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In the KEYNOTE-158 study (NCT02628067), pembrolizumab showed a high objective response rate and durable clinical benefit for patients with previously treated, unresectable/metastatic microsatellite instability-high (MSI-H)/mismatch repair‒deficient (dMMR) non-colorectal solid tumours. We present health-related quality of life (HRQoL) results from the MSI-H/dMMR population (cohort K).Eligible patients had previously treated MSI-H/dMMR advanced non-colorectal solid tumours, measurable disease per RECIST v1.1, and ECOG performance status ≤1. Patients received pembrolizumab 200 mg Q3W for 35 cycles (2 years). The EORTC Quality of Life Questionnaire (QLQ-C30) and EQ-5D-3L were administered at baseline, at regular intervals throughout treatment, and 30 days after treatment discontinuation. Prespecified analyses (exploratory endpoints) included the magnitude of change from baseline to post-baseline timepoints in all patients and by the best overall response for QLQ-C30 global health status (GHS)/QoL, QLQ-C30 functional/symptom scales/items, and EQ-5D-3L visual analogue scale (VAS) score.At data cutoff (October 5, 2020), 351 patients were enrolled, of whom 311 and 315 completed baseline QLQ-C30 and EQ-5D-3L questionnaires, respectively. QLQ-C30 GHS/QoL scores improved from baseline to week 9 (mean [95% CI] change, 3.07 [0.19-5.94]), then remained stable or improved by week 111, with greater improvements observed in patients with a best response of complete response (CR) or partial response (PR) (10.85 [6.36-15.35]). Patients with CR/PR showed improvements in physical (5.58 [1.91-9.25]), role (9.88 [3.80-15.97]), emotional (5.62 [1.56-9.68]), and social (8.33 [2.70-13.97]) functioning, and stable cognitive functioning (1.74 [-1.45 to 4.94]).Pembrolizumab generally improved or preserved HRQoL in patients with previously treated MSI-H/dMMR advanced non-colorectal solid tumours.

Objective: To estimate per-event cost and economic burden associated with managing the most common and/or severe metastatic melanoma (MM) treatment-related adverse events (AEs) in Australia, France, Germany, Italy, and the UK. Methods: AEs associated with chemotherapy (dacarbazine, paclitaxel, fotemustine), immunotherapy (ipilimumab), and targeted therapy (vemurafenib) were identified by literature review. Medical resource use data associated with managing AEs were collected through two blinded Delphi panel cycles in each of the five countries. Published costs were used to estimate per-event costs and combined with AEs incidence, treatment usage, and MM prevalence to estimate the economic burden for each country. Results: The costliest AEs were grade 3/4 events due to immunotherapy (Australia/France: colitis; UK: diarrhea) and chemotherapy (Germany/Italy: neutropenia/leukopenia). Treatment of AEs specific to chemotherapy (Australia/Germany/Italy/France: neutropenia/leukopenia) and targeted therapy (UK: squamous cell carcinoma) contributed heavily to country-specific economic burden. Limitations: Economic burden was estimated assuming that each patient experienced an AE only once. In addition, the context of settings was heterogeneous and the number of Delphi panel experts was limited. Conclusions: Management costs for MM treatment-associated AEs can be substantial. Results could be incorporated in economic models that support reimbursement dossiers. With the availability of newer treatments, establishment of a baseline measure of the economic burden of AEs will be crucial for assessing their impact on patients and regional healthcare systems.

In the COMBI-v trial, patients with previously untreated BRAF Val600Glu or Val600Lys mutant unresectable or metastatic melanoma who were treated with the combination of dabrafenib and trametinib had significantly longer overall and progression-free survival than those treated with vemurafenib alone. Here, we present the effects of treatments on health-related quality of life (HRQoL), an exploratory endpoint in the COMBI-v study.COMBI-v was an open-label, randomised phase 3 study in which 704 patients with metastatic melanoma with a BRAF Val600 mutation were randomly assigned (1:1) by an interactive voice response system to receive either a combination of dabrafenib (150 mg twice-daily) and trametinib (2 mg once-daily) or vemurafenib monotherapy (960 mg twice-daily) orally as first-line therapy. The primary endpoint was overall survival. In this pre-specified exploratory analysis, we prospectively assessed HRQoL in the intention-to-treat population with the European Organisation for Research and Treatment of Cancer quality of life (EORTC QLQ-C30), EuroQoL-5D (EQ-5D), and Melanoma Subscale of the Functional Assessment of Cancer Therapy-Melanoma (FACT-M), completed at baseline, during study treatment, at disease progression, and after progression. We used a mixed-model, repeated measures ANCOVA to assess differences in mean scores between groups with baseline score as covariate; all p-values are descriptive. The COMBI-v trial is registered with ClinicalTrials.gov, number NCT01597908, and is ongoing for the primary endpoint, but is not recruiting patients.From June 4, 2012, to Oct 7, 2013, 1645 patients at 193 centres worldwide were screened for eligibility, and 704 patients were randomly assigned to dabrafenib plus trametinib (n=352) or vemurafenib (n=352). Questionnaire completion rates for both groups were high (95% at baseline,80% at follow-up assessments, and70% at disease progression) with similar HRQoL and symptom scores reported at baseline in both treatment groups for all questionnaires. Differences in mean scores between treatment groups were significant and clinically meaningful in favour of the combination compared with vemurafenib monotherapy for most domains across all three questionnaires during study treatment and at disease progression, including EORTC QLQ-C30 global health (7·92, 7·62, 6·86, 7·47, 5·16, 7·56, and 7·57 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; p0·001 for all assessments except p=0·005 at week 40), EORTC QLQ-C30 pain (-13·20, -8·05, -8·82, -12·69, -12·46, -11·41, and -10·57 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; all p0·001), EQ-5D thermometer scores (7·96, 8·05, 6·83, 11·53, 7·41, 9·08, and 10·51 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; p0·001 for all assessments except p=0·006 at week 32), and FACT-M Melanoma Subscale score (3·62, 2·93, 2·45, 3·39, 2·85, 3·00, and 3·68 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; all p0·001).From the patient's perspective, which integrates not only survival advantage but also disease-associated and adverse-event-associated symptoms, treatment with the combination of a BRAF inhibitor plus a MEK inhibitor (dabrafenib plus trametinib) adds a clear benefit over monotherapy with the BRAF inhibitor vemurafenib and supports the combination therapy as standard of care in this population.

Malignant melanoma patients frequently relapse with metastases in the brain, making it the third most common cancer-causing brain metastases in the USA. Management of brain metastases remains challenging because of the rapid progression of disease and ineffectiveness of conventional therapies. This retrospective study, with a 'pre/post' design, quantifies the economic burden of brain metastases among melanoma patients in the USA. A large managed-care insurance claims database (2000 Q1-2011 Q3) was used to identify patients with melanoma and brain metastases. The preperiod was defined as the 6 months before the index date (diagnosis of first observed brain metastases) and postperiod as the period following the index date up to 12 months. All-cause and brain metastasis-related healthcare resource utilization and healthcare costs were compared on a per-patient-per-month (PPPM) basis between preperiods and postperiods. The study included 6076 patients (mean age 63.4 years); 57.6% were men. Significant differences (P

Background: In a randomized phase III study (BREAK-3), dabrafenib showed prolonged progression-free survival (PFS) (median 5.1 versus 2.7 months; hazard ratio = 0.30; 95% confidence interval 0.18–0.53; P < 0.0001) compared with dacarbazine (DTIC) in patients with BRAF V600E metastatic melanoma. Assessing how these results are transformed into a real health benefit for patients is crucial. Methods: The EORTC QLQ-C30 questionnaire assessed quality of life (QoL) at baseline and follow-up visits. Results: For DTIC, all functional dimensions except role dimension worsened from baseline at follow-up. For dabrafenib, all functionality dimensions remained stable relative to baseline or improved at week 6; mean change in seven symptom dimensions improved from baseline, with appetite loss, insomnia, nausea and vomiting, and pain showing the greatest improvement. In the DTIC arm, symptom dimensions were unchanged or worsened from baseline for all symptoms except pain (week 6), with the greatest exacerbations observed for fatigue and nausea and vomiting. Mixed-model-repeated measures analyses showed significant (P < 0.05) and/or clinically meaningful improvements from baseline in favor of dabrafenib for emotional and social functioning, nausea and vomiting, appetite loss, diarrhea, fatigue, dyspnea, and insomnia at weeks 6 and/or 12. After crossing over to dabrafenib upon progression (n = 35), improvements in all QoL dimensions were evident after receiving dabrafenib for 6 (n = 31) to 12 (n = 25) weeks. Conclusions: This first reported QoL analysis for a BRAF inhibitor in metastatic melanoma demonstrates that the high tumor response rates and PFS superiority of dabrafenib over DTIC is not only a theoretical advantage, but also transforms in a rapid functional and symptomatic benefit for the patient. Clinical Trials.gov identifier NCT01227889.

Background Progression-free survival (PFS) was significantly longer for the lapatinib plus trastuzumab (L+T) arm than for L alone in a phase III, randomized, open-label study of women with human epidermal growth factor receptor 2 positive metastatic breast cancer who had documented progression on at least one T-containing regimen in the metastatic setting. This analysis focused on impact of treatments on health-related quality of life (HRQOL). Methods HRQOL was assessed using the Functional Assessment of Cancer Therapy–Breast (FACT-B) questionnaire. Changes from baseline and time to deterioration were analyzed in the intent-to-treat population. Results Differences between the treatment arms in adjusted mean change from baseline favored the L+T arm, ranging from 0.0 to 4.1 (FACT-B), 1.0–4.0 [Functional Assessment of Cancer Therapy–General (FACT-G)], and 0.5–2.7 (Trial Outcome Index). Most differences were not statistically significant, except for FACT-G at week 12 (delta = 4.0, P = 0.037). Similar results were found in a sensitivity analysis that included HRQOL records up to patient withdrawal from original randomized treatment. The longer time to HRQOL deterioration in the L+T arm was not statistically significant (FACT-B hazard ratio, 0.82; 95% confidence interval 0.56–1.20). Conclusion The addition of lapatinib to trastuzumab prolonged PFS while improving or maintaining near-term HRQOL, suggesting a meaningful clinical benefit to patients.

Compare first-line lapatinib plus letrozole (L + Let) versus letrozole monotherapy (Let) in hormone-receptor-positive HER2 + metastatic breast cancer, employing Q-TWiST (quality-adjusted time without symptoms and toxicity) analysis to account for differences in progression times, with offsets for the impact of adverse events during the treatment period.The area under survival curves for each treatment group was partitioned into distinct health states of varying utility: toxicity (TOX), time without toxicity or disease progression (TWiST), and the period following disease progression until death or end of follow-up (REL). The utility-weighted sum of the mean health state durations was derived for each group. The threshold utility analysis evaluates how varying utility values across the states affects Q-TWiST differences between groups, although the method is limited by not varying utilities within each health state.The primary analysis population was the HER2 + subgroup (n = 219). There was no significant difference between treatments in mean duration of grade 3/4 adverse events prior to progression (L + Let = 1.95 weeks; Let = 2.14 weeks; P = 0.90). Using utility weights of 0.5 for TOX and REL, L + Let was favored for quality-adjusted survival by 8.8 weeks (P = 0.09). The Q-TWiST difference between treatment groups ranged from 8 to 9.5 weeks, favoring combination therapy for all hypothetical utility levels, but none of the comparisons were statistically significant at P = 0.05.No significant differences were found between L + Let versus Let in mean duration of severe adverse events. Quality-adjusted survival was favored for the combination treatment arm for all utility levels examined when toxicity was defined by grade 3/4 AEs, but differences between groups were not statistically significant.

In a phase III trial of women with HER2+ metastatic breast cancer (MBC) previously treated with trastuzumab, an anthracycline, and taxanes (EGF100151), lapatinib plus capecitabine (L+C) improved time to progression (TTP) versus capecitabine monotherapy (C-only). In a trial including HER2+ MBC patients who had received at least one prior course of trastuzumab and no more than one prior course of palliative chemotherapy (GBG 26/BIG 03-05), continued trastuzumab plus capecitabine (T+C) also improved TTP.An economic model using patient-level data from EGF100151 and published results of GBG 26/BIG 03-05 as well as other literature were used to evaluate the incremental cost per quality-adjusted life-year [QALY] gained with L+C versus C-only and versus T+C in women with HER2+ MBC previously treated with trastuzumab from the UK National Health Service (NHS) perspective.Expected costs were £28,816 with L+C, £13,985 with C-only and £28,924 with T+C. Corresponding QALYs were 0.927, 0.737 and 0.896. In the base case, L+C was estimated to provide more QALYs at a lower cost compared with T+C; cost per QALY gained was £77,993 with L+C versus C-only. In pairwise probabilistic sensitivity analyses, the probability that L+C is preferred to C-only was 0.03 given a threshold of £30,000. The probability that L+C is preferred to T+C was 0.54 regardless of the threshold.When compared against capecitabine alone, the addition of lapatinib has a cost-effectiveness ratio exceeding the threshold normally used by NICE. Compared with T+C, L+C is dominant in the base case and approximately equally likely to be cost-effective in probabilistic sensitivity analyses over a wide range of threshold values.

EGF103009 (ClinicalTrials.gov identifier: NCT00105950) was a phase 2, open-label, multicenter study that showed lapatinib monotherapy to be clinically active in women with relapsed or refractory HER2+ (ErbB2+) inflammatory breast cancer that progressed following prior therapy with anthracyclines, taxanes, and trastuzumab. The objective of the present study was to assess the impact of lapatinib on quality of life (QOL) and pain symptoms in these patients.QOL and pain assessments were added during a study amendment and hence only 33 of 126 HER2+ patients were available for baseline assessment. QOL and pain were assessed using the EORTC QLQ-C30 and Brief Pain Inventory-Short Form (BPI-SF) questionnaires, respectively. Both questionnaires were completed at baseline and every 4 weeks thereafter. Change from baseline in QOL and pain scores were summarized by visit. In a post hoc analysis, scores were compared between patients with different clinical response status.Over 60% of the 33 HER2+ patients with the baseline assessments completed the first three postbaseline assessments (week 4, n = 26; week 8, n = 21; week 12, n = 20). At week 8, improvement from baseline in mean EORTC QLQ-C30 scores was observed for global QOL (delta = 14.5; 95% CI: 4.0, 25.0), role functioning (delta = 15; 95% CI: 0.9, 29.1), social functioning (delta = 14.9; 95% CI: -0.5, 30.3), and physical functioning subscales (delta = 9.0; 95% CI: 1.2, 16.8). All symptom scales (except diarrhea) improved from baseline at most scheduled visits during the 20-week follow-up period. Mean scores for all four BPI-SF summary pain scores at week 8 suggested improvement in pain severity and pain interference. Clinical responders had improved scores on most aspects of QOL, compared with declining scores among nonresponders to treatment.The QOL improvement among the small number of patients with QOL data indicates that lapatinib monotherapy may improve level of functioning/QOL and provide relief from symptoms, including pain, in the short term. These QOL benefits add to the clinical improvement associated with lapatinib therapy in heavily pretreated patients with an aggressive form of breast cancer.

In a phase 3 randomized, multicenter, double-blind, placebo-controlled study, first-line therapy with lapatinib plus paclitaxel significantly improved clinical outcomes based on a pre-planned analysis of ErbB2+ metastatic breast cancer patients (GSK Study #EGF30001; ClinicalTrials.gov identifier: NCT00075270). Patients with ErbB2- or untested did not significantly benefit. This article focuses on the quality of life (QOL) and quality-adjusted survival outcomes (Q-TWiST) in the study.QOL was assessed using the Functional Assessment of Cancer Therapy-Breast (FACT-B). Changes from baseline were analyzed using ANCOVAs, repeated measures and pattern mixture modeling. The Q-TWiST method was used to examine the trade-off between toxicities and delayed progression.The study included 579 subjects, of whom 86 were ErbB2+. In the ITT population, no significant differences in QOL or Q-TWiST scores were observed. In the ErbB2+ subgroup, the lapatinib plus paclitaxel (L + P) arm demonstrated stable FACT-B scores over the first year, while average scores for patients on P + placebo (P + pla) monotherapy decreased (change from baseline: L + P, p = 0.99; P + pla, p = 0.01). Clinically meaningful differences were observed between treatment arms on the FACT-B, Trial Outcome Index and breast cancer subscale scores. Pattern mixture models suggested more QOL differentiation between treatments among patients who progressed or withdrew early. Q-TWiST differences between the arms in the ErbB2+ subgroup ranged from 2 to 15 weeks with an L + P advantage across all utility weight combinations.In the ITT population, results provide no evidence of QOL differences between treatment groups. In a small, prospectively-defined subgroup of ErbB2+ patients, L + P resulted in more stable QOL and more quality-adjusted survival than paclitaxel monotherapy, representing clinically important differences between treatments.

Background: To improve medication-taking behavior, it is important to identify factors that may contribute to suboptimal compliance and persistence with osteoporosis medications. Objective: The purpose of this descriptive analysis was to identify concurrent prescription medication use (number and type) among women receiving daily or weekly oral bisphosphonate therapy. Methods: Patient prescription data were collected from November 1999 to June 2004 from a US patient claims database accessed through Wolters Kluwer Health (formerly NDC Health), which represents >65 million patients annually. Women aged ≥50 years who were receiving daily or weekly oral bisphosphonate medication during the study months were included. Concomitant medications were defined based on ≥14 days of prescription supply in the same month as bisphosphonate therapy. Data were examined to determine the frequency with which certain drugs and drug classes were prescribed concomitantly with bisphosphonates. Each study month was treated independently to assess concomitant medication use. Results: Over the study period, the number of female bisphosphonate recipients in the database increased from 78,909 to 250,286. At the end of the study, 16.2%, 12.2%, 8.7%, and 19.1% of bisphosphonate recipients were prescribed 3, 4, 5, or ≥6 concomitant medications, respectively. The most commonly prescribed concomitant drug classes were cholesterol reducers, diuretics, β-blockers, calcium channel blockers, synthetic thyroid hormones, angiotensin-converting enzyme inhibitors, systemic analgesics/anti-inflammatory drugs, and antispasmodics/antisecretory drugs. From July 2001 until the end of the study, the number of concomitant medications was higher for women receiving daily bisphosphonates than for those receiving weekly bisphosphonates, 4.16 versus 3.77 as of June 2004. In addition, the mean number of concomitant medications prescribed increased with age: in the aged 50 to 64 years cohort, the aged 65 to 74 years cohort, and the aged ≥75 years cohort, the mean number was 3.09, 3.62, and 3.97, respectively, as of June 2004. Conclusion: This analysis suggests that women prescribed bisphosphonates have a high medication burden, with the majority of patients (56%) taking ≥3 concomitant prescription medications.

An estimated $8.1 billion (in 2004 dollars) is spent annually on total health care costs for the treatment of breast cancer in the United States. Breast cancer has traditionally been treated with intravenous (IV) cancer therapies that entail not only the drug acquisition cost, but additional costs of personnel time, supplies, and equipment used in the preparation and administration of the IV drug. A systematic study of the costs of IV administration in the metastatic breast cancer (MBC) population has not been performed.To assess the cost components, overall and by payer type and patient age group, for administering a single-agent IV breast cancer drug to women with MBC in the United States.Women diagnosed with MBC (ICD-9-CM codes 174.XX and 196.XX-198.XX) reported any time between January 1, 2003, and May 31, 2006, and receiving single-agent IV breast cancer therapy (including intramuscular fulvestrant) during a visit were identified (using HCPCS and CPT codes) from an administrative claims database supporting 46 general/oncology clinics in the United States. Study drugs were either FDA-approved for breast cancer or recommended for use as preferred single agents per National Comprehensive Cancer Network (NCCN) clinical practice guidelines for breast cancer. Costs were estimated using the contracted allowed payment, which is the amount that the provider is eligible to receive from all parties, including payers and patients. Costs were measured using 2 approaches-average cost per IV-administration visit and average cost per patient per month (PPPM).Over the 41-month study period (through May 31, 2006), 46,273 patients had a breast cancer diagnosis, of which 8,533 (18.4%) were metastatic; 828 (9.7%) of these patients received 1 of 11 single-agent IV breast cancer drugs over 7,406 visits. Mean (SD) total payments across all drugs and cost components were $2,477 ($1,842) per visit and $4,966 ($3,841) PPPM, of which IV administration costs were 10.2% of per-visit and 11.4% of PPPM costs, and other drugs and services provided during IV administration were 30.8% of per-visit and 32.2% of PPPM costs. In both the per-visit and PPPM analyses, approximately 80% of costs for other drugs and services (approximately 25% of total treatment costs) were attributed to (a) antihypercalcemic agents (e.g., zoledronic acid: 6%-8% of total treatment cost), (b) colony-stimulating factors (CSFs) (e.g., pegfilgrastim, epoetin: 6%-7%), or (c) other anticancer agents being used off-label or for other conditions (e.g., bevacizumab, irinotecan, carboplatin, vincristine: 11%-12%). The remaining 20% of costs for other drugs and services (about 6% of total costs) were attributable primarily to antiemetic agents (e.g., palonosetron, granisetron) and miscellaneous or unclassified products. Non-protein-bound paclitaxel was the most commonly used IV therapy at a mean cost of $2,804 per visit, with IV administration accounting for $353 (12.6%) and other services accounting for $1,237 (44.1%) of total costs per visit. The second most commonly used IV therapy was trastuzumab at a mean cost of $2,526 per visit, with IV administration accounting for $214 (8.5%) and other services accounting for $336 (13.3%) of total costs per visit.For patients being administered a single FDA-approved or NCCN-recommended IV drug for treatment of MBC, IV administration costs accounted for approximately 10%-11% of total cost, and the study drugs accounted for 56%-59%. Other drugs and services accounted for 31%-32%, most of which was attributable to antihypercalcemic agents, CSFs, anticancer drugs being used off-label for breast cancer or for other conditions, and antiemetic agents. Although costs of IV administration are 10%-11% of total IV chemotherapy costs for MBC and would clearly be avoided with the use of oral agents, the extent to which other costs would be avoided or incurred with use of oral agents is unknown and requires further research.

The addition of lapatinib (Tykerb/Tyverb) to capecitabine (Xeloda) delays disease progression more effectively than capecitabine monotherapy in women with previously treated HER2+ metastatic breast cancer (MBC). The quality-adjusted time without symptoms of disease or toxicity of treatment (Q-TWiST) method was used to compare treatments. The area under survival curves was partitioned into health states: toxicity (TOX), time without symptoms of disease progression or toxicity (TWiST), and relapse period until death or end of follow-up (REL). Average times spent in each state, weighted by utility, were derived and comparisons of Q-TWiST between groups performed with varying combinations of the utility weights. Utility weights of 0.5 for both TOX and REL, that is, counting 2 days of TOX or REL as 1 day of TWiST, resulted in a 7-week difference in quality-adjusted survival favouring combination therapy (P=0.0013). The Q-TWiST difference is clinically meaningful and was statistically significant across an entire matrix of possible utility weights. Results were robust in sensitivity analyses. An analysis with utilities based on EQ-5D scores was consistent with the above findings. Combination therapy of lapatinib with capecitabine resulted in greater quality-adjusted survival than capecitabine monotherapy in trastuzumab-refractory MBC patients.

Purpose This multicenter phase III study evaluated the efficacy and safety of lapatinib, an epidermal growth factor receptor/ErbB2 inhibitor, administered concomitantly with chemoradiotherapy and as maintenance monotherapy in patients with high-risk surgically treated squamous cell carcinoma of the head and neck (SCCHN). Patients and Methods Patients with resected stage II to IVA SCCHN, with a surgical margin ≤ 5 mm and/or extracapsular extension, were randomly assigned to chemoradiotherapy (66 Gy total radiation dose and cisplatin 100 mg/m2 per day administered on days 1, 22, and 43) plus placebo or lapatinib (1,500 mg per day) before and during chemoradiotherapy, followed by 12 months of maintenance monotherapy. Results Six hundred eighty-eight patients were enrolled (lapatinib, n = 346; placebo, n = 342). With a median follow-up time of 35.3 months, the study ended early because of the apparent plateauing of disease-free survival (DFS) events. Median DFS assessed by an independent review committee was 53.6 months and not reached for lapatinib and placebo, respectively (hazard ratio, 1.10; 95% CI, 0.85 to 1.43). Investigator-assessed results confirmed the independent review committee assessment. No significant differences in DFS by human papillomavirus status or overall survival were observed between treatment arms. Similar numbers of patients in both treatment arms experienced adverse events (AEs), with more patients in the lapatinib arm than the placebo arm experiencing serious AEs (48% v 40%, respectively). The most commonly observed treatment-related AEs were diarrhea and rash, both predominantly in the lapatinib arm. Conclusion Addition of lapatinib to chemoradiotherapy and its use as long-term maintenance therapy does not offer any efficacy benefits and had additional toxicity compared with placebo in patients with surgically treated high-risk SCCHN.

Patients with BRAF V600E mutation-positive melanoma who were assigned to 150 mg dabrafenib twice daily combined with 2 mg trametinib once daily in a phase I/II study showed a median overall survival (OS) of 23.8 months, compared with 20.2 months for patients assigned to dabrafenib alone [hazard ratio (HR)=0.73, 95% confidence interval (CI) 0.43-1.24; data cutoff March 2013], on the basis of an intention-to-treat analysis. Because patients assigned to dabrafenib monotherapy were allowed to switch to combination therapy upon disease progression, we attempted to adjust for confounding effects on OS. Randomization-based adjustment methods, Rank Preserving Structural Failure Time Models and the Iterative Parameter Estimation algorithm, were used. Two analyses, 'treatment group' (assumes that treatment effect continues beyond treatment discontinuation) and 'on treatment' (assumes that the treatment effect disappears upon treatment discontinuation), were used to test assumptions on the durability of the treatment effect. A total of 45/54 (83%) patients assigned to dabrafenib monotherapy switched to the trametinib/dabrafenib combination. Adjusted OS HRs ranged from 0.47 to 0.50, depending on the analysis, compared with the unadjusted OS HR of 0.73. CIs continued to cross 1.00; thus, adjusted estimates did not provide statistically significant evidence of a treatment benefit on survival. Reduction of HRs after adjusting for the effect of treatment switching suggests that the intention-to-treat analysis underestimates the effect of dabrafenib plus trametinib on OS, although several factors, such as small trial size and methodological assumptions, affect the certainty of the conclusions.

Trametinib, a selective inhibitor of mitogen‐activated protein kinase kinase 1 (MEK1) and MEK2, significantly improves progression‐free survival compared with chemotherapy in patients with BRAF V600E/K mutation–positive advanced or metastatic melanoma (MM). However, the pivotal clinical trial permitted randomized chemotherapy control group patients to switch to trametinib after disease progression, which confounded estimates of the overall survival (OS) advantage of trametinib. Our purpose was to estimate the switching‐adjusted treatment effect of trametinib for OS and assess the suitability of each adjustment method in the primary efficacy population. Of the patients randomized to chemotherapy, 67.4% switched to trametinib. We applied the rank‐preserving structural failure time model, inverse probability of censoring weights, and a two‐stage accelerated failure time model to obtain estimates of the relative treatment effect adjusted for switching. The intent‐to‐treat (ITT) analysis estimated a 28% reduction in the hazard of death with trametinib treatment (hazard ratio [HR], 0.72; 95% CI, 0.52–0.98) for patients in the primary efficacy population (data cut May 20, 2013). Adjustment analyses deemed plausible provided OS HR point estimates ranging from 0.48 to 0.53. Similar reductions in the HR were estimated for the first‐line metastatic subgroup. Treatment with trametinib, compared with chemotherapy, significantly reduced the risk of death and risk of disease progression in patients with BRAF V600E/K mutation–positive advanced melanoma or MM. Adjusting for switching resulted in lower HRs than those obtained from standard ITT analyses. However, CI are wide and results are sensitive to the assumptions associated with each adjustment method.

Background. Patients with previously untreated BRAF V600E mutation-positive melanoma in BREAK-3 showed a median overall survival (OS) of 18.2 months for dabrafenib versus 15.6 months for dacarbazine (hazard ratio [HR], 0.76; 95% confidence interval, 0.48–1.21). Because patients receiving dacarbazine were allowed to switch to dabrafenib at disease progression, we attempted to adjust for the confounding effects on OS. Materials and Methods. Rank preserving structural failure time models (RPSFTMs) and the iterative parameter estimation (IPE) algorithm were used. Two analyses, “treatment group” (assumes treatment effect could continue until death) and “on-treatment observed” (assumes treatment effect disappears with discontinuation), were used to test the assumptions around the durability of the treatment effect. Results. A total of 36 of 63 patients (57%) receiving dacarbazine switched to dabrafenib. The adjusted OS HRs ranged from 0.50 to 0.55, depending on the analysis. The RPSFTM and IPE “treatment group” and “on-treatment observed” analyses performed similarly well. Conclusion. RPSFTM and IPE analyses resulted in point estimates for the OS HR that indicate a substantial increase in the treatment effect compared with the unadjusted OS HR of 0.76. The results are uncertain because of the assumptions associated with the adjustment methods. The confidence intervals continued to cross 1.00; thus, the adjusted estimates did not provide statistically significant evidence of a treatment benefit on survival. However, it is clear that a standard intention-to-treat analysis will be confounded in the presence of treatment switching—a reliance on unadjusted analyses could lead to inappropriate practice. Adjustment analyses provide useful additional information on the estimated treatment effects to inform decision making. Implications for Practice: Treatment switching is common in oncology trials, and the implications of this for the interpretation of the clinical effectiveness and cost-effectiveness of the novel treatment are important to consider. If patients who switch treatments benefit from the experimental treatment and a standard intention-to-treat analysis is conducted, the overall survival advantage associated with the new treatment could be underestimated. The present study applied established statistical methods to adjust for treatment switching in a trial that compared dabrafenib and dacarbazine for metastatic melanoma. The results showed that this led to a substantially increased estimate of the overall survival treatment effect associated with dabrafenib.

Background: Oral hypoglycemic agents (OHAs) are an important component in the management of type 2 diabetes mellitus (DM). Large-sclae studies have demonstrated that tight glycemic control with such agents can reduce the frequency and severity of long-term DM-related complications. Objectives: The main goal of this study was to examine the impact of depression on utilization patterns of OHAs in patients newly diagnosed with type 2 DM. A secondary objective was to estimate the impact of depression on discontinuation and modification of pharmacotherapy for DM in these patients. Methods: Patients newly diagnosed with type 2 DM during a 3-year period (1998–2000) were identified from a Medicaid claims database. Presence of preexisting depression was determined on the basis of International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. The patient cohort was followed up until they received their first prescription for an OHA (1998–2001); this date was treated as the index date for the study. Utilization patterns (ie, discontinuation, augmentation, switching, nonmodification) for OHAs were computed for a 12-month follow-up period after the index date. A multivariate framework was used to estimate the impact of depression on utilization patterns, controlling for confounders such as demographics, comorbidity, provider interaction, drug regimen complexity, and DM severity. Results: A total of 1237 newly diagnosed type 2 DM patients were identified (depressed, n=446; nondepressed, n=791). A higher number of depressed patients (23.32%) switched or augmented therapy compared with nondepressed patients (16.18%). Also, a higher fraction of depressed patients (39.46%) discontinued OHA therapy compared with nondepressed patients (32.87%). Results of a multinomial logistic regression indicated that, controlling for covariates, patients with depression were 1.72 times more likely to switch ( P =0.046) and 1.89 times more likely to augment therapy ( P =0.004) compared with nondepressed patients. Logistic regression analysis also indicated that, controlling for confounding covariates, patients with depression were 1.72 times more likely to modify initial OHA therapy compared with patients without depression ( P =0.003). Conclusion: Depression was significantly associated with utilization patterns of OHAs in these patients newly diagnosed with type 2 DM, thus possibly affecting their disease management.

Background: The use of colonoscopy as a primary screening tool for colorectal cancer is gaining momentum owing to several studies suggesting superior effectiveness and the recent, favorable decision by Medicare to cover all routine screening colonoscopies. This study documents the use of colonoscopy versus other tests to screen for colorectal cancer. Materials and Methods: Data from the 2000 National Health Interview Survey were analyzed. Fecal occult blood test (FOBT), sigmoidoscopy, and colonoscopy done for any reason and for routine screening only were analyzed for those ≥50 years without previously diagnosed colorectal cancer (n = 12,505). Results: The proportion of the total eligible population receiving any of the recommended tests for all possible reasons and for screening purposes only is 34.6% and 25.1%, respectively. For routine screening purposes, the test most commonly utilized was FOBT (55.6%) followed by colonoscopy (29.1%) and sigmoidoscopy (15.3%). When usage was assessed for all reasons, FOBT was still most commonly utilized (45.8%) followed by colonoscopy (38.7%) and sigmoidoscopy (15.5%). The elderly, non-White males and those with private insurance have a higher probability of receiving colonoscopy than FOBT. Several regional differences exist, including higher probability of undergoing sigmoidoscopy versus colonoscopy in the West. Conclusions: Only one fourth (upper limit one third) of the study population complied with colorectal cancer screening recommendations. Nearly one third of the routine screening tests done in 2000 were colonoscopies. This study provides baseline values that can be used to project future colonoscopy demand and identify potential supply barriers.

Objective: Study objectives were to determine surveillance and polyp recurrence rates among older, increased-risk patients who have been diagnosed and excised of colorectal polyps. The high incidence of colorectal cancers in the Medicare-eligible population, the strong evidence linking reductions in mortality from colorectal cancer by removal of colorectal polyps, and the paucity of postpolypectomy surveillance data in this population all supported the need for this study. Methods: This retrospective study used Medicare claims data to identify a cohort of 19,895 beneficiaries ages ≥65 years diagnosed and excised of colorectal polyps in 1994. Survival analysis was used to compute surveillance and polyp recurrence rates over 5 years. Log-rank test was used for all statistical comparisons. Results: Median time to first surveillance was 2.6 years. Surveillance rates for 1, 3, and 5 years were 17.6%, 55.8%, and 74.5%, respectively. Twenty-six percent had no surveillance event. Polyp recurrence rates for 1, 3, and 5 years were 10.9%, 38.2%, and 52.6%, respectively. Males and younger patients were more likely to undergo surveillance and showed higher polyp recurrence rates. Conclusions: The high likelihood of polyp recurrence underscores the need for continued efforts to promote awareness of and compliance with postpolypectomy surveillance. Efforts to increase surveillance rates among individuals diagnosed with colorectal polyps and making available additional treatment options that may prevent the recurrence of polyps and/or their possible progression to colorectal cancer should help make significant progress in reaching the Healthy People 2010 goal of reducing colorectal cancer deaths by 34% by the year 2010.

The specific study goal was to identify predictors of influenza and pneumonia immunizations in rural adults 18 to 64 years of age in Appalachia. The survey data used were collected from 931 adults from eight rural counties as part of a larger study. Information collected included influenza and pneumonia vaccination status, demographic and insurance coverage information, and immunization-related knowledge and beliefs. Immunization rates were 41.3 percent for influenza and 19.9 percent for pneumonia. Logistic regression analysis indicated that perceived disease susceptibility, perceived benefit, perceived harm, and insurance coverage for immunizations were significant predictors of both types of immunization, with insurance coverage being the strongest predictor. The findings can be used in development of promotional campaigns for increasing immunizations in this underserved rural population.

Aim To present the impact of treatments on health-related quality of life (HRQoL) from the double-blind, randomised phase III COMBI-d study that investigated the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600E/K-mutant metastatic melanoma. COMBI-d showed significantly prolonged progression-free survival for the combination. Methods HRQoL was evaluated using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30, a generic cancer questionnaire (completed at baseline, during study treatment, at progression and post progression) assessing various dimensions (global health/QoL, functional status, and symptom impact). A mixed-model, repeated-measures analyses of covariance evaluated differences between arms. Results Questionnaire completion rates were >95% at baseline, >85% to week 40 and >70% at disease progression. Baseline scores across both arms were comparable for all dimensions. Global health dimension scores were significantly better at weeks 8, 16 and 24 for patients receiving the combination during treatment and at progression. The majority of functional dimension scores (physical, social, role, emotional and cognitive functioning) trended in favour of the combination. Pain scores were significantly improved and clinically meaningful (6–13 point difference) for patients receiving the combination for all follow-up assessments versus those receiving dabrafenib monotherapy. For other symptom dimensions (nausea and vomiting, diarrhoea, dyspnoea, and constipation), scores trended in favour of dabrafenib monotherapy. Conclusion This analysis demonstrates that the combination of dabrafenib and trametinib provides better preservation of HRQoL and pain improvements versus dabrafenib monotherapy while also delaying progression. (Clinicaltrials.gov registration number: NCT01584648).

OBJECTIVE: To estimate the overall healthcare expenditures of patients with Barrett's esophagus in the West Virginia Medicaid population. METHODS: West Virginia Medicaid—paid claims data for the period January 1, 1995, to December 31, 1999, were used for the study. The population included all individuals eligible for West Virginia Medicaid during the study period except for Medicare eligible– And Medicaid managed—care recipients. A prevalence-based approach was used to determine the cost of illness for Barrett's esophagus. RESULTS: The total cost of illness for Barrett's esophagus more than tripled, from $182 399 in 1995 to $623 864 in 1999, with approximately a 4 1/2-fold increase in medical and more than a threefold increase in pharmacy costs. The average cost of treating Barrett's esophagus was found to be approximately $1207 per patient in 1999. Overall, pharmacy costs accounted for >66% of the total costs. Controlling for age, gender, and number of comorbidities, patients with Barrett's esophagus incur 21.2% higher overall costs than patients with gastroesophageal reflux disease and 62.4% higher overall costs than the general Medicaid population. CONCLUSIONS: The increasing prevalence of and resource utilization for Barrett's esophagus provide a framework for further analysis and implementation of policies aimed at appropriate allocation of resources for the state's Medicaid program.

To evaluate the cost effectiveness of dabrafenib versus dacarbazine and vemurafenib as first-line treatments in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma from a Canadian healthcare system perspective. A partitioned-survival analysis model with three mutually exclusive health states (pre-progression, post-progression, and dead) was used. The proportion of patients in each state was calculated using survival distributions for progression-free and overall survival derived from pivotal trials of dabrafenib and vemurafenib. For each treatment, expected progression-free, post-progression, overall, and quality-adjusted life-years (QALYs), and costs were calculated. Costs were based on list prices, a clinician survey, and published sources. A 5-year time horizon was used in the base case. Costs (in 2012 Canadian dollars [CA$]) and QALYs were discounted at 5 % annually. Deterministic and probabilistic sensitivity analyses were conducted. Dabrafenib was estimated to yield 0.2055 more QALYs at higher cost than dacarbazine. The incremental cost-effectiveness ratio was CA$363,136/QALY. In probabilistic sensitivity analyses, at a threshold of CA$200,000/QALY, there was an 8.2 % probability that dabrafenib is cost effective versus dacarbazine. In deterministic sensitivity analyses, cost effectiveness was sensitive to survival distributions, utilities, and time horizon, with the hazard ratio for overall survival for dabrafenib versus dacarbazine being the most sensitive parameter. Assuming a class effect for efficacy of BRAF inhibitors, dabrafenib was dominant versus vemurafenib (less costly, equally effective), reflecting its assumed lower daily cost. Assuming no class effect, dabrafenib yielded 0.0486 more QALYs than vemurafenib. At a threshold of CA$200,000/QALY, dabrafenib is unlikely to be cost effective compared with dacarbazine. It is not possible to make reliable conclusions regarding the relative cost effectiveness of dabrafenib versus vemurafenib based on available information.

OBJECTIVE: To conduct an assessment of the needs and interests of West Virginia pharmacists with respect to continuing education (CE) and certificate programs (CP) versus a nontraditional PharmD program (NTP). METHODS: A cross-sectional study was conducted. The survey was mailed to 2800 West Virginia University School of Pharmacy alumni and West Virginia licensed pharmacists. The survey collected data pertaining to pharmacists' perceptions for the needs of CE, CP, and the NTP program; the optimal structuring of these programs; and the demographics of participants. RESULTS: A 24% (674) usable response rate was achieved from two mailings. Respondents were asked to address all areas of interest: approximately 75% showed interest in enrolling in CE, 45% in CP, and 40% in the NTP program. Interest levels varied across demographic and practice characteristics. Seven methods of instruction were evaluated by pharmacists, with live lectures being the most preferred for both CE and CP. Interest for specific content areas and topics for CE workshops and CP were identified. The type and amount of employer support and willingness to pay for enrollment in the two types of programs were obtained. Markets' needs for CE and CP were identified for five typical pharmacists' profiles (e.g., staff pharmacists in community practice). CONCLUSIONS: Results can be used by CE providers to develop CE and CP programs of most interest to pharmacists and target them to appropriate demographic segments in order to be cost-effective.

In a randomized phase III study, trametinib prolonged progression-free survival and improved overall survival versus chemotherapy in patients with BRAF V600 mutation-positive melanoma.Patients' quality of life (QOL) was assessed at baseline and follow-up visits using the European Organisation for Research and Treatment of Cancer Core QOL questionnaire.In the primary efficacy population (BRAF V600E+, no brain metastases) from baseline to weeks 6 and 12, patients' global health status scores worsened by 4-5 points with chemotherapy but improved by 2-3 points with trametinib. Rapid and substantive reductions in QOL functionality (e.g. role functioning, 8-11 points at weeks 6 and 12) and symptom exacerbation (e.g. fatigue, 4-8 points; nausea and vomiting, 5 points, both at weeks 6 and 12) were observed in chemotherapy-treated patients. In contrast, trametinib-treated patients reported small improvements or slight worsening from baseline at week 12, depending on the functional dimension and symptom. The mean symptom-scale scores for chemotherapy-treated patients increased from baseline (symptoms worsened) for seven of eight symptoms at week 6 (except insomnia) and six of eight symptoms at week 12 (except dyspnea and insomnia). In contrast, at weeks 6 and 12, the mean symptom-scale scores for trametinib decreased from baseline (symptoms improved) for pain (11-12 points), insomnia (10-12 points), and appetite loss (1-5 points), whereas those for diarrhea worsened (15-16 points). Mixed-model repeated-measures analyses showed significant (P0.05) and/or clinically meaningful improvements (small to moderate) from baseline in favor of trametinib for global health; physical, role, and social functioning; fatigue; pain; insomnia; nausea and vomiting; constipation; dyspnea; and appetite at weeks 6 and/or 12. QOL results for the intent-to-treat population were consistent.This first QOL assessment for a MEK inhibitor in metastatic melanoma demonstrated that trametinib was associated with less functional impairment, smaller declines in health status, and less exacerbation of symptoms versus chemotherapy.

The purpose of this exploratory study was to survey physicians' attitudes surrounding the 'gift relationship' between pharmaceutical companies and physicians. A survey was mailed to 1000 randomly selected West Virginia physicians, of which 283 (28.3%) responses were received. The most commonly received gifts reported by the study physicians were trinkets (77.4%), followed by books (41.7%) and meals (41%). Principal component analysis and varimax rotation identified seven physician belief constructs. The mean ratings of the constructs indicated that the physicians slightly agreed that pharmaceutical companies give gifts to physicians to influence their prescribing, moderately disagreed that they do so as a form of professional recognition of physicians, and strongly disagreed that their prescribing behaviour could be influenced by the gifts they receive. Physicians slightly disagreed that pharmaceutical companies' sponsoring of CME programmes are only promotional gimmicks. Although the study physicians slightly disagreed that it may be inappropriate for them to accept gifts from pharmaceutical companies, they seemed slightly averse to having 'gift relationships' between pharmaceutical companies and physicians made public. Correlation analysis suggested that physicians who have a large number of patients in their practice, see a larger number of patients per day, or write a large number of prescriptions per day are more likely to be offered gifts by pharmaceutical companies, and they are also more likely to condone the practice of gift giving and receiving.

Background: Third-generation aromatase inhibitors (letrozole, anastrozole) have shown superior efficacy in early and advanced breast cancer compared with tamoxifen. For HR+, HER2+ MBC, combination of an AI with an anti-HER2 agent (lapatinib or trastuzumab) has shown clinical benefit. Methods: Six databases were searched until January 2009 for randomized controlled clinical trials, assessing the safety and efficacy of first-line treatments for postmenopausal women with HR+ and HER2 (ErbB2) positive MBC, who have not received prior therapy for advanced or metastatic disease. Relevant interventions were lapatinib, aromatase inhibitors, tamoxifen, and trastuzumab. Outcomes included overall survival (OS), progression-free-survival (PFS), time-to-progression (TTP), and objective response rate (ORR). Results: Eighteen studies (62 papers) were included. Lapatinib + letrozole was significantly superior to letrozole alone based on a direct head-to-head study in terms of PFS/TTP and ORR. Using a network meta-analysis, compared with lapatinib+letrozole, tamoxifen (HR 0.45 (95% CI: 0.32, 0.65) and anastrozole (HR 0.53 (0.36, 0.80)) scored significantly worse in terms of PFS/TTP and ORR (tamoxifen: OR 0.25 (0.12, 0.53), anastrozole: OR 0.27 (0.12, 0.58). The combination also seemed significantly superior to exemestane in terms of PFS/TTP (HR 0.52 (0.34, 0.79)). Lapatinib + letrozole also seemed better, although not significantly, in terms of OS versus tamoxifen: HR 0.74 (0.49, 1.12), anastrozole: HR 0.71 (0.45, 1.14) and exemestane: HR 0.65 (0.39, 1.11). When compared with trastuzumab + anastrozole, lapatinib + letrozole seemed to be better in terms of OS (HR 0.85 (0.47, 1.54)), PFS/TTP (HR 0.89 (0.54, 1.47)) and ORR (OR 0.92 (0.24, 3.48)), although, none of these results were significant. Discussion: Lapatinib + letrozole was significantly superior to letrozole in terms of PFS/TTP and ORR based on a direct head-to-head study. Indirect comparisons appeared to favor lapatinib + letrozole versus other first-line treatments used in this patient population in terms of three main outcomes: OS, PFS/TTP and ORR. Indirect comparison results are based on a network analysis for which the basic assumptions of homogeneity, similarity and consistency were not fulfilled. Therefore, despite the fact that these are the best available data, the results need to be interpreted with caution.

Squamous cell carcinoma of the head and neck (SCCHN) places a high burden on society and poses complex challenges to healthcare providers.Retrospective claims-based analysis of commercially insured patients identified between 01-31-04 and 12-31-07 with diagnostic evidence of cancer of the lip, tongue, oral cavity, pharynx, or larynx who underwent surgical resection during identification period. Outcomes included treatment patterns, healthcare utilization, and costs. All study variables were analyzed descriptively.Among the 1104 patients in the final study sample, 71.9% were male, with mean age 56.6 years. On average, patients were followed for 830 days (range of mean days: 805 for lip or tongue cancer to 847 for pharyngeal cancer). About half received radiation therapy during follow-up, whereas only 16.2% received chemotherapy. Patients with pharyngeal cancer were most likely to undergo chemotherapy. After their index surgery, 57.9% of patients had ≥1 inpatient stay, 44.9% had ≥1 ER visit, and all had ≥1 ambulatory visit. The percentage with ≥1 inpatient stay post-index was highest among patients with pharyngeal cancer (73.0%) and lowest in the laryngeal cancer cohort (49.5%). Mean number of hospitalized days, ER visits, and ambulatory visits was 0.45, 0.69, and 27.4, respectively, per-patient per-year. Overall, patients incurred ~$94 million in cost following index surgery ($85,000 per-person, on average). Mean total healthcare cost was $34,450 per-patient per-year, the bulk of which comprised medical expenses ($32,401). The highest mean healthcare cost was incurred by the pharyngeal cancer cohort ($40,214).Patients with resected SCCHN incur substantial healthcare costs and have high utilization rates. Results of this analysis are primarily applicable to resected SCCHN in a managed-care setting, and therefore may not be generalizable to the entire US population. Furthermore, disease stage is an important factor impacting outcomes, but these analyses did not stratify patients according to disease stage.

Eosinophilic esophagitis (EE), a rare chronic inflammatory condition of the esophagus, is predominantly observed in children and is primarily manifested with feeding difficulties. To our knowledge, no self- or caregiver-reported questionnaires are available to assess pediatric EE symptoms and their impact as reported directly by children or their parents/caregivers. The objectives of this study were to characterize the symptoms and impact of EE among children as reported by patients and parents/caregivers and to assess the content validity of two newly developed pediatric eosinophilic esophagitis symptom questionnaires, one parent/caregiver-reported questionnaire for ages 2-7 years and one child-reported questionnaire for ages 8-17 years. The questionnaires were developed based on a review of the literature and clinical expert consultation.This cross-sectional study involving one-on-one interviews with patients and caregivers was conducted at an American Partnership for Eosinophilic Disorders conference. Parents of patients aged 2-7 years (n = 12) and patients aged 8-17 years (n = 16) were first asked about symptoms and their impact on everyday life, using open-ended questions. Participants then completed the appropriate symptom questionnaire and were asked to provide feedback on the relevance, comprehensiveness, and clarity of each item and other questionnaire issues (time to complete, length, format, etc.). All reported symptoms were enumerated, and the feedback on the symptom questionnaires was analyzed qualitatively.The majority of study participants were white (82%) and male (86%). The most frequently reported symptoms of 2-7-year olds were vomiting (92%), "reflux" (50%), dysphagia (25%), abdominal pain (25%), and trouble sleeping (25%). The 8-17-year group reported abdominal pain (56%), vomiting (31%), throat pain (25%), diarrhea (25%), and food getting stuck (25%). Symptoms and treatment were reported to have a major impact on daily life, particularly on school, after-school activities and social events, feeling frustrated regarding symptoms and treatment, and feeling "different". Overall, participants thought that the questionnaires were clear, relevant, and appropriate for symptom assessment.This study was based on a small and convenient sample of participants attending an EE conference and hence may not be representative of the general EE patient population.EE is associated with a range of symptoms that vary in terms of the type, frequency and severity across and within patients. The results provide adequate support for the content validity of the self- and caregiver-reported versions of the symptom-specific questionnaires. Minor modifications were made based on the feedback obtained. A psychometric evaluation of the revised questionnaires is needed next to assess the construct validity, reliability, and responsiveness of the measures.

The relationship between overall survival (OS) and disease progression end points has been demonstrated in colorectal, colon, and non-small cell lung cancers. We assessed the association between OS and time-to-progression (TTP) or progression-free survival (PFS) in metastatic breast cancer (MBC) studies. A literature search retrieved all randomised controlled trials since 1994 in patients with MBC in which OS and either TTP or PFS were reported. Summary data on trial and patient characteristics were abstracted. Study effect sizes were derived as the ratio of median progression (or survival) times, which approximates the hazard ratio. Effects were centred at zero for regression analyses weighted by sample size. Numerous treatments were represented in 67 studies (17 081 patients). Modeling showed a positive association between outcomes for progression and survival (R(2)=0.30) with a slope of 0.32 (P

The randomized phase III trial EGF100151 demonstrated that the combination of lapatinib plus capecitabine (L + C) significantly improved time to progression (TTP) compared with capecitabine alone (C) in heavily pretreated patients with HER2+ (ErbB2+) advanced or metastatic breast cancer. This analysis assessed the effects of study treatments on quality of life (QOL) among patients in EGF100151. Quality of life was assessed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) and EuroQoL (EQ-5D) questionnaires. Patients completed questionnaires during efficacy and safety assessment visits (i.e., at screening visit, every 6 weeks for the first 24 weeks, every 12 weeks thereafter, and at discontinuation of study treatment). Primary analyses compared the treatment groups based on change from baseline QOL. Exploratory analyses compared proportion of patients achieving minimum important differences (MID) in QOL scores and the relationship between QOL and tumor status. Quality of life for patients in both treatment groups was maintained during 24 weeks of follow-up. Adjusted mean changes from baseline in all QOL scores for the L + C arm were comparable to those for the C arm. The between-group differences ranged from 0.7 to 2.2 (FACT-B total) and 0.3 to 1.8 (EQ-5D visual analog scale) and were consistently in favor of the L + C arm, although not statistically significant. Patients with an objective tumor response or stable disease showed clinically meaningful differences in QOL scores compared to patients with progressive disease. A greater proportion of patients receiving L + C versus C achieved the MID for all five QOL scores, although differences were not statistically significant. The addition of lapatinib to capecitabine significantly increases TTP without any evidence of a deleterious effect on patients’ QOL, confirming its clinical benefit in this heavily pretreated patient population with advanced HER2+ breast cancer that has progressed on trastuzumab therapy.

Studies have shown that weekly bisphosphonate dosing results in improved persistence compared to daily dosing among patients with postmenopausal osteoporosis, yet more than 50% of patients discontinue therapy within a year. An oral, less frequent administration bisphosphonate provides an opportunity to improve persistence, a parameter not well modeled in previous cost-effectiveness analyses of osteoporosis therapies.We developed a Markov model to estimate the effect of improved persistence on the cost-effectiveness of bisphosphonates among postmenopausal women with established osteoporosis (vertebral fracture and bone mineral density T-scoreor= -2.5) and an average age of 78 years. Fracture risks, clinical efficacy, mortality, resource use, costs, and utilities were obtained from the published literature. Persistence rates were derived primarily from a published clinical trial. Approximately 50% greater persistence with a monthly versus a weekly therapy was assumed on the basis of the PERSIST study, a 6-month, randomized, head-to-head prospective study that investigated treatment persistence in postmenopausal osteoporotic women on monthly versus weekly bisphosphonate therapy. Persistence was extrapolated to a maximum of 5 years. Following discontinuation, treatment benefit declined linearly and proportionally to the duration of active treatment.Based on model estimates, more fractures were avoided (versus no treatment) with monthly bisphosphonate (58.1 per 1000 treated women) than with weekly bisphosphonates (33.8 per 1000 treated women), resulting in lower fracture care costs per woman ($7317 and $7548, respectively). The incremental cost per quality-adjusted life-year gained was lower with a monthly bisphosphonate ($13,749) than with weekly bisphosphonates ($16,657) when compared to no treatment. The incremental cost per quality-adjusted life-year of a monthly bisphosphonate was $9476 when compared to a weekly bisphosphonate.In postmenopausal women with established osteoporosis, improvement in persistence with a less frequently administered oral bisphosphonate therapy could augment the fracture benefit and thereby improve cost-effectiveness. Further studies are required to refine the estimates of cost-effectiveness in order to address limited availability of adherence and fracture risk data.

Breast cancer is the most commonly diagnosed non-skin cancer and second leading cause of cancer deaths among women in the US. This study compared healthcare resource utilization and costs in women with breast cancer to a control group in a managed care population. Women ≥ 18 years with breast cancer were identified using ICD-9 codes from claims databases of five US health plans during 2004. A randomly matched control group of women without cancer served as a comparator group. Healthcare costs included all medical and pharmacy costs during the year. Comparisons were made using per patient per month (PPPM) costs (total costs per patient within 2004 calendar year/months of eligibility). 10,697 women (mean age 55 years) with breast cancer were identified (prevalence of 250 per 100,000) in 2004, with prevalence increasing with age. Mean attributable PPPM costs associated with breast cancer were $2,896 (median = $1,940) with hospitalization contributing most of the costs ($1,340), followed by pharmacotherapy ($537), and surgical intervention ($470). Mean unadjusted all-cause PPPM total costs were $4,421 (median = $2,964) compared to $3,352 (median = $665) p < 0.0001) for cases and controls respectively. Multivariate analyses controlling for differences in comorbidities showed mean adjusted PPPM costs to be 2.28 times (p

To estimate the incidence, prevalence, and economic burden of secondary breast cancer brain metastases (BCBM) among a US-based population of patients with primary breast cancer. Female patients diagnosed with secondary BCBM between 1/2002 and 12/2004 and with a brain or head diagnostic test within 30 days of the BCBM diagnosis were identified in a US commercial insurance claims database. A 12-month look-back period was used to identify patients with a breast cancer diagnosis and those with and without a history of BCBM. Patients were required to be continuously enrolled in their health plan for the duration of the study. Incident BCBM patients were matched to a control group of breast cancer patients with no evidence of BCBM. Patient characteristics at baseline, incidence and prevalence rates, and resource utilization and health care costs were determined. From 2002 to 2004, 779 incident and 995 prevalent BCBM patients and 8,518 primary breast cancer patients were identified. The incidence of BCBM during this time period was 9.1% (95% CI = 8.5%, 9.8%); the prevalence of BCBM was 11.7% (95% CI = 11.0%, 12.4%), with rates increasing from 2002 to 2004. About 22% of incident patients died (based on a proxy measure) during the follow-up period, an average of 158 days (95% CI = 131.1, 183.9) from the index BCBM diagnosis. A 1:1 match of incident BCBM patients to controls resulted in 775 patients in each group. At 6 months follow-up (N = 398), incident BCBM patients had significantly more hospital stays (mean 1.1 vs. 0.5, P

Background The Osteoporosis Patient Satisfaction Questionnaire (OPSAT-Q) is a new measure of patient satisfaction with bisphosphonate treatment for osteoporosis. The objective of this study was to evaluate the psychometric characteristics of the OPSAT-Q. Methods The OPSAT-Q contains 16 items in four subscales: Convenience, Confidence with Daily Activities, Side Effects, and Overall Satisfaction. All four subscale scores and an overall composite satisfaction score (CSS) can be computed. The OPSAT-Q, Osteoporosis Targeted Quality of Life (OPTQoL), and sociodemographic/clinical questionnaires, including 3 global items on convenience, functioning and side effects, were self-administered to women with osteoporosis or osteopenia recruited from four US clinics. Analyses included item and scale performance, internal consistency reliability, reproducibility, and construct validity. Reproducibility was measured using the intraclass correlation coefficient (ICC) via a follow-up questionnaire completed by participants 2 weeks post baseline. Results 104 women with a mean age of 65.1 years participated. The majority were Caucasian (64.4%), living with someone (74%), and not currently employed (58.7%). 73% had osteoporosis and 27% had osteopenia. 80% were taking weekly bisphosphonates and 18% were taking daily medication (2% missing data). On a scale of 0–100, individual patient subscale scores ranged from 17 to 100 and CSS scores ranged from 44 to 100. All scores showed acceptable internal consistency reliability (Cronbach's alpha > 0.70) (range 0.72 to 0.89). Reproducibility ranged from 0.62 (Daily Activities) to 0.79 (Side Effects) for the subscales; reproducibility for the CSS was 0.81. Significant correlations were found between the OPSAT-Q subscales and conceptually similar global measures (p < 0.001). Conclusion The findings from this study confirm the validity and reliability of the OPSAT-Q and support the proposed composition of four subscales and a composite score. They also support the use of the OPSAT-Q to examine the impact of bisphosphonate dosing frequency on patient satisfaction.

The objective of the study was to estimate the effect of depression on health care utilization and costs in patients newly diagnosed with type 2 diabetes. Patients were identified during a four-year enrollment period (1998-2001) from a Medicaid claims database. The final cohort consisted of 4,294 patients with type 2 diabetes (1,525 patients with depression; 2,769 patients without depression). Multivariate results indicated that significant utilization differences existed between the two groups: Patients who were depressed incurred a higher number of physician office visits, emergency room/inpatient admissions, and more prescriptions compared with patients who had diabetes but were not depressed. Patients with depression had nearly 65% higher overall health care costs than those without depression. Recognizing that depression is as a risk factor for increasing health care expenditures has the potential to improve diabetes management and related outcomes.

Background:Adherence to oral hypoglycemic agents (OHAs) is important for adequate glycemic control and prevention of future complications in patients with type 2 diabetes.Objective:To examine the impact of depression on adherence to OHAs in patients newly diagnosed with type 2 diabetes.Methods:Patients newly diagnosed with type 2 diabetes during a 4 year period were identified from a Medicaid claims database. Presence of preexisting depression was determined on the basis of ICD-9-CM codes. Adherence to OHAs was computed using prescription refill data for a 12 month follow-up period from the date of the index OHA prescription. Two separate adherence indices (Medication Possession Ratio-1 [MPR-1], Medication Possession Ratio-2 [MPR-2]) were computed. The impact of depression on adherence was assessed after controlling for confounders such as demographics, comorbidity, provider interaction, complexity of regimen, and diabetes severity.Results:A total of 1326 newly diagnosed patients with type 2 diabetes were identified (depressed = 471; nondepressed = 855). Results of the study indicated that patients with depression had significantly lower adherence (MPR-1 86%; MPR-2 66%) to OHAs compared with patients without depression (MPR-1 89%; MPR-2 73%). Multivariate results indicated that depression was a significant predictor of adherence, with depressed patients being 3–6% less adherent to OHAs than nondepressed patients, after controlling for confounding factors.Conclusions:Depression significantly impacts adherence to OHAs in patients with type 2 diabetes. The study results imply that depression screening and treatment need to be included in the protocol for management of patients with type 2 diabetes.

Poor compliance and persistence with bisphosphonates is a concern in postmenopausal osteoporosis due to its negative impact on fracture risk and healthcare costs as well as quality of life. Reducing oral bisphosphonate dosing frequency is one measure available to increase therapy convenience and practicality, with the hope of improving compliance and persistence. This study compared compliance and persistence with weekly and daily bisphosphonate regimens for postmenopausal osteoporosis.Administrative claims data (1997-2002) from 30 health plans were used to identify postmenopausal women (45 years) with osteoporosis, who had been newly prescribed a once-weekly (QW alendronate 35 mg or 70 mg) or once-daily (QD alendronate 5 mg or 10 mg or risedronate 5 mg) bisphosphonate. QW and QD cohorts were followed for 12 months from initial prescription. Medication possession ratios (MPRs) measured refill compliance during follow-up. Persistence was calculated as the number of days from the initial prescription to a lapse of30 days after completion of the previous refill.Data were available for 2741 women (QW, N = 731, QD, N = 2010). QW users had significantly higher medication compliance than QD users (69.2% vs. 57.6% MPR, por = 0.0001). QW users persisted with therapy significantly longer than QD users (p0.0001) and had higher rates of retention on treatment at 12 months than QD users (44.2% QW; 31.7% QD). Dosing frequency was the strongest predictor of time to discontinuation (p0.0001).Postmenopausal women prescribed a weekly bisphosphonate had significantly better compliance and persistence than those taking more frequent, daily bisphosphonate doses. However, compliance and persistence rates for both regimens were suboptimal, suggesting that less frequent dosing intervals may provide an opportunity to further improve the consistent use of bisphosphonate therapy.

Acute myocardial infarction (AMI) is associated with high mortality in the United States. Beta-blockers have been shown to reduce mortality and reinfarction rates when used for long-term prevention after an AMI. However, this therapy is both underused and misused. The effect of this practice on outcomes needs to be investigated.This study was undertaken to evaluate the effect on patient outcomes (ie, fatality, health care utilization, and costs) of appropriate and inappropriate prescribing of beta-blocker therapy after AMI in a Medicaid population aged65 years.Data for 1 year before and after AMI were extracted from West Virginia Medicaid claims from January 1, 1996, to June 30, 2001. Information was obtained regarding prescriptions for beta-blockers for these patients within 90 days after discharge. Patients were divided into 2 groups: those who were prescribed therapy appropriately and those who were prescribed therapy inappropriately (underuse or misuse). Fatality rates during 1 year after discharge were compared using chi-square analysis. The study used regression analysis to model health care utilization and costs as a function of appropriately/inappropriately prescribed groups.Data were assessed for 488 eligible patients (mean [SD] age, 53.70 [8.14] years; 246 men [50.4%], 242 women [49.6%]). Overall, 309 patients (63.3%) had appropriate prescribing of beta-blockers; at the end of 1 year, these patients had a significantly lower all-cause death rate compared with those who were prescribed therapy inappropriately (P = 0.030). Although the cardiac death rate was slightly lower for the appropriate group, the difference was not statistically significant. The appropriately prescribed group had significantly higher health care utilization in the follow-up period (P0.050 for hospital visits, emergency department visits, and length of stay). These groups demonstrated differences in a few variables at baseline (age, presence of absolute contraindications, presence of hypertension, number of noncardiac admissions before AMI, and use of beta-blockers before AMI: all, P0.050), implying different severity levels. Patient health status at the time of the incident AMI had a confounding effect on health care utilization, and there were indications that the appropriate group had greater severity compared with the inappropriate group.Appropriate prescribing of beta-blockers for secondary prevention after an AMI was associated with better survival in this population. However, the effects of inappropriate and appropriate beta-blocker prescribing on health care utilization need to be evaluated prospectively so that all severity indicators can be properly adjusted.

The overall purpose of this study was to identify predictors of influenza and pneumonia vaccination among rural senior adults. A mail survey was conducted in eight rural counties. Reported immunization rate for influenza (81.5%) among respondents was higher as compared to pneumonia (74.7%). Knowing someone with influenza was the strongest predictor of influenza vaccination and knowing someone with pneumonia was the strongest predictor of pneumonia vaccination. Belief that vaccinations are always beneficial was also a significant predictor. While several of the findings of this study are consistent with factors reported in literature to be significant predictors of immunization behavior for this age group, surprisingly, access was not a significant predictor for this rural sample.

Objective. To review screening rates and factors impacting patient utilization of colorectal cancer screening tests. Methods. We searched Medline, CancerLit, and PsycInfo for articles on colorectal cancer screening adherence. US studies on average-risk individuals were reviewed to identify: (1) utilization/adherence rates, (2) predictors of patient adherence, (3) correlation between long-term adherence and type of test selected, (4) predictors of physician recommendation of screening tests, and (5) patterns in the type of test recommended by physicians. Results. In 2000, only 34% of the US population obtained screening within recommended time frames (fecal occult blood test annually, flexible sigmoidoscopy every 5 years, or colonoscopy every 10 years). Positive attitude toward screening and physician recommendation result in high adherence while fear of finding cancer and the belief that cancer is fatal result in low adherence. Physician specialty impacts the type of test recommended, while perceived lack of patient adherence is not a consistent barrier to recommending screening tests. Matching individuals with their choice of screening test and newer technology, such as virtual colonoscopy, may help increase adherence. Conclusion. Additional studies are required on differences in adherence between tests, whether patient preferences impact adherence, and how the physician–patient relationship can be fostered to increase adherence.

Objectives To determine national adult immunization rates for influenza and pneumonia and assess the effect of various predisposing factors on immunization status for both diseases. Design Retrospective, cross-sectional, random national sample data from the Centers for Disease Control and Prevention's 1999 Behavioral Risk Factor Surveillance System survey. Data extraction and analysis were conducted using SPSS and STATA, with adjustments made for weighted data. Participants Individuals aged 65years and older and individuals aged 50 to 64years (for influenza only). Results Immunization rates in the 65 and older age group were 66.7% for influenza and 53.8% for pneumonia; immunization rate for influenza in the 50 to 64 age group was 35.6%. Predisposing factors such as race (white) and education (high school and above) positively influenced immunization status. Enabling factors such as income, health insurance, and physician visits and need-related factors such as health status and comorbidities exhibited a strong relationship with influenza and pneumonia vaccination status in both study populations. Health care coverage (odds ratio [OR] = 1.76 for influenza and OR=1.66 for pneumonia in the 65years and older group; OR=1.80 for influenza in the 50 to 64years age group) and physician visit in the last year (OR = 2.00 for influenza and OR=1.87 for pneumonia for 65years and older group; OR=1.86 for influenza in the 50 to 64years age group) were strong positive predictors of vaccination status. Individuals with comorbidities and those who perceived their health as being poor had high vaccination rates. Conclusion Understanding the positive and negative influences on adult immunization status will allow pharmacists to better identify and target prospective recipients of immunization services.

Objective: The purpose of this study was to identify the medications that are consumed by a rural obstetric population during pregnancy. Study Design: Over a period of 26 months, pregnant women were interviewed about medication use. Interviews on subsequent visits provided a longitudinal study of medication usage and discontinuation. Trend differences were analyzed according to the number of medications, the trimester of use, and insurance status. Results: Five hundred seventy-eight participants had 2086 interviews. The compilation of the interviews showed that 95.8% of the participants took prescription medications, 92.6% of the participants self-medicated with over-the-counter medications, and 45.2% of the participants used herbal medications. Over time, consumption of over-the-counter medications exceeded prescription medication use. Fifteen percent of the pregnant women took ibuprofen at some point during the pregnancy (5.7% in the third trimester). Eight percent of the women were noncompliant and 20% incompletely compliant with prenatal vitamin and mineral formulations. Conclusion: Medication use was substantial in this population. Medications (eg, ibuprofen) that are contraindicated in pregnancy were used at unexpectedly high rates. Of the three medication classes, over-the-counter medications were used most frequently. (Am J Obstet Gynecol 2003;188:1039-45.)

High rates of morbidity and mortality in the Appalachian region of the country warrant examination of the preventive care behavior of its residents. This study determined compliance rates for breast and cervical cancer screening recommendations for women residing in Appalachian states and identified predictors of such compliance using the Behavioral Risk Factor Surveillance System data (1995-97). Healthy People 2000 goals were used as benchmarks for progress. Appalachian women have made good progress toward goals pertaining to breast and cervical cancer screening. Compliance with other preventive services, having insurance coverage, residing in urban areas, better self-reported health, and higher education were independently associated with increased odds of compliance with annual-screening recommendations. Risk factors of obesity and smoking were associated with decreased odds of compliance. Findings should be useful to health care providers, policy makers, and researchers in their efforts to educate, encourage, and promote preventive care behavior among residents of Appalachia.

Postmenopausal women with estrogen deficiency are at high risk for osteoporosis. Estrogen therapy has been shown to be effective in preventing postmenopausal bone loss and maintaining bone mineral density. The increasing number of women at risk for osteoporosis and the high cost of treating this condition emphasizes the importance of preventing osteoporosis. This study was designed to identify trends and predictors of estrogen use for osteoporosis prevention among postmenopausal women. A retrospective, cross-sectional study was conducted using Behavioral Risk Factor Surveillance System data (1997-1999). Women 35 years and older who had passed menopause or were currently going through menopause were identified from the states including the BRFSS module that asked questions about estrogen use. Results showed an increasing prevalence in estrogen use from 1997 to 1999 for osteoporosis prevention. In 1999, almost a third of the postmenopausal women surveyed used estrogen to prevent osteoporosis. Prevalence was higher among women 45-64 years of age, whites, and those with higher education levels. Physician counseling on the benefits and risks of estrogen therapy was the strongest predictor of estrogen use for prevention of osteoporosis. Insurance coverage and compliance with other preventive behaviors such as mammograms and Pap smears were also strongly associated with greater estrogen use. However, women who were at risk for acute drinking, not married, overweight or obese, and diabetic were all less likely to receive estrogen therapy for osteoporosis prevention. The relationships demonstrated between estrogen use and demographic characteristics, lifestyle behaviors and health care access and utilization factors underline the importance of targeting specific groups of women for promoting its protective effect against osteoporosis.