A randomized phase II study of paclitaxel and bevacizumab with and without gemcitabine as first-line treatment for metastatic breast cancer.

BACKGROUND: The addition of bevacizumab to paclitaxel improved progression-free survival (PFS) of patients with metastatic breast cancer (MBC). We examined the efficacy and safety of adding gemcitabine to paclitaxel/bevacizumab (PB). PATIENTS AND METHODS: In this multicenter, open-label, randomized phase II trial, women with locally advanced or MBC were randomly assigned to receive paclitaxel 90 mg/m(2) (days 1, 8, 15) and bevacizumab 10 mg/kg (days 1, 15) with or without gemcitabine 1500 mg/m(2) (days 1, 15) in 28-day cycles. Patients with prior cytotoxic therapy for MBC were ineligible. The primary endpoint was investigator-assessed overall response rate (ORR); secondary endpoints were PFS, overall survival (OS), safety, and quality of life. RESULTS: Ninety-four patients received PB, and 93 received paclitaxel/bevacizumab/gemcitabine (PB+G). The ORRs were 48.9% (95% confidence interval [CI], 38.5%-59.5%) and 58.7% (95% CI, 47.9%-68.9%; P = .117) with PB and PB+G, respectively. The median PFS was 8.8 months (95% CI, 8.1-10.4 months) and 11.3 months (95% CI, 9.7-12.7 months; P = .247; hazard ratio, 0.82); the median OS was 25.0 months (95% CI, 18.8-not assessable [N/A] months) and 24.3 months (95% CI, 20.3-N/A months; P = .475; hazard ratio, 0.84), with PB and PB+G, respectively. There was significantly more grade 3-4 neutropenia (P = .001) and dyspnea (P = .014) with PB+G. Patients treated with PB experienced more improvement in total FACT-B (Functional Assessment of Cancer Therapy-Breast) (P = .021), FACT-B Social/Family Well-being (P = .041), and Breast Cancer-Additional Concerns (P = .008) scores than patients treated with PB+G. CONCLUSION: The addition of gemcitabine to PB was not associated with a statistically significant improvement in ORR. Treatment with PB+G increased the incidence of severe neutropenia and dyspnea, although the regimen generally was well tolerated.

Does Type of Tumor Histology Impact Survival among Patients with Stage IIIB/IV Non-Small Cell Lung Cancer Treated with First-Line Doublet Chemotherapy?

Chemotherapy regimens may have differential efficacy by histology in nonsmall cell lung cancer (NSCLC). We examined the impact of histology on survival of patients (N = 2,644) with stage IIIB/IV NSCLC who received first-line cisplatin/carboplatin plus gemcitabine (C/C+G) and cisplatin/carboplatin plus a taxane (C/C+T) identified retrospectively in the SEER cancer registry (1997-2002). Patients with squamous and nonsquamous cell carcinoma survived 8.5 months and 8.1 months, respectively (P = .018). No statistically significant difference was observed in survival between C/C+G and C/C+T in both histologies. Adjusting for clinical and demographic characteristics, the effect of treatment regimen on survival did not differ by histology (P for interaction = .257). There was no statistically significant difference in hazard of death by histology in both groups. These results contrast the predictive role of histology and improved survival outcomes observed for cisplatin-pemetrexed regimens in advanced nonsquamous NSCLC.

Neutropenia-related costs in patients treated with first-line chemotherapy for advanced non-small cell lung cancer.

BACKGROUND: Neutropenia is a major adverse event often associated with chemotherapy administration. Neutropenia-related complications often lead to increased use of costly health care including inpatient and outpatient services. Monitoring and treatment of neutropenia thus place an economic burden on the health care system. OBJECTIVES: To evaluate (a) costs and medical resource use for chemotherapy- related afebrile and febrile neutropenia in an elderly population with Stage IIIB or Stage IV non-small cell lung cancer (NSCLC), and (b) costs unrelated to neutropenia and total all-cause health care costs during first-line chemotherapy. METHODS: Study patients in this retrospective database analysis were aged 65 years or older with a diagnosis of Stage IIIB or Stage IV NSCLC in the Surveillance, Epidemiology and End Results (SEER) cancer registry from 1998 through 2002. Neutropenia was identified by the presence of a primary or secondary diagnosis code for diseases of white blood cells (ICD-9-CM = 288.xx) during a period of first-line chemotherapy treatment. Febrile neutropenia was defined by (a) an inpatient hospitalization with a primary or secondary diagnosis for neutropenia occurring at any time during first-line chemotherapy or (b) intravenous or intramuscular antibiotic administration occurring after the initial neutropenia diagnosis and during first-line chemotherapy. Patients with neutropenia without these events were considered to have afebrile neutropenia. Patients were followed in the SEER-Medicare database to evaluate costs (defined as all Medicare payments, primary insurer payments, and patient copayments and deductibles) and resource use associated with afebrile or febrile neutropenia while on first-line chemotherapy. If a patient switched to second-line chemotherapy, the day prior to the switch was defined as the end of first-line treatment. If a switch to second-line therapy did not occur, then first-line therapy was assumed to end 30 days following administration of the last first-line agent. Costs were summed for 2 main types of cost measures: neutropenia-related costs, defined as costs for claims with either a primary or secondary diagnosis of neutropenia, and costs unrelated to neutropenia. Costs were classified using ICD-9-CM diagnosis and procedure codes appearing on the claims, with confidence intervals [CIs] for cost measures estimated by using nonparametric bootstrapping methods. Group comparisons of patient characteristics, medical utilization, and cost study measures were made using 2-sided Pearson chi-square and t-test statistics for categorical and continuous measures, respectively. The no neutropenia group was used as the reference category for comparisons involving patient characteristic, medical utilization, and total all-cause health care cost study measures. For total neutropenia-related costs, afebrile and febrile neutropenia study groups were compared. RESULTS: Among elderly patients treated first-line for advanced NSCLC, 5,138 met inclusion criteria, of whom 1,228 (23.9%) developed afebrile (n = 740, 14.4%) or febrile neutropenia (n = 488, 9.5%) while on first-line chemotherapy. Mean per patient costs for treating neutropenia during first-line chemotherapy were $12,148 (standard deviation [SD] = $15,432, 95% confidence interval [CI] = $10,915-$13,607) for patients with febrile neutropenia and $3,099 (SD = $4,541, 95% CI = $2,796-$3,431) for patients with afebrile neutropenia (P<0.001), with mean (SD) length of follow-up (duration of first-line chemotherapy) of 4.5 (4.8) and 5.5 (7.0) months, respectively. Expressed as a percentage of total all-cause health care costs during first-line chemotherapy, neutropenia-related costs accounted for 32.2% of total costs for patients with febrile neutropenia (mean [SD] = $37,694 [$26,078]) and 9.1% of total costs for patients with afebrile neutropenia (mean [SD] = $34,204 [$26,317]). Mean neutropenia-related costs per patient per month (PPPM) during first-line chemotherapy were $2,700 for patients with febrile neutropenia and $563 for patients with afebrile neutropenia. PPPM costs unrelated to neutropenia for patients with afebrile neutropenia, febrile neutropenia, and no neutropenia, respectively, were $5,655, $5,677, and $6,146. In sensitivity analyses, results were highly sensitive to the definition of neutropenia (i.e., claims with primary diagnosis only vs. primary or secondary diagnosis) but insensitive to the type of chemotherapy regimen. CONCLUSION: Neutropenia is a major adverse event that places patients at an increased risk of infection and subsequent morbidity and mortality. For elderly patients undergoing first-line chemotherapy for NSCLC, neutropenia, particularly febrile neutropenia, is associated with substantially higher total all-cause health care costs.

The cost of comorbid depression and pain for individuals diagnosed with generalized anxiety disorder.

Patients with generalized anxiety disorder (GAD) often have comorbid medical and psychiatric disorders and may incur higher costs. In this study, a total of 36,435 GAD patients aged 18 to 64 were identified from a claims database. Patient's total health care and component costs were compared between GAD patients with and without comorbid depression and pain using general linear models. The average total annual cost for all the GAD patients in the study was $7451. Compared with patients with GAD-only, the estimated total cost was $762 higher for GAD with depression (p < 0.001), $2989 higher for GAD with pain (p < 0.001), and $6073 higher for GAD with both depression and pain (p < 0.001). Comorbid depression and pain had significant impact on costs, especially those with pain or with both depression and pain. This suggests that an optimal strategy for GAD should take into account comorbid pain and depression.

Costs of first-line doublet chemotherapy and lifetime medical care in advanced non-small-cell lung cancer in the United States.

OBJECTIVES: The purpose of this study was to identify total lifetime medical-care costs and costs associated with first-line chemotherapy treatment among older patients with stage IIIB/IV non-small-cell lung cancer treated with commonly used two-drug chemotherapy ("doublet") regimens in the United States. METHODS: Study patients included individuals aged 65 years and older who received a diagnosis of stage IIIB/IV non-small-cell lung cancer in a Surveillance, Epidemiology and End Results cancer registry between 1997 and 2002 and who received first-line treatment with commonly used doublet regimens. Patients were followed retrospectively in the Surveillance, Epidemiology and End Results-Medicare database to evaluate lifetime medical-care costs and costs while on first-line chemotherapy treatment. Pairwise comparisons of treatment costs were estimated by using nonparametric bootstrap methods. RESULTS: Lifetime medical-care costs totaled approximately $70,000 and on-treatment costs for first-line chemotherapy totaled approximately $30,000 among study patients and were dominated by hospitalization and physician costs. Lifetime costs were significantly higher among patients treated with first-line cisplatin/carboplatin (platinum) plus a taxane compared with those who received platinum plus gemcitabine [difference: $4781 ($1558-$8039)] or other doublet therapy [difference: $5961 ($2333-$9614)]. Total on-treatment costs for first-line chemotherapy were significantly higher among patients treated with platinum plus a taxane compared with those who received platinum plus gemcitabine [difference: $5825 ($3872-$7770)], platinum plus another agent [difference: $5968 ($3995-$7975)], or another doublet therapy [difference: $3663 ($1620-$5740)]. CONCLUSIONS: There is a cost differential between first-line doublet regimens in terms of lifetime and on-treatment costs. Although doublet therapy with platinum and a taxane was the most frequently utilized regimen, it was associated with the highest lifetime and on-treatment costs.

Trends and predictors of first-line chemotherapy use among elderly patients with advanced non-small cell lung cancer in the United States.

PURPOSE: This study assessed first-line chemotherapy treatment patterns over time and identified predictors of chemotherapy use and treatment selection among elderly patients with newly diagnosed Stage IIIB/IV non-small cell lung cancer (NSCLC) in the United States. METHODS: Patients aged 65 years and older newly diagnosed with Stage IIIB/IV NSCLC between 1997 and 2002 were identified and followed through 2003 using the Surveillance, Epidemiology and End Results (SEER)-Medicare database to evaluate temporal trends in chemotherapy treatment. Multivariate logistic regression models were estimated to identify predictors of chemotherapy treatment and factors associated with use of cisplatin/carboplatin (platinum) and either a taxane or gemcitabine versus other treatments. RESULTS: Chemotherapy use increased from approximately 28% of Stage IIIB/IV NSCLC patients diagnosed in 1997 to 36% of patients diagnosed in 2002. Doublet therapy was most commonly used as first-line therapy, received by 74% of chemotherapy-treated patients across all study years. Use of doublet therapy with platinum and either a taxane or gemcitabine also increased over time (with the largest increase for gemcitabine combinations from 0.3% in 1997 to 11.8% in 2002). Males were more likely than females to be treated with chemotherapy (odds ratios [95% CI]: 1.14 [1.06-1.22]), as were patients in the Northeast and South relative to patients in the West (1.24 [1.13-1.36] and 1.33 [1.20-1.47], respectively). CONCLUSION: Use of first-line chemotherapy treatment among elderly Stage IIIB/IV NSCLC patients is low, but appears to be increasing, with potential regional and gender differences in treatment. These findings are likely to be of interest to clinicians and policymakers.

Use of effect size to determine optimal dose of duloxetine in major depressive disorder.

OBJECTIVE: At effective doses, patients with major depressive disorder (MDD) treated with duloxetine have been found to experience significant symptom improvement as measured by HAMD(17) total score. In addition, duloxetine-treated patients have significantly higher remission and response rates compared with placebo. The objective of this analysis is to determine the optimal dose of duloxetine in MDD. MATERIALS AND METHODS: Effect size for duloxetine 40mg, 60mg, 80mg, and 120mg per day were estimated using all 6 acute phase III clinical trials in patients with MDD. The tolerability of duloxetine 40mg, 60mg, 80mg, and 120mg were evaluated using pooled data from the 6 studies. The primary efficacy measure in all trials was the HAMD(17) total score, from which were determined the effect size for HAMD(17) change scores, response rates (50% reduction from baseline to endpoint), and remission rates (HAMD(17) total score < or =7). RESULTS: A total of 1619 randomized patients were included in these studies, of which 632 were treated with placebo; 177 with duloxetine 40mg/day; 251 with 60mg/day; 363 with 80mg/day; and 196 with 120mg/day. An evaluation of increments in effect size between doses consistently showed that the most notable gain in effect size for efficacy was the 40-60mg/day dosage range. All dosages from 60 to 120mg were effective. The tolerability assessment indicated duloxetine at 40-120mg/day is well tolerated. Furthermore, the initial doses of 40-80mg/day were found to have comparable tolerability. CONCLUSIONS: The effect size analyses demonstrate that duloxetine 40mg has minimum efficacy, and that duloxetine 60-120mg/day is effective in the treatment of patients with MDD. An initial dose less than 60mg/day might provide better tolerability for some patients diagnosed with MDD.

The cost of treating anxiety: the medical and demographic correlates that impact total medical costs.

The purpose of this retrospective, multivariate analysis is to examine how medical conditions and demographic characteristics affect the costs of treating individuals diagnosed with anxiety. Data from MarketScan Databases [The MEDSTAT Group, 2000] were used to identify individuals with new episodes of anxiety. Multivariate analysis was used, with the dependent variable being the log of total medical costs. This analysis controlled for demographic characteristics, medical comorbidities, anxiety diagnosis, and prior resource utilization. A smearing estimate is used to calculate the total medical costs for patients with any anxiety disorder. The mean estimated total medical cost for individuals diagnosed with any anxiety disorder was $6,475. The multivariate model indicates that controlling for demographics and other disease states, generalized anxiety disorder (GAD), panic disorders, and posttraumatic stress disorder (PTSD) are associated with a $2,138, $1,603, and $3,940 increase, respectively, in the total medical cost (P < .0001). The incremental impact of depression, other anxiety disorders, and prior mental health diagnoses on the total medical costs were $1,945, $1,900, and $1,515, respectively (P < .0001). Individuals with the highest costs, and therefore the greatest need for intervention, are anxious patients with depression, individuals diagnosed with PTSD or GAD, and individuals diagnosed with both anxiety and a comorbid medical condition such as an acute myocardial infarction or diabetes.

The benefits of switching smoking cessation drugs to over-the-counter status.

This paper provides an analysis of the benefits to society from the conversion of nicotine replacement drugs (nicotine patches and gum) in 1996 from sale by prescription only in the United States to over-the-counter (OTC) sales. To estimate these benefits, we first estimate statistical demand functions for nicotine patches and gum. Second, we calculate the effects of OTC conversion on sales of each type of nicotine replacement drug. Third, we survey the literature on the effects of nicotine replacement drugs on total quits of cigarette smoking. Fourth, we survey the literature on the effects of quits achieved on expected lifespan, and on the estimated monetary value of longer lives from smoking cessation. Finally, we use all this evidence to calculate the value of the social benefits of the OTC conversion to the US. As a result of the OTC conversion, consumption of nicotine replacement drugs has increased substantially, by 78-92% for nicotine patches and 180% for nicotine gum. We estimate that the resulting increase in smoking cessation generated annual net social benefits of the order of magnitude of 1.8-2 billion dollars, based on conservative estimates both of the number of quits achieved and the value of added quality-adjusted life years from the reduced smoking.