample. Participants had a wide range of cancer diagnoses and all stages of cancer. Fifteen subjects were undergoing treatment when they enrolled in the study. More than half of the subjects exercised prior to their cancer diagnoses, but fewer than half were able to resume an exercise routine following their cancer diagnoses. METHODS: Subjects met two days each week for 12 weeks for exercise and education. MAIN RESEARCH VARIABLES: Exercise tolerance as measured with a graded exercise test, activity and sleep patterns as measured with a wrist actigraph, and quality of life (QOL) as measured with the Cancer Rehabilitation Evaluation System-Short Form. FINDINGS: Significant improvements were observed over time in exercise tolerance, selected activity and sleep patterns, and QOL among the 46 (74%) subjects who completed the program. CONCLUSIONS: Patients with various types and stages of cancer can safely exercise using a cardiac rehabilitation model and can realize significant improvements in exercise tolerance, selected activity and sleep patterns, and QOL. IMPLICATIONS FOR NURSING: Most people are aware that regular exercise is part of a healthy lifestyle. After cancer diagnosis and treatment, patients experience uncertainty regarding how to resume exercise or how to begin an exercise program as part of their rehabilitation. Participation in a structured exercise program can provide patients with a safe environment within which to exercise at an intensity appropriate to their individual needs.

Decomposition chemistry of human remains: a new methodology for determining the postmortem interval.

This study was conducted to characterize the chemistry associated with the decomposition of human remains with the objective of identifying time-dependent biomarkers of decomposition. The purpose of this work was to develop an accurate and precise method for measuring the postmortem interval (PMI) of human remains. Eighteen subjects were placed within a decay research facility throughout a four-year time period and allowed to decompose naturally. Field autopsies were performed and tissue samples were regularly collected until the tissues decomposed to the point where they were no longer recognizable (encompassing a cumulative degree hour (CDH) range of approximately 1000 (approximately 3 weeks)). Analysis of the biomarkers (amino acids, neurotransmitters, and decompositional by-products) in various organs (liver, kidney, heart, brain, muscle) revealed distinct patterns useful for determining the PMI when based on CDHs. Proper use of the methods described herein allow for PMIs so accurate that the estimate is limited by the ability to obtain correct temperature data at a crime scene rather than sample variability.