Health-related quality of life outcomes for the LEAP study-CALGB 70305 (Alliance): A lymphedema prevention intervention trial for newly diagnosed breast cancer patients.

BACKGROUND: Lymphedema is an adverse effect of breast cancer treatment that causes swelling and pain in the arm and hand. We tested 2 lymphedema prevention interventions and their impact on health-related quality of life (HRQOL) in a group-randomized trial at 38 cooperative group sites within the United States. METHODS: Patients were recruited before breast surgery. Sites were randomly assigned to education-only (EO) lymphedema prevention or education plus exercise and physical therapy (LEAP). Lymphedema was defined as a ≥10% difference in arm volume at any time from baseline to 18 months postsurgery. HRQOL was assessed using the Functional Assessment of Cancer Therapy-Breast plus 4 lymphedema items (FACT-B+4). Longitudinal mixed model regression analysis, adjusting for key demographic and clinical variables, examined participants' HRQOL by intervention group and lymphedema status. RESULTS: A total of 547 patients (56% LEAP) were enrolled and completed HRQOL assessments. The results revealed no differences between the interventions in preventing lymphedema (P = .37) or HRQOL (FACT-B+4 total score; P = .8777). At 18 months, the presence of lymphedema was associated with HRQOL at borderline significance (P = .0825). However, African American patients reported greater lymphedema symptoms (P = .0002) and better emotional functioning (P = .0335) than patients of other races or ethnicities. Lower HRQOL during the intervention was associated with younger age (P ≤ .0001), Eastern Cooperative Oncology Group performance status >0 (P = .0002), ≥1 positive lymph nodes (P = .0009), having no education beyond high school (P < .0001), having undergone chemotherapy (P = .0242), and having had only axillary node dissection or sentinel node biopsy versus both (P = .0007). CONCLUSION: The tested interventions did not differ in preventing lymphedema or in HRQOL outcomes. African American women reported greater HRQOL impacts due to lymphedema symptoms than women of other races or ethnicities.

A randomized study to prevent lymphedema in women treated for breast cancer: CALGB 70305 (Alliance).

BACKGROUND: Lymphedema affects many women who are treated for breast cancer. We examined the effectiveness of an education-only (EO) versus education plus sleeve compression/exercise intervention (lymphedema education and prevention [LEAP]) on lymphedema incidence and range of motion (ROM) in a group-randomized trial across 38 cooperative group sites. METHODS: The treating institution was randomly assigned to either EO or LEAP by a study statistician. All patients at a treating institution participated in the same intervention (EO or LEAP) to minimize contamination bias. Participants completed surveys, arm volume measurements, and self-reported ROM assessments before surgery and at 12 and 18 months after surgery. Lymphedema was defined as a ≥10% difference in limb volume at any time post-surgery up to 18 months after surgery or diagnosis by a health provider. Cochran-Mantel-Haenszel tests were used to compare lymphedema-free rates between groups, stratified by lymph node surgery type. Self-reported ROM differences were compared between groups. RESULTS: A total of 554 participants (56% LEAP) were included in the analyses. At 18 months, lymphedema-free rates were 58% (EO) versus 55% (LEAP) (P = .37). ROM for both arms was greater in LEAP versus EO at 12 months; by 18 months, most women reported full ROM, regardless of group. In LEAP, only one-third wore a sleeve ≥75% of the time; 50% performed lymphedema exercises at least weekly. CONCLUSION: Lymphedema incidence did not differ by intervention group at 18 months. Poor adherence in the LEAP group may have contributed. However, physical therapy may speed recovery of ROM. Further research is needed to effectively reduce the incidence and severity of lymphedema in patients who have breast cancer.

Individualized decision aid for diverse women with lupus nephritis (IDEA-WON): A randomized controlled trial.

BACKGROUND: Treatment decision-making regarding immunosuppressive therapy is challenging for individuals with lupus. We assessed the effectiveness of a decision aid for immunosuppressive therapy in lupus nephritis. METHODS AND FINDINGS: In a United States multicenter, open-label, randomized controlled trial (RCT), adult women with lupus nephritis, mostly from racial/ethnic minority backgrounds with low socioeconomic status (SES), seen in in- or outpatient settings, were randomized to an individualized, culturally tailored, computerized decision aid versus American College of Rheumatology (ACR) lupus pamphlet (1:1 ratio), using computer-generated randomization. We hypothesized that the co-primary outcomes of decisional conflict and informed choice regarding immunosuppressive medications would improve more in the decision aid group. Of 301 randomized women, 298 were analyzed; 47% were African-American, 26% Hispanic, and 15% white. Mean age (standard deviation [SD]) was 37 (12) years, 57% had annual income of <$40,000, and 36% had a high school education or less. Compared with the provision of the ACR lupus pamphlet (n = 147), participants randomized to the decision aid (n = 151) had (1) a clinically meaningful and statistically significant reduction in decisional conflict, 21.8 (standard error [SE], 2.5) versus 12.7 (SE, 2.0; p = 0.005) and (2) no difference in informed choice in the main analysis, 41% versus 31% (p = 0.08), but clinically meaningful and statistically significant difference in sensitivity analysis (net values for immunosuppressives positive [in favor] versus negative [against]), 50% versus 35% (p = 0.006). Unresolved decisional conflict was lower in the decision aid versus pamphlet groups, 22% versus 44% (p < 0.001). Significantly more patients in the decision aid versus pamphlet group rated information to be excellent for understanding lupus nephritis (49% versus 33%), risk factors (43% versus 27%), medication options (50% versus 33%; p ≤ 0.003 for all); and the ease of use of materials was higher in the decision aid versus pamphlet groups (51% versus 38%; p = 0.006). Key study limitations were the exclusion of men, short follow-up, and the lack of clinical outcomes, including medication adherence. CONCLUSIONS: An individualized decision aid was more effective than usual care in reducing decisional conflict for choice of immunosuppressive medications in women with lupus nephritis. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02319525.

Application of a novel socioeconomic measure using individual housing data in asthma research: an exploratory study.

BACKGROUND: A housing-based socioeconomic index (HOUSES) was previously developed to overcome an absence of socioeconomic status (SES) measures in common databases. HOUSES is associated with child health outcomes in Olmsted County, Minnesota, USA, but generalisability to other geographic areas is unclear. AIM: To assess whether HOUSES is associated with asthma outcomes outside Olmsted County, Minnesota, USA. METHODS: Using a random sample of children with asthma from Sanford Children's Hospital, Sioux Falls, SD, USA, asthma status was determined. The primary outcome was asthma control status using Asthma Control Test and a secondary outcome was risk of persistent asthma. Home address information and property data were merged to formulate HOUSES. Other SES measures were examined: income, parental education (PE), Hollingshead and Nakao-Treas index. RESULTS: Of a random sample of 200 children, 80 (40%) participated in the study. Of those, 13% had poorly controlled asthma. Addresses of 94% were matched with property data. HOUSES had moderate-good correlation with other SES measures except PE. Poor asthma control rates were 31.6%, 4.8% and 5.6% for patients in the lowest, intermediate and highest tertiles of HOUSES, respectively (P=0.023). HOUSES as a continuous variable was inversely associated with poorly controlled asthma (adjusted odds ratio (OR)=0.21 per 1 unit increase of HOUSES, 95% confidence interval (CI), 0.05-0.89, P=0.035). HOUSES as a continuous variable was inversely related to risk of persistent asthma (OR: 0.36 per 1 unit increase of HOUSES, 95% CI, 0.12-1.04, P=0.06). CONCLUSIONS: HOUSES appears to be generalisable and available as a measure of SES in asthma research in the absence of conventional SES measures.

Distress and career satisfaction among 14 surgical specialties, comparing academic and private practice settings.

OBJECTIVE(S): We compared distress parameters and career satisfaction from survey results of surgeons from 14 specialties practicing in an academic versus private practice environment. METHODS: The 2008 American College of Surgeons survey evaluated demographic variables, practice characteristics, career satisfaction, and distress parameters using validated instruments. RESULTS: The practice setting (academic vs. private practice) was independently associated with burnout in a multivariate (MV) analysis (odds ratio [OR] 1.172, P = 0.02). Academic surgeons were less likely to experience burnout compared to those in private practice (37.7% vs. 43.1%), less likely to screen positive for depression (27.6% vs. 33%) or to have suicide ideation (4.7% vs. 7.4%; all P < 0.0001). They were also more likely to have career satisfaction (77.4% of academic surgeons would become a surgeon again vs. 64.9% for those in private practice; P < 0.0001)) and to recommend a medical career to their children (61.3% vs. 43.7%, P < 0.0001). For academic surgeons, the most significant positive associations with burnout were: (1) trauma surgery (OR 1.513, P = 0.0059), (2) nights on call (OR 1.062, P = 0.0123), and (3) hours worked (OR 1.019, P < 0.0001), whereas the negative associations were: (1) having older children (>22 years; OR 0.529, P < 0.0001), (2) pediatric surgery (OR 0.583, P = 0.0053), (3) cardiothoracic surgery (OR 0.626, P = 0.0117), and (4) being male (OR 0.787, P = 0.0491). In a private practice setting, the most significant positive associations with burnout were: (1) urologic surgery (OR 1.497, P = 0.0086), (2) having 31% to 50% time for nonclinical activities (OR 1.404, P = 0.0409), (3) incentive based pay (OR 1.344, P < 0.0001), (4) nights on call (OR 1.045, P = 0.0029), and (5) hours worked (OR 1.015, P < 0.0001), whereas the negative associations were: (1) older children (OR 0.677, P = 0.0001), (2) physician spouse (OR 0.753, P = 0.0093), and (3) older age (OR 0.989, P = 0.0158). The independent factors relating to career satisfaction for surgeons in private practice and academic practice were also different. CONCLUSIONS: Factors associated with burnout were distinct for academic and private practice surgeons. Distress parameters were lower and career satisfaction higher for academic surgeons.

The value of a symptom cluster of fatigue, dyspnea, and cough in predicting clinical outcomes in lung cancer survivors.

CONTEXT: Aggregates of concurrent symptoms, known as symptom clusters (SxCls), are reported to have prognostic capabilities beyond that of single symptom alone. A SxCl of fatigue, dyspnea, and cough has been delineated in a number of lung cancer cohorts. OBJECTIVES: The objective of this study was to characterize this SxCl's predictive value for important clinical outcomes relative to that of its component symptoms. METHODS: Analysis of an eight-year prospective cohort study that assessed 2405 patients with LC for self-reported symptom burden, employment status, and physical activity with the Baecke questionnaire, and overall quality of life (QoL) was undertaken using nested Cox and generalized linear multilevel mixed models. Models were adjusted for longitudinally assessed demographics, cancer progression and tobacco use, and cancer progression. RESULTS: The SxCl, as well as its individual symptoms and symptom pairs, were all negatively associated with survival in Cox models of Years 1-3 after diagnosis. Only in Year 3 did the SxCl prognosticate survival (and then marginally) better than single symptoms or symptom pairs; fatigue was strongly associated (P≤0.0005) with survival at all time points. The SxCl was not predictive of participants' employment status, physical activity, or QoL, whereas the presence of fatigue, dyspnea, or their combination was strongly associated with these outcomes. CONCLUSION: Fatigue and dyspnea are strongly associated with poor clinical outcomes in LC survivors; however, a SxCl that includes fatigue, dyspnea, and cough as part as its components does not appear to significantly improve their predictive capability.

Fatigue, dyspnea, and cough comprise a persistent symptom cluster up to five years after diagnosis with lung cancer.

CONTEXT: Aggregates of concurrent symptoms, known as symptom clusters (SxCls), have been described in predominantly cross-sectional samples of lung cancer (LC) patients undergoing treatment. OBJECTIVES: The objective of this study was to delineate SxCls in LC survivors up to five years after diagnosis, investigate their stability over time, and identify determinants of SxCl development and resolution. METHODS: A sensitivity approach involving multiple exploratory and confirmatory analyses was applied to an eight-year prospective cohort study that annually assessed 2405 patients with LC for symptom burden with the Lung Cancer Symptom Scale and Linear Analogue Self-Assessment. RESULTS: A single robust SxCl of fatigue, cough, and dyspnea was identified in 14.6%, 12.9%, 14.1%, 14.6%, and 15.4% of participants at Years 1-5 after diagnosis, respectively. Participants with the SxCl (SxCl (+)) were more likely to die than those without it; but this tendency diminished over time. SxCl persistence varied, with ≥40% of surviving patients annually transitioning to or from the SxCl(+) state until Year 4, after which the SxCl became increasingly stable. The SxCl was more likely to develop among male survivors who underwent surgery, received radiation, and were current smokers. CONCLUSION: A single SxCl comprising dyspnea, fatigue, and cough has a stable prevalence among LC survivors up to five years after diagnosis but is not stable among individuals. Initially, after diagnosis, the SxCl is associated with a greater risk of death; however, after Year 2, the SxCl becomes increasingly stable and provides a marker for parenchymal lung injury.

Surgeon distress as calibrated by hours worked and nights on call.

BACKGROUND: The relationships of working hours and nights on call per week with various parameters of distress among practicing surgeons have not been previously examined in detail. STUDY DESIGN: More than 7,900 members of the American College of Surgeons responded to an anonymous, cross-sectional survey. The survey included self-assessment of their practice setting, a validated depression screening tool, and standardized assessments of burnout and quality of life. RESULTS: There was a clear gradient between hours and burnout, with the prevalence of burnout ranging from 30% for surgeons working <60 hours/week, 44% for 60 to 80 hours/week, and 50% for those working >80 hours/week (p < 0.001). When correlated with number of nights on call, burnout exhibited a threshold effect at ≥2 nights on call/week (≤1 nights on call/week, 30%; ≥2 nights on call/week, 44% to 46%; p < 0.0001). Screening positive for depression rate also correlated strongly with hours and nights on call (both p < 0.0001). Those who worked >80 hours/week reported a higher rate of medical errors compared with those who worked <60 hours/week (10.7% versus 6.9%; p < 0.001), and were twice as likely to attribute the error to burnout (20.1% versus 8.9%; p = 0.001). Not surprisingly, work and home conflicts were higher among surgeons who worked longer hours or had ≥2 nights on call. A significantly higher proportion of surgeons who worked >80 hours/week or had >2 nights on call/week would not become a surgeon again (p < 0.0001). CONCLUSIONS: Number of hours worked and nights on call per week appear to have a substantial impact on surgeons, both professionally and personally. These factors are strongly related to burnout, depression, career satisfaction, and work and home conflicts.

Phase 1 trial of flavopiridol combined with cisplatin or carboplatin in patients with advanced malignancies with the assessment of pharmacokinetic and pharmacodynamic end points.

PURPOSE: Flavopiridol, a cyclin-dependent kinase inhibitor, transcription inhibitor, and DNA-interacting agent, was combined with cisplatin or carboplatin to establish toxicities, evaluate pharmacokinetics, and examine its effects on patient cancers and levels of selected polypeptides in patient peripheral blood mononuclear cells (PBMC). EXPERIMENTAL DESIGN: Therapy was given every 3 weeks. Stage I: cisplatin was fixed at 30 mg/m2 with escalating flavopiridol. Stage II: flavopiridol was fixed at the stage I maximum tolerated dose (MTD) with escalation of cisplatin. Stage III: flavopiridol was fixed at the stage I MTD with escalation of carboplatin. RESULTS: Thirty-nine patients were treated with 136 cycles of chemotherapy. Neutropenia was seen in only 11% of patients. Grade 3 flavopiridol/CDDP toxicities were nausea (30%), vomiting (19%), diarrhea (15%), dehydration (15%), and neutropenia (10%). Flavopiridol combined with carboplatin resulted in unexpectedly high toxicities and one treatment-related death. Stable disease (>3 months) was seen in 34% of treated patients, but there were no objective responses. The stage II MTD was 60 mg/m2 cisplatin and 100 mg/m2/24 hours flavopiridol. As given, CDDP did not alter flavopiridol pharmacokinetics. Flavopiridol induced increased p53 and pSTAT3 levels in patient PBMCs but had no effects on cyclin D1, phosphoRNA polymerase II, or Mcl-1. CONCLUSIONS: Flavopiridol and cisplatin can be safely combined in the treatment of cancer patients. Unexpected toxicity in flavopiridol/carboplatin-treated patients attenuates enthusiasm for this alternative combination. Analysis of polypeptide levels in patient PBMCs suggests that flavopiridol may be affecting some, but not all, of its known in vitro molecular targets in vivo.

Associations between plasma insulin-like growth factor proteins and C-peptide and quality of life in patients with metastatic colorectal cancer.

OBJECTIVE: Predictors of quality of life (QOL) in patients with metastatic colorectal cancer are lacking. The insulin-like growth factor (IGF) family of proteins is associated with QOL in noncancer populations. We sought to study whether these proteins are associated with QOL in patients with colorectal cancer. METHOD: We used a cohort of 526 patients with metastatic colorectal cancer treated with combination chemotherapy. Plasma samples of IGF-I, IGF-II, IGF binding protein-3, and C-peptide were collected before initiation of chemotherapy. QOL was measured by the uniscale instrument and the Symptom Distress Scale at baseline and throughout treatment. RESULTS: Baseline plasma levels of IGF-I and IGF-II before initiation of chemotherapy were significantly associated with several important baseline QOL measures in patients with metastatic colorectal cancer. Patients with lower levels of IGF-I reported increased distress with regard to appearance, appetite, cough, and nausea intensity after adjustment for potential confounders. Similarly, decreased levels of IGF-II were predictive of worse quality related to appearance, appetite, fatigue, nausea frequency and intensity, pain frequency, and composite Symptom Distress Scale score. IGF binding protein-3 and C-peptide were not predictive of baseline QOL. Baseline biomarkers were not associated with subsequent changes in QOL during treatment. Higher body mass index was significantly associated with superior baseline QOL in several areas; nonetheless, the association of IGF-I and IGF-II with baseline QOL measures remained significant even after controlling for baseline body mass index. CONCLUSION: Baseline plasma IGF-I and IGF-II are significantly associated with symptom distress. Whether this association is simply reflective of patient nutritional status and/or disease burden or represents an independent biological effect of IGFs on QOL remains uncertain. Nonetheless, these data suggest that molecular biomarkers may be useful predictors of QOL in cancer patients.

Phase I and pharmacokinetic study of two different schedules of oxaliplatin, irinotecan, Fluorouracil, and leucovorin in patients with solid tumors.

PURPOSE: We sought to determine the maximum-tolerated dose (MTD) and evaluate the toxicities and clinical activity of two irinotecan (CPT-11), fluorouracil (FU), leucovorin (LV), and oxaliplatin schedules in patients with advanced solid tumors. Additionally, we investigated the effect of CPT-11 on oxaliplatin pharmacokinetics. PATIENTS AND METHODS: Thirteen patients (cohort 1) received intravenous CPT-11 (infusion) and FU/LV (bolus) on days 1, 8, 15, and 22 and oxaliplatin (infusion) on days 1 and 15 every 6 weeks for a total 37 courses (median, three courses) at three dose levels. Twenty-two cohort 2 patients received intravenous CPT-11/oxaliplatin (infusion, day 1) and FU/LV (90-minute bolus infusion, days 2 to 5) every 3 weeks for a total of 122 courses (median, four courses) at three dose levels. Pharmacokinetic and neurotoxicity assessments were performed at the cohort 2 MTD. RESULTS: Dose-limiting toxicity (DLT) seen in both cohorts at the starting dose required dose de-escalation. Cohort 1 DLT included diarrhea and neutropenia. In cohort 2, diarrhea, vomiting, dehydration, neutropenia, febrile neutropenia, and paresthesias were DLTs. Antitumor activity was seen in both cohorts. In cohort 2, the total platinum area under the curve of patients increased 17% in cycle 2 (P =.048), but objective neurotoxicity was not seen. CONCLUSION: The toxicities resulting from the addition of oxaliplatin to CPT-11/FU/LV are significant but manageable. The MTDs for the weekly schedule are CPT-11 (75 mg/m2), oxaliplatin (50 mg/m2), FU (320 mg/m2), and LV (20 mg/m2); and, for the 3-weekly schedule, the MTDs are CPT-11 (175 mg/m2), oxaliplatin (85 mg/m2), FU (240 mg/m2), and LV (20 mg/m2). Second-cycle platinum accumulation raises the possibility for enhanced cumulative neurotoxicity with CPT-11/oxaliplatin combinations.