Jane L. Wheeler

Effect of palliative oxygen versus room air in relief of breathlessness in patients with refractory dyspnoea: a double-blind, randomised controlled trial

BACKGROUND Palliative oxygen therapy is widely used for treatment of dyspnoea in individuals with life-limiting illness who are ineligible for long-term oxygen therapy. We assessed the effectiveness of oxygen compared with room air delivered by nasal cannula for relief of breathlessness in this population of patients. METHODS Adults from outpatient clinics at nine sites in Australia, the USA, and the UK were eligible for enrolment in this double-blind, randomised controlled trial if they had life-limiting illness, refractory dyspnoea, and partial pressure of oxygen in arterial blood (PaO(2)) more than 7.3 kPa. Participants were randomly assigned in a 1:1 ratio by a central computer-generated system to receive oxygen or room air via a concentrator through a nasal cannula at 2 L per min for 7 days. Participants were instructed to use the concentrator for at least 15 h per day. The randomisation sequence was stratified by baseline PaO(2) with balanced blocks of four patients. The primary outcome measure was breathlessness (0-10 numerical rating scale [NRS]), measured twice a day (morning and evening). All randomised patients who completed an assessment were included in the primary analysis for that data point (no data were imputed). This study is registered, numbers NCT00327873 and ISRCTN67448752. FINDINGS 239 participants were randomly assigned to treatment (oxygen, n=120; room air, n=119). 112 (93%) patients assigned to receive oxygen and 99 (83%) assigned to receive room air completed all 7 days of assessments. From baseline to day 6, mean morning breathlessness changed by -0.9 points (95% CI -1.3 to -0.5) in patients assigned to receive oxygen and by -0.7 points (-1.2 to -0.2) in patients assigned to receive room air (p=0.504). Mean evening breathlessness changed by -0.3 points (-0.7 to 0.1) in the oxygen group and by -0.5 (-0.9 to -0.1) in the room air group (p=0.554). The frequency of side-effects did not differ between groups. Extreme drowsiness was reported by 12 (10%) of 116 patients assigned to receive oxygen compared with 14 (13%) of 108 patients assigned to receive room air. Two (2%) patients in the oxygen group reported extreme symptoms of nasal irritation compared with seven (6%) in the room air group. One patient reported an extremely troublesome nose bleed (oxygen group). INTERPRETATION Since oxygen delivered by a nasal cannula provides no additional symptomatic benefit for relief of refractory dyspnoea in patients with life-limiting illness compared with room air, less burdensome strategies should be considered after brief assessment of the effect of oxygen therapy on the individual patient. FUNDING US National Institutes of Health, Australian National Health and Medical Research Council, Duke Institute for Care at the End of Life, and Doris Duke Charitable Foundation.

Electronic patient-reported data capture as a foundation of rapid learning cancer care.

Background:“Rapid learning healthcare” presents a new infrastructure to support comparative effectiveness research. By leveraging heterogeneous datasets (eg, clinical, administrative, genomic, registry, and research), health information technology, and sophisticated iterative analyses, rapid learning healthcare provides a real-time framework in which clinical studies can evaluate the relative impact of therapeutic approaches on a diverse array of measures. Purpose:This article describes an effort, at 1 academic medical center, to demonstrate what rapid learning healthcare might look like in operation. The article describes the process of developing and testing the components of this new model of integrated clinical/research function, with the pilot site being an academic oncology clinic and with electronic patient-reported outcomes (ePROs) being the foundational dataset. Research Design:Steps included: feasibility study of the ePRO system; validation study of ePRO collection across 3 cancers; linking ePRO and other datasets; implementation; stakeholder alignment and buy in, and; demonstration through use cases. Subjects:Two use cases are presented; participants were metastatic breast cancer (n = 65) and gastrointestinal cancer (n = 113) patients at 2 academic medical centers. Results:(1) Patient-reported symptom data were collected with tablet computers; patients with breast and gastrointestinal cancer indicated high levels of sexual distress, which prompted multidisciplinary response, design of an intervention, and successful application for funding to study the interventions impact. (2) The system evaluated the longitudinal impact of a psychosocial care program provided to patients with breast cancer. Participants used tablet computers to complete PRO surveys; data indicated significant impact on psychosocial outcomes, notably distress and despair, despite advanced disease. Results return to the clinic, allowing iterative update and evaluation. Conclusions:An ePRO-based rapid learning cancer clinic is feasible, providing real-time research-quality data to support comparative effectiveness research.

Improving Health Care Efficiency and Quality Using Tablet Personal Computers to Collect Research-Quality, Patient-Reported Data

OBJECTIVE To determine whether e/Tablets (wireless tablet computers used in community oncology clinics to collect review of systems information at point of care) are feasible, acceptable, and valid for collecting research-quality data in academic oncology. DATA/SETTING: Primary/Duke Breast Cancer Clinic. DESIGN Pilot study enrolling sample of 66 breast cancer patients. METHODS Data were collected using paper- and e/Tablet-based surveys: Functional Assessment of Cancer Therapy General, Functional Assessment of Cancer Therapy-Breast, MD Anderson Symptom Inventory, Functional Assessment of Chronic Illness Therapy (FACIT), Self-Efficacy; and two questionnaires: feasibility, satisfaction. PRINCIPAL FINDINGS Patients supported e/Tablets as: easy to read (94 percent), easy to respond to (98 percent), comfortable weight (87 percent). Generally, electronic responses validly reflected responses provided by standard paper data collection on nearly all subscales tested. CONCLUSIONS e/Tablets offer a valid, feasible, acceptable method for collecting research-quality, patient-reported outcomes data in outpatient academic oncology.

Systematic review: reliability of compendia methods for off-label oncology indications.

The U.S. Food and Drug Administration (FDA) approves drugs for specific uses, yet physicians routinely prescribe FDA-approved drugs for uses other than those for which they received approval (1); such uses are known as off-label indications. Off-label prescribing is common across medical disciplines; however, it is critical in oncology, in which effective treatment options are often limited, prognoses are grim, and submission of FDA applications for every combination of agent and cancer is impractical. In 1991, a U.S. General Accounting Office study (2) reported that up to 33% of all anticancer drug prescriptions were written for off-label indications. By 2005, the National Comprehensive Cancer Network estimated that 50% to 75% of all uses of cancer therapy were off-label (3). The Social Security Act, section 1861(t)(2)(B)(ii)(I) and (II), within the Omnibus Budget Reconciliation Act of 1993 (4), stipulates the Medicare insurability of anticancer drugs and biologics for off-label uses. This statute recognizes certain compendia as authoritative sources for determining a medically accepted indication of drugs and biological agents, unless the Secretary of Health and Human Services determines otherwise. The statute originally designated 3 compendia: American Medical Association Drug Evaluations, American Hospital Formulary Service Drug Information (5), and United States Pharmacopeia Drug Information for the Health Professional (6). Although the statute pertained specifically to Centers for Medicare & Medicaid Services (CMS), most other payers and state legislatures have followed suit (7). The list of approved compendia has shifted over the past 15 years. American Medical Association Drug Evaluations was discontinued, and United States Pharmacopeia Drug Information for the Health Professional subsumed its contents. United States Pharmacopeia Drug Information for the Health Professional was then discontinued in 2007, and its contents were rolled into a successor, DrugPoints. In 2008, CMS added Clinical Pharmacology, DRUGDEX, and National Comprehensive Cancer Network Drugs and Biologics Compendium to its list of approved compendia, bringing the total to 5 (8). In response to concerns about the influence of compendia, CMS proposed various changes, including review of currently approved compendia, additional compendia approval, and an annual review process. To inform policy discussions, they commissioned the Agency for Healthcare Research and Quality to sponsor our project exploring the extent to which compendia provide comprehensive, evidence-based, and timely information for guiding off-label prescribing of cancer drugs. Methods Our study had 4 components: comparative descriptions of each compendiums stated methods for including new, off-label indications of FDA-approved drugs; systematic literature review for 14 selected off-label indications in 2006; an updated comparison for 1 indication in 2008; and analysis of each compendiums content and citations against their stated methods and the evidence identified in our systematic reviews. Comparative Description of Methods Used by Compendia To better understand how compendia develop their content, we compared 6 compendia that we chose through discussions with 10 oncology pharmacists and oncologists at Duke University and Tufts Medical Centers. We confirmed the list through discussions with the Agency for Healthcare Research and Quality, CMS, and financial officers at Duke University Medical Center. Our final compendia list included American Hospital Formulary Service Drug Information (5), United States Pharmacopeia Drug Information for the Health Professional (6), DRUGDEX Information System (United States Pharmacopeia Drug Information for the Health Professional and DRUGDEX, both available through Thomson Reuters) (9), Drug Facts and Comparisons (10), National Comprehensive Cancer Network Drugs and Biologics Compendium (11), and Clinical Pharmacology (12). This list includes the compendia approved by CMS as well as 2 nonapproved compendia. These compendia list more than 40000 drugs, and their editors are generally pharmacologists with training in research and evidence synthesis. In 2006, we gathered information on each compendiums methods by abstracting descriptive information from publicly available sources, conducting a 1-hour telephone interview with a senior editor from each compendium, and allowing the editors to respond to a methods table that summarized the information collected in the interview. We developed a list of evaluation criteria which we used to compare published methods and guide interviews. We then compared each compendiums methods with evaluation criteria and summarized the results. In 2008, we repeated the data abstraction to determine whether the compendia had updated their publicized methods. We did not include DrugPoints in the 2008 review because it differed structurally from the other compendia and could not be directly compared. Literature Review of Evidence for 14 Off-Label Indications We selected off-label indications for 14 agent and cancer combinations that included both newer and older agents, common and rare types of cancer, and biologics and drugs. In 2006, we systematically searched MEDLINE, the Cochrane Central Register of Controlled Trials, and American Society of Clinical Oncology annual meeting abstracts (2004 and 2005) to identify English-language studies in humans. We included prospective clinical trials (phases I to III), case reports, and retrospective case series that reported tumor response, survival, quality of life, symptoms, and adverse effects. We excluded narrative reviews and studies that described only predictors of response, pharmacokinetics, or nonhuman results. For eligible studies, 1 reviewer abstracted data into evidence tables and a second reviewer verified the completed tables. For each agent and cancer combination, we created a summary table that listed the number of articles identified by study design and key outcomes. We scored identified studies by design (for example, phase I to III), size, and outcomes reported (for example, tumor response, survival, quality of life, or adverse effects). Our intention was not to expose the compendiawhich perform a vital function in oncologybut rather to examine their methods and the resulting comprehensiveness of their contents. We therefore did not score the evidence included in the compendia according to classic quality criteria. Instead, we adopted a conservative approach to content evaluation that entailed a simple count of independent studies, presentations of data, and other metrics but did not include evaluation of the quality and validity of the studies themselves. We used study design as a proxy for quality and validity, with phase III studies considered generally more valid than phase I or II studies. Update of 1 Agent and Cancer Combination In 2008, we repeated the systematic review for a single agent and cancer combination (gemcitabine for bladder cancer) by using the same methods, except we sought 2006 and 2007 conference abstracts. We chose the gemcitabine for bladder cancer indication because gemcitabine has been FDA-approved for longer than the other reviewed agents; gemcitabine has been widely studied (with the largest number of citations in our 2006 review); and, of the 3 gemcitabine combinations included, gemcitabine for bladder cancer had the fastest-evolving evidence base. This combination thus afforded compendia the most opportunity to demonstrate improvement. Analysis of Compendium Content Against Evaluation Criteria In 2006, we abstracted data for each of the 14 agent and cancer combinations from each of the 6 compendia. We evaluated all available versions (print and electronic) of the 6 compendia in 2006 but recorded data from the most current and complete version; in all cases, this was an electronic version. Data included whether the indication was explicitly stated; how the indication was graded; and comments on further refinement regarding the stage of cancer, treatment timing, route of administration, and use of monotherapy or combination therapy. We recorded outcomes mentioned specifically for the off-label use; toxicity data; presence of citations to evidence specifically regarding the off-label indication; number, identity, and years of citations; and time since any updates to the monograph or entry. We stratified publications cited in the compendia by study design, noting abstracts separately, and tabulated whether each compendium cited each publication; we compared the results with those of our systematic review. We updated this process in 2008 for the gemcitabine for bladder cancer indication. Role of the Funding Source The CMS funded the initial 2006 report through the Agency for Healthcare Research and Qualitys Evidence-Based Practice Center program. These agencies participated in formulating questions, reviewing the list of agent and cancer combinations, and commenting on report findings. The 2008 update of the report was unfunded. The agencies had no role in the writing or approval of the manuscript. Results Comparison of Stated Methods Used by Compendia All compendia described their scope and editorial policies, which did not change between the 2006 and 2008 reviews (Appendix Table 1). Because United States Pharmacopeia Drug Information for the Health Professional was discontinued in 2007, our results do not include that compendium even though it was part of the 2006 review. Here, we focus our evaluation on frequency of updates, use of available evidence, and transparency of decision-making processes. Appendix Table 1. Stated Methods of Selected Compendia Compendia had different update cycles for electronic versions, which varied from daily to quarterly (Table 1). Several compendia published multiple electronic editions; these differed in content and update schedules. Compendia did not always provide revision dates for drug m

Validation of the Patient Care Monitor (Version 2.0): A Review of System Assessment Instrument for Cancer Patients

CONTEXT The Patient Care Monitor (PCM) is a review of systems survey delivered by means of an electronic patient-reported outcomes (ePRO) data capture system that uses wireless tablet computers. Although the PCM 1.0 is validated, the updated PCM 2.0 has not been validated nor tested in the academic setting. OBJECTIVES To validate and test the PCM 2.0 in three cancer populations. METHODS Two hundred seventy-five individuals participated in three clinical trials enrolling breast (n=65), gastrointestinal (n=113), and lung (n=97) cancer patients. Internal consistency was evaluated using Cronbachs alpha coefficients calculated for six PCM subscales (general physical symptoms, treatment side effects, distress, despair, impaired performance, and impaired ambulation) and a Quality-of-Life Index. Construct validity was evaluated through Pearsons correlation between PCM subscales and subscales of the Functional Assessment of Cancer Therapy--General (FACT-G), the M.D. Anderson Symptom Inventory (MDASI), and the Functional Assessment of Chronic Illness Therapy--Fatigue (FACIT-F). The participants had the following characteristics: mean age was 58 years (standard deviation: 11), 52% were females, 79% were whites, 17% were blacks, 62% had no college degree, and 78% had metastatic or recurrent disease. RESULTS Raw and normalized scores for PCM 2.0 subscales were internally consistent across study cohorts. PCM 2.0 subscales correlated significantly (P<0.05) with the corresponding subscales on FACT-G, MDASI, and FACIT-F, with the exception of FACT-G social well-being, particularly for the lung cancer population. These correlations demonstrated construct validity. PCM 2.0 results followed expected patterns by cancer etiology. Prior reports demonstrate patient satisfaction with PCM 2.0. CONCLUSION Within three unique academic oncology populations, PCM 2.0 is a valid ePRO instrument for assessing symptoms with seven patient-centered subscale or index domains.

A strategy to advance the evidence base in palliative medicine: formation of a palliative care research cooperative group.

BACKGROUND Palliative medicine has made rapid progress in establishing its scientific and clinical legitimacy, yet the evidence base to support clinical practice remains deficient in both the quantity and quality of published studies. Historically, the conduct of research in palliative care populations has been impeded by multiple barriers including health care system fragmentation, small number and size of potential sites for recruitment, vulnerability of the population, perceptions of inappropriateness, ethical concerns, and gate-keeping. METHODS A group of experienced investigators with backgrounds in palliative care research convened to consider developing a research cooperative group as a mechanism for generating high-quality evidence on prioritized, clinically relevant topics in palliative care. RESULTS The resulting Palliative Care Research Cooperative (PCRC) agreed on a set of core principles: active, interdisciplinary membership; commitment to shared research purposes; heterogeneity of participating sites; development of research capacity in participating sites; standardization of methodologies, such as consenting and data collection/management; agile response to research requests from government, industry, and investigators; focus on translation; education and training of future palliative care researchers; actionable results that can inform clinical practice and policy. Consensus was achieved on a first collaborative study, a randomized clinical trial of statin discontinuation versus continuation in patients with a prognosis of less than 6 months who are taking statins for primary or secondary prevention. This article describes the formation of the PCRC, highlighting processes and decisions taken to optimize the cooperative groups success.

A framework for generalizability in palliative care.

Palliative medicine has only recently joined the ranks of evidence-based medical subspecialties. Palliative medicine is a rapidly evolving field, which is quickly moving to redress its historical paucity of high-quality research evidence. This burgeoning evidence base can help support the application of evidence-based principles in palliative and hospice clinical care and service delivery. New knowledge is generally taken into practice relatively slowly by established practitioners. At present, the translation of evidence into palliative and hospice care clinical practice lags behind emerging research evidence in palliative care at even greater rates for three critical reasons: 1) the application of research results to specific clinical subpopulations is complicated by the heterogeneity of palliative care study subpopulations and by the lack of a recognized schema for describing populations or services; 2) definitional issues in service provision are, at best, confusing; and 3) fundamental research concepts (e.g., external validity, effect size, generalizability, applicability) are difficult to apply meaningfully in palliative care. This article provides a suggested framework for classifying palliative care research subpopulations and the clinical subpopulations to which the research findings are being applied to improve the ability of clinicians, health planners, and funders to interpret and apply palliative care research in real-world settings. The framework has five domains: patients and caregivers; health professionals; service issues; health and social policy; and research.

Dyspnea Review for the Palliative Care Professional: Treatment Goals and Therapeutic Options

Although dyspnea is frequently encountered in the palliative care setting, its optimal management remains uncertain. Clinical approaches begin with accurate assessment, as delineated in part one of this two-part series. Comprehensive dyspnea assessment, which encompasses the physical, emotional, social, and spiritual aspects of this complex symptom, guide the clinician in choosing therapeutic approaches herein presented as part two. Global management of dyspnea is appropriate both as complementary to disease-targeted treatments that target the underlying etiology, and as the sole focus when the symptom has become intractable, disease is maximally treated, and goals of care shift to comfort and quality of life. In this setting, current evidence supports the use of oral or parenteral opioids as the mainstay of dyspnea management, and of inhaled furosemide and anxiolytics as adjuncts. Nonpharmacologic interventions such as acupuncture and pulmonary rehabilitation have potential effectiveness, although further research is needed, and use of a simple fan warrants consideration given its potential benefit and minimal burden and cost.

Defining distinct caregiver subpopulations by intensity of end-of-life care provided

Interventions designed to assist informal caregivers who serve individuals at or near the end of life have predominantly focused on caregiving spouses. Can we define other caregiver subpopulations – by intensity of care provided – so as to enable better a) identification of caregiver needs and b) targeting of support to caregivers? The Health Omnibus Survey, an annual face-to-face survey in South Australia, collects health-related data from a representative sample of 4400 households. Piloted questions included in the 2001–2005 Health Omnibus surveys addressed death of a loved one, caregiving provided, impact of caregiving and caregiver characteristics. Of 18,224 respondents, 5302 reported a loved one’s death due to terminal illness in the previous 5 years. In all, 502 (10%) provided daily care [5–7 days/week], 619 (12%) provided intermittent care [2–4 days/week] and 425 (8%) provided rare care. Active (daily plus intermittent) caregivers, compared with non-active (rare) caregivers, were more often women (63% vs 50%; P < 0.0001). Daily caregivers were distinguishable from intermittent; daily caregivers were more often widowed (95% vs 7%; P < 0.0001) and ≥60 years (80% vs 64%; P < 0.0001); intermittent caregivers were more commonly children/parents (35%), other relatives (33%), or friends (26%; P < 0.0001) and were better educated, more active in paid work and wealthier. Financial burden, experience at time of death, ability to move on after the death and need for grief support also differed by intensity of caregiving. Caregiver subpopulations can be defined according to intensity of caregiving with distinct demographic features helping to distinguish them.

Correlates of quality of life-related outcomes in breast cancer patients participating in the Pathfinders pilot study.

Objective: In a pilot study, participation in the Pathfinders program was associated with reductions in distress and despair and improvements in quality of life (QOL) among advanced breast cancer patients. This study explores the relationship between psychosocial resources invoked through the Pathfinders intervention and outcomes.